Anti body targets associated with low HIV viral load

Abstract

Peptides generating antibodies to human immunodeficiency virus (HIV) post-infection were identified. Higher antibody reactivity to these peptides was associated, with lower viral load post-infection.

Description

ANTIBODY TARGETS ASSOCIATED WITH LOW HIV VIRAL LOADThe present application claims the benefit of U.S. provisional application no. 63 / 655,038 filed June 02, 2024, and U.S. provisional application no. 63 / 654,746 filed May 31, 2024, both of which applications are incorporated by reference herein in their entireties.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0001] This invention was made with government support under grant UM 1 -AI068613 awarded by the National Institutes of Health. The government has certain rights in die invention.FIELD

[0002] In general, this disclosure is directed to compositions in the treatment of human immunodeficiency virus (HIV) post-infection.BACKGROUND

[0003] HIV viral load usually peaks near the time of seroconversion and decreases asHIV-specific immune responses develop ( 1 , 2). Most people living with HIV (PWH) establish a viral load set point shortly after infection that reflects the balance between ongoing viral replication and immune clearance (1-6). This set point is usually stable during chronic HIV infection but can vary widely between persons ( 1, 2, 7). Higher viral loads are associated with increased HIV-related morbidity and mortality (8-15) and increased on-going transmission (12, 16, 17). Effective antiretroviral treatment (ART) reduces HIV viral load to low levels, improving clinical outcomes (18-23) and reducing transmission risk (24-28).

[0004] Some PWH can control viral replication in the absence of ART. These individuals are often classified as elite or viremic controllers based on viral load measurements obtained at least one year apart (elite controllers: <50 copies / mL, viremic controllers <2,000 copies / mL) (29-32). Use of a cutoff of 2,000 copies / mL for viremic controllers was suggested by Pereye and colleagues in 2007 (29), based on studies that demonstrated that viral loads <1-2,000 copies / mL were associated with slower disease progression and reduced HIV transmission (33-35). HIV control develops in the early stages of infection (30, 36, 37); some controllers have fewer symptoms in early infection compared to non-controllers (36, 38, 39). HIV control is also associated with slower disease progression and reduced HIV-related mortality (30, 40). Themechanisms responsible for HIV control are poorly understood and appear to involve complex interactions between viral and host factors (29, 32, 40). Improved understanding of these mechanisms could inform development of immune-based interventions for HIV prevention and treatment.

[0005] Most research on HIV control has focused on the role of cellular immunity (29, 32, 40). A role for humoral immunity in HIV control was generally dismissed following early studies that found lower titers of HIV-specific antibodies and neutralizing antibodies among controllers (29, 41 -46), consistent with findings in non-controllers that antibody responses are less robust when PWH are vitally suppressed on ART (47-50). However, recent studies have identified control lers who have higher levels of antibody dependent cellular cytotoxicity (ADCC) (51), broadly neutralizing antibody (bNab) responses (52-54), and isotype diversity with associated polyfunctionality (55-59); more robust responses against broad targets in HIV gag have also been observed in controllers (55, 60-62).SUMMARY

[0006] We have now identified human immunodeficiency virus (HIV) antibody targets associated with lower viral load (VL) and HIV controller status 1-2 years after infection. Robust aggregate responses to these targets and broad antibody reactivity across the HIV genome were also associated with lower VL and controller status. These findings provide novel insights into the relationship between humoral immunity and viral containment that could help inform the design of antibody-based approaches for reducing HIV VL. These antibody peptide targets can be administered as a vaccine and / or antibodies which specifically bind these targets can be administered.

[0007] Accordingly, in certain aspects, a vaccine formulation comprises a therapeutically effective amount of one or more immunogenic human immunodeficiency virus (HIV) peptides. In certain embodiments, the peptides induce a post-HIV infection immune response. In certain embodiments, the peptides derived from one or more HIV peptide clusters comprise cluster 1 : gag [pl 7; N-terminus]; cluster 2; gag [p24; C-terminus]; cluster 3: integrase [C -terminus]; cluster 4: vpu [N-terminus]; cluster 5: envelope [gpl20; V3 loop and CD4 binding loop]; cluster 6: envelope [gpl20 / gp41; V5 and fusion peptide]; cluster 7: envelope [gp41; C-terminal heptadrepeat region, (HR2), cluster a (first zinc finger region of the nucleocapsid protein, gag p7); cluster b (N-terminus of protease), cluster c (N-terminus of integrase) or combinations thereof. In certain embodiments, the peptides derived from one or more HIV peptide clusters comprise peptides comprising cluster a (first zinc finger region of the nucleocapsid protein, gag p7); cluster b (N-temunus of protease), cluster c (N-terminus of integrase;) or combinations thereof. In certain embodiments, the one or more peptides comprise at least a 90% sequence identity to peptides set forth in Tables 1, 2 or combinations thereof. In certain embodiments, the one or more peptides comprise peptides set forth in Tables 1, 2 or combinations thereof. In certain embodiments, the one or more HIV peptides comprising SEQ ID NOs: 1-43 further comprise one or more amino acid residue insertions, deletions, substitutions or combinations thereof. In certain embodiments, the one or the one or more HIV peptides comprising SEQ ID NOs: M3 further comprise one or more unnatural amino acids. In certain embodiments, the one or more HIV peptides comprising SEQ ID NOs: 1-43 further comprise one or more synthetic amino acids. In certain embodiments, die one or more HIV peptides comprising SEQ ID NOs: M3 further comprise one or more amino acid modifications comprising glycosylation, deglycosylation, acetylation, phosphorylation, pegylation, lipidation or combinations thereof. In certain embodiments, the one or more HIV peptides comprising SEQ ID NOs: M3 further comprise one or more of a scaffold, an immunogenic carrier, an adjuvant, an antibody, antibody fragments, an immunoglobulin Fc region, an aptamer, a delectable label, a ligand, a therapeutic agent, a cytotoxic agent, a receptor or fragments thereof.

[0008] In another aspect, a vaccine formulation comprises one or more peptides comprising SEQ ID NOs: 1 -43. In certain embodiments, the one or more peptides comprise a scaffold, wherein the scaffold increases immunogenicity as compared to a peptide without a scaffold.

[0009] In another aspect, a method of treating a subject with a human immunodeficiency virus (HIV) infection, comprises administering to the subject, a pharmaceutical composition comprising a vector encoding one or more one or more HIV peptides ha ving at least a 90% sequence identity to peptides comprising SEQ ID NOs: .1-43, or a pharmaceutical composition comprising a therapeutically effective amount of one or more HIV peptides having at least a 90%sequence identity to peptides comprising SEQ ID NOs: 1-43. In certain embodiments, the one or more HIV peptides comprise one or more peptides comprising SEQ H> NOs: 1-43. In certain embodiments, the pharmaceutical composition comprising a vector encoding one or more one or more HIV peptides comprising SEQ ID NOs: 1-43, or a pharmaceutical composition Comprising a therapeutically effective amount of one or more HI V peptides comprising SEQ ID NOs: 1-43, are administered post-infection. In certain embodiments, the one or more peptides induce an immune response to HIV. In certain embodiments, the method further comprises administering one or more secondary therapeutic agents. In certain embodiments, the one or more secondary therapeutic agents comprise immunotherapies, one or more anti-viral agents and combinations thereof. In certain embodiments, the one or more antiviral agents comprise antibodies, aptamers, adjuvants, anti-sense oligonucleotides, chemokines, cytokines, gene-editing agents, immune stimulating agents, immune modulating agents, B-cell modulators, T-cell modulators, NK cell modulators, antigen presenting cell modulators, enzymes, siRNA’s, ribavirin, protease inhibitors, helicase inhibitors, polymerase inhibitors, integrase inhibitors, helicase inhibitors, neuraminidase inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, purine nucleosides, chemokine receptor antagonists, interleukins, or combinations thereof. In certain embodiments, the one or more peptides are formulated with a pharmaceutical carrier, a delivery vehicle or combinations thereof. In certain embodiments, the one or more peptides are formulated with a scaffold.

[0010] In another aspect, a method of treating a subject infected with a human immunodeficiency virus (HIV) infection, comprises administering to foe subject, a pharmaceutical composition comprising an antibody which specifically binds to any one peptide having at least a 90% sequence identity to peptides comprising SEQ ID NOs: 1-43. In certain embodiments, the antibody specifically binds to any one peptide comprising SEQ ID NOs: 1-43. In certain embodiments, the antibodies are administered in combination with one or more peptides comprising SEQ ID NOs: 1-43 and / or a vector encoding any one or more of SEQ ID NOs: 1-43.

[0011] In another aspect, a vector comprises a nucleic acid, sequence encoding one or more peptides comprising SEQ ID NOs: 1-43.

[0012] In another aspect, an isolated cell comprises a vector encoding one or more peptides comprising SEQ ID NOs: 1-43.

[0013] In another aspect, a vaccine comprises a polynucleotide encoding one or more peptides comprising SEQ ID NOs: 1-43. In certain embodiments, the one or more peptides comprising SEQ ID NOs: M3 have at least a 60%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, sequence identity to its corresponding sequence.

[0014] In another aspect, an antibody which specifically binds to any one peptide having at least a 90% sequence identity to peptides comprising SEQ ID NOs: 1 -43. In certain embodiments, the antibody specifically binds to any one peptide comprising SEQ ID NOs: M3. In certain embodiments the antibody comprises monoclonal antibodies, polyclonal antibodies, multispecific antibodies, chimeric antibodies, humanized antibodies or fragments thereof.

[0015] Definitions{00016] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (e.g., crystallography, in cell culture, molecular genetics, and biochemistry).

[0017] As used herein, the singular forms “a”, “an” and “the” are intended to include die plural forms as well, unless the context clearly indicates otherwise. Furthermore, to the extent that the terms “including”, “includes”, “having”, “has” “with”, or variants thereof are used in either the detailed description and / or the claims, such terms are intended to be inclusive in a manner similar to the term “comprising” .

[0018] Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless odrerwise clear from context, all numerical values provided herein are modified by the term about. Further, the term “about” when used in connection with one or more numbers or numerical ranges, should be understood torefer to all such numbers, including all numbers in a range and modifies that range by extending the boundaries above and below the numerical values set forth. The recitation of numerical ranges by endpoints includes all numbers, e.g., whole integers, including fractions thereof, subsumed within that range (for example, the recitation of 1 to 5 includes 1 , 2, 3, 4, arid 5, as well as fractions thereof, e.g., 1.5, 2.25, 3.75, 4.1, and the like) and any range within that range.

[0019] As used herein, the terms “agent’* or “moiety” ate meant to encompass any molecule, chemical entity, composition, drug, therapeutic agent, chemotherapeutic agent, or biological agent capable of preventing, ameliorating, or treating a disease or other medical condition. The term includes small molecule compounds, antisense reagents, siRNA reagents, antibodies, hormones, oligonucleotides, enzymes, peptides organic or inorganic molecules, natural or synthetic compounds and the like. An agent can be assayed in accordance with the methods of the disclosure at any stage during clinical trials, during pre-trial testing, or following FDA- approval.

[0020] The term “amino acid” as used herein refers to naturally occurring and synthetic or non-naturally occurring a, p, y, and 8 amino acids, and includes but is not limited to, amino acids found in proteins, i.e., glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine. Alternatively, the amino acid can be a derivative of alanyl, valinyl, leucinyljsoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl. serinyl, fereoninyl, cysteinyl, tyrosinyl asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, p-alanyl, P-valinyl, p-leucinyl, P-isoleucinyl, p-prolinyl, p-phenylalaninyl, |$- tryptophanyl, P-methioninyl, 0-glycinyl, p-serinyl, p-threoninyl, p-cysteinyl, |3-tyrosinyl, p- asparaginyl, p-glutaminyl, (3-aspartoyl, ^-glutaroyl, P-Iysinyl, [3-argininyl or ^-histidinyl When the term amino acid is used, it is considered to be a specific and independent disclosure of each of the esters of a, p, y, and 5 glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine in fee D and L-configurations. Examples of non-naturally occurring amino acids include, but are not limited to, D-amino acids (i e., an amino acid of an opposite chirality to the naturally-occurring form), N-a-methyl amino acids, C-a-methyl aminoacids, 0-methy l amino acids and D- or L-p-amino acids. Other non-naturally occurring amino acids include, for example, fi-alanine (fi-AIa), norleucine (Nie), norvaline (Nva), homoarginine (Bar), 4-aminobutyric acid (y-Abu), 2-aminoisobutyric acid (Aib), 6-aminohexanoic acid (e-Ahx), ornithine (om), sarcosine, a-amino isobutyric acid, 3-aminopropionic acid, 2,3-diaminopropionic acid (2,3-diaP), D- or L-pbenylglycine, D-(trifluoromethyl)-pheny1alanine, and D-p- fluorophenylalanine.

[0021] The term “amino acid sequence” is the order in which amino acid residues, connected by peptide bonds, lie in the chain in peptides and proteins.

[0022] The term “and / or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “A and B,n“A or B," “A” (alone), and “B” (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0023] The term “antibody" herein is used in the broadest sense and includes polyclonal and monoclonal antibodies, including intact antibodies and functional (antigen-binding) antibody fragments, including fragment antigen binding (Fab) fragments, F(ab’)2 fragments, Fab* fragments, Fv fragments, recombinant IgG (rlgG) fragments, variable heavy chain (VH) regions capable of specifically binding the antigen, single chain antibody fragments, including single chain variable fragments (scFv), and single domain antibodies (e.g., sdAb, sdFv, nanobody) fragments. Hie term encompasses genetically engineered and / or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multispecific, e.g., bispecific, antibodies, diabodies, triabodies, and tetrabodies, tandem di-scFv, tandem tri-scFv. Unless otherwise staled, the term “antibody” should be understood to encompass functional antibody fragments thereof. The term also encompasses intact or full-length antibodies, including antibodies of any class or sub-class, including IgG and sub-classes thereof, IgM, IgE, IgA, and IgD. The term “antibody" is inclusive of all species, including human and humanized antibodies and the antigenic target, can be from any species. Thus, an antibody, for example, which binds to an antigen “X" can bemouse anti-human X, human anti-human X; humanized anti-human X, goat anti-human X; goat anti-mouse X; rat anti-human X; mouse anti-rat X and the like. The combinations of antibody generated in a certain species against an antigen target, e.g. “X1”, from another species, or in some instances the same species (for example, in autoimmune or inflammatory response) are limitless and all species are embodied in this disclosure.

[0024] In some embodiments, the antigen-binding domain is a humanized antibody of fragments thereof. A “humanized” antibock is an antibody in which all or substantially all complementarity determining region (CDR) amino acid residues are derived from non-human CDRs and all or substantially all framework region (FR) amino acid residues are derived from human FRs. A humanized antibody optionally may include at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of a non-human antibody, refers to a variant of die non-human antibody that has undergone humanization, typically to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g. , foe antibody from which foe CDR residues are derived), e.g. , to restore or improve antibody specificity or affinity.

[0025] In some embodiments, the heavy and light chains of an antibody can be full- length or can be an antigen-binding portion (a Fab, F(ab*)2, Fv or a single chain Fv fragment (scFv)). In other embodiments, the antibody heavy chain constant region is chosen from, e.g., IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, and IgE, particularly chosen ftom, e.g., IgGl, IgG2, IgG3, and IgG4, more particularly, IgGl (e.g., human IgGl). In another embodiment, the antibody light chain constant region is chosen ftom, e g., kappa or lambda, particularly kappa.

[0026] Among the provided antibodies are antibody fragments. An “antibody fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds foe antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab', Fab’-SH, F(ab’)a; diabodies; linear antibodies; variable heavy chain (VH) regions, single-chain antibody molecules such as scFvs and singledomain Vn single antibodies; and multispecific antibodies formed from antibody fragments. Inparticular embodiments, the antibodies are single-chain antibody fragments comprising a variable heavy chain region and / or a variable light chain region, such as scFvs,

[0027] The term “variable region” or “variable domain”, when used in reference to an antibody, such as an antibody fragment, refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable domains of the heavy chain and light chain (VH and Vt, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three CDRs. (See, e.g., Kindt t-z al. Kuby Immunology, 6th ed.. W.H. Freeman and Co., page 91 (2007). A single Vn or Vi. domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a V» or VL domain from an antibody that binds the antigen to screen a library of complementary Vi, or VH domains, respectively. See, e.g., Portolano er al, J. Immunol. 150:880-887 (1993); Clarkson etal, Nature 352:624-628 (1991).

[0028] Single-domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain embodiments, a single-domain antibody is a human single-domain antibody.

[0929] Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells. In some embodiments, the antibodies are recombinantly-produced fragments, such as fragments comprising arrangements that do not occur naturally, such as those with two or more antibody regions or chains joined by synthetic linkers, e.g., peptide linkers, and / or that are may hot be produced by enzyme digestion of a naturally-occurring intact antibody. In some aspects, the antibody fragments are scFvs.

[0030] In the descriptions herein and in the claims, phrases such as “at least one of” or “one or more of” may occur followed by a conjunctive list of dements or features. The term “and / or” may also occur in a list of two or more elements or features. Unless otherwise implicitly or explicitly contradicted by the context in which it is used, such a phrase is intended to mean any of the listed elements or features individually or airy of the recited elements or features in combination with any of the other recited dements or features. For example, the phrases “at leastone of A and B ” “one or more of A and B;” and “A and / or B” are each intended to mean “ A alone, B alone, or A and B together.” A similar interpretation is also intended for lists including three or more items. For example, the phrases “at least one of A, B, and C;” “one or more of A, B, and C;” and “A, B, and / or C” are each intended to mean “A alone, B alone, C alone, A and B together, A and C together, B and C together, or A and B and C together.” In addition, use of the term “based on,” above and in the claims is intended to mean, “based at least in part on,” such that at) unrecited feature or element is also permissible.

[0031] The transitional term “comprising,” which is synonymous with “including,” “having”, “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. By contrast, the transitional phrase “consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional phrase “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristicCs)” of the claimed disclosure.

[0032] As used herein, the term “cellular immune response” can be used interchangeably with the term “cell-mediated immune response” and refers to an immune response that does not predominantly involve antibodies. Instead, a cellular immune response involves the activation of different immune cells (e,g., phagocytes and antigen-specific cytotoxic T-lymphocytes) that produce various effector molecules (e.g., cytokines, perforin, granzymes) upon activation (e.g., via antigen stimulation). As used herein, the term “humoral immune response” refers to an immune response predominantly mediated by macromolecules found in extracellular fluids, such as secreted antibodies, complement proteins, and certain antimicrobial peptides. The term “antibody- mediated immune response” refers to an aspect of a humoral immune response that is mediated by antibodies.

[0033] The term “combination therapy”, as used herein, refers to those situations in which two or more different pharmaceutical agents (e.g., SEQ ID NOs: M3 or variants thereof and a chemotherapeutic agent) are administered in overlapping regimens so that tire subject is simultaneously exposed to both agents. When used in combination therapy, two or more different agents may be administered simultaneously or separately. This administration in combination can include simultaneous administration of the two or more agents in the same dosage form,simultaneous administration in separate dosage forms, and separate administration. That is, two or more agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, two or more agents can be simultaneously administered, wherein die agents are present in separate formulations. In anotiter alternative, a first agent can be administered just followed by one or more additional agents. In the separate administration protocol, two or more agents may be administered a few minutes apart, or a few hours apart, or a few days apart[00034$ As used herein, an “adjuvant” refers to a substance that enhances the body’s immune response to an antigen or a vaccine and may be added to the formulation that includes the immunizing agent. Adjuvants provide enhanced immune response even after administration of only a single dose of the vaccine. Adjuvants may include, for example, aluminum hydroxide and aluminum phosphate, saponins e.g., Quil A, QS-21 (Cambridge Biotech Inc., Cambridge Mass.), GP1-0100 (Galenica Pharmaceuticals, Inc., Birmingham, Ala.), non-metabolizable oil, mineral and / or plant / vegetable and / or animal oils, polymers, carbomers, surfactants, natural organic compounds, plant extracts, carbohydrates, cholesterol, lipids, water-in-oil emulsion, oil- in-water emulsion, water-in-oil-in-water emulsion, HRA-3 (acrylic acid saccharide cross-linked polymer), HRA-3 with cottonseed oil (CSO), or an acrylic acid polyol cross-linked polymer. Hie emulsion can be based in particular on light liquid paraffin oil (European Pharmacopeia type); isoprenoid oil such as squalane or squalene; oil resulting from the oligomerization of alkenes, in particular of isobutene or decene; esters of acids or of alcohols containing a linear alkyl group, more particularly plant oils, ethyl oleate, propylene glycol di-(caprylate / caprate), glyceryl tri- (caprylate / caprate) or propylene glycol dioleate; esters of branched fatty acids or alcohols, in particular isostearic acid esters. The oil is used in combination with emulsifiers to form the emulsion. The emulsifiers comprise nonionic surfactants, in particular esters of sorbitan, of manoide (e.g., anhydromannitol oleate), of glycol, of polyglycerol, of propylene glycol and of oleic, isostearic, ricinoleic or hydroxystearic acid, which are optionally ethoxylated, and polyoxypropylene-polyoxyethylene copolymer blocks, in particular die PLURONIC™ brand products, especially LI 21. See Hunter et al., The Theory and Practical Application of Adjuvants (Ed. Stewart-Tull, D. E. S.) John Wiley and Sons, NY, pp 51-94 (1995) and Todd et al., Vaccine 15:564-570 (1997). In a preferred embodiment the adjuvant is at a concentration of about 0.01 toabout 50%, at a concentration of about 2% to 30%, at a concentration of about 5% to about 25%, at a concentration of about 7% to about 22%, and at a concentration of about 10% to about 20% by volume of the final product Examples of suitable adjuvants are described in LIS, Patent Application Publication No. US2004 / 0213817 Al . “Adjuvanted” refen to a composition that incorporates or is combined with an adjuvant

[0035] As used herein, an “antibody” may be a polyclonal antisera or monoclonal antibody. The term antibody may include any of the various classes or sub classes of immunoglobulin (e.g., IgG, IgA, IgM, IgD, or IgE derived from any animal, e.g., any of the animals conventionally used, e.g., sheep, rabbits, goats, or mice, or human), e.g., the antibody comprises a monoclonal antibody , e,g., an HIV monoclonal antibody. An “isolated antibody as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds HIV and is substantially free of antibodies that specifically bind antigens other than HIV). Moreover, an isolated antibody may be substantially free of other cellular material and / or chemicals. The terms “monoclonal antibody” or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.{00036] An “antibody fragment” comprises a portion of an intact antibody, preferably the antigen binding and / or die variable region of the intact antibody. Non-limiting examples of antibody fragments include Fab, Fab*, F(ab‘)2 and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules and multi specific antibodies formed from antibody fragments.

[0037] As used herein, “antigen” is defined as a molecule that provokes an immune, response. This immune response may involve either antibody production, or the activation of specific immunologically competent cells, or both. For example, any macromolecule, including virtually all proteins or peptides, can save as an antigen. Furthermore, antigens can be derived from recombinant or genomic DNA. A skilled artisan will understand that any DNA, which comprises a nucleotide sequence or a partial nucleotide sequence encoding a protein that elicits an immune response therefore encodes an “antigen” as that term is used herein.

[0038] The term “anti-viral agent” as used herein, refers to any molecule that is used for the treatment of a virus and include agents which alleviate any symptoms associated with the virus, for example, anti-pyretic agents, anti-inflammatory agents, chemotherapeutic agents, and the like. An antiviral agent includes, without limitation: antibodies, aptamers, adjuvants, antisense oligonucleotides, chemokines, cytokines, gene-editing agents, immune stimulating agents, immune modulating agents, B-cell modulators, T-cell modulators, NK cell modulators, antigen presenting cell modulators, enzymes, siRNA’s, ribavirin, protease inhibitors, helicase inhibitors, polymerase inhibitors, helicase inhibitors, neuraminidase inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, purine nucleosides, chemokine receptor antagonists, interleukins, or combinations thereof. The term also refers to non-nucleoside reverse transcriptase inhibitors (NNRTls), nucleoside reverse transcriptase inhibitors (NRTIs), analogs, variants etc.

[0039] The term “chimeric antibody” is intended to refer to antibodies in which the variable region sequences are derived from one species and die constant region sequences are derived from another species, such as an antibody in which the variable region sequences are derived from a mouse antibody and the constant region sequences are derived from a human antibody.

[0040] As used herein, the terms “comprising,” “comprise” or “comprised,” and variations thereof, in reference to defined or described elements of an item, composition, apparatus, method, process, system, etc. are meant to be inclusive or open ended, permitting additional elements, thereby indicating that the defined or described item, composition, apparatus, method, process, system, etc. includes those specified elements-or, as appropriate, equivalents thereof— and that other elements can be included and still fall within the scope / definition of the defined hem, composition, apparatus, method, process, system, etc.

[0041] As used herein, the terms “conjugated,” “linked,” “attached,” “fused” and “tethered,” when used with respect to two or more moieties, means that the moieties or domains are physically associated or connected with one another, either directly or via one or more additional moieties that serve as a linking agent, to form a structure that is sufficiently stable so that the moieties remain physically associated under the conditions in which die structure is used,e.g., physiological conditions. The linkage can be based on genetic fusion according to the methods known in the art or can be performed by, e.g., chemical cross-linking. The compounds and targeting agents may be linked by a flexible linker, such as a polypeptide linker. The polypeptide linker can comprise plural, hydrophilic or peptide-bonded amino acids of varying lengths. The term “associated” will be used for the sake of brevity and is meant to include all possible methods of physically associating each compound to a targeting ligand.

[0042] The term “disease” refers to any deviation from the normal health of a mammal and includes a state when disease symptoms are present, as well as conditions in which a deviation (e.g., human immunodeficiency virus (HIV)) has occurred, but symptoms are not yet manifested.

[0043] An “elite controller” or “HIV controller” is a person living with HIV who is able to maintain low (er.g. undetectable) viral loads for at least 12 months despite not having started antiretroviral therapy (ARI). Elite controllers are rare: for every two hundred people living with HIV, approximately one may be an elite controller [0.5%), The frequency is higher in some cohorts / populations. In certain aspects, an elite controller may be defined as having VLs < 50. In certain aspects, the general term “controller may be defined as having VLs < 2000.

[0044] By “encoding” or “encoded”, “encodes”, with respect to a specified nucleic acid, is meant comprising the information for translation into the specified protein. A nucleic acid encoding a protein may comprise non-translated sequences (e,g., introns) within translated regions of the nucleic acid, or may lack such intervening non-translated sequences (e.g., as in cDNA). The information by which a protein is encoded is specified by the use of codons.

[0045] The term “epitope” as used herein refers to a sequence of at least about 3 to 5, at least about 5 to 10 or 15, and not more than about 1,000 amino acids (or any integer value between 3 and 1 ,000), which define a sequence that by itself or as part of a larger sequence, binds to an antibody generated in response to such sequence. There is no critical upper limit to the length of the fragment, which may comprise nearly the fiill-length of the protein sequence, or even a fusion protein comprising two or more epitopes from the HIV polyprotein. An epitope for use in the subject disclosure is not limited to a polypeptide having the exact sequence of the portion of the parent protein from which it is derived. Indeed, viral genomes are in a state ofconstant flux and contain several variable domains which exhibit relatively high degrees of variability between isolates. Thus, the term “epitope” encompasses sequences identical to the native sequence, as well as modifications to the native sequence, such as deletions, additions and substitutions (generally conservative in nature). In certain embodiments, an epitope determinant include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl, or sulfonyl, and, in certain embodiments, may have specific three-dimensional structural characteristics, and or specific charge characteristics.

[0046] As used herein, the term “immune response,” or “inducing an immune response” means a process involving foe activation and / or induction of an effector function in, by way of non-limiting examples, a T cell, B cell, natural killer (NK) cell, and / or an antigen-presenting cell (APC). Thus, an immune response, as would be understood by foe skilled artisan, includes, but is not limited to, any detectable antigen-specific activation and / or induction of a helper T cell or cytotoxic T cell activity or response, production of antibodies, antigen presenting cel! activity or infiltration, macrophage activity or infiltration, neutrophil activity or infiltration, and foe like. Accordingly, an immune response can comprise a humoral immune response (e.g., mediated by B-cells), cellular immune response (e.g., mediated by T cells), or both humoral and cellular immune responses.

[0047] “An immunogenic carrier” is a molecule or moiety to which an immunogen or a hapten can be coupled in order to enhance or enable the elicitation of an immune response against the immunogen / hapten. Immunogenic carriers are in classical cases relatively Large molecules (such as tetanus toxoid, KLH, diphtheria toxoid etc.) which can be fused or conjugated to an immunogen / hapten, which is not sufficiently immunogenic in its own right -- typically, the immunogenic carrier is capable of eliciting a strong T-helper lymphocyte response against the combined substance constituted by the immunogen and the immunogenic carrier, and this in turn provides for improved responses against foe immunogen by B-lymphocytes and cytotoxic lymphocytes. More recently, the large carrier molecules have to a certain extent been substituted by so-called promiscuous T-helper epitopes, i.e., shorter peptides that are recognized by a large firaction of HLA haplotypes in a population, and which elicit T-helper lymphocyte responses.

[0048] An “immunological response” to an HIV antigen (including both polypeptide and polynucleotides encoding polypeptides that are expressed in vivo) or composition is the development in a subject of a humoral and / or a cellular immune response to molecules present in the composition of interest. For purposes of the present disclosure, a “humoral immune response” refers to an Immune response mediated by antibody molecules, while a “cellular immune response” is one mediated by T-lymphocytes and / or other white blood cells. One important aspect of cellular immunity involves an antigen-specific response by cytolytic T-cells (“CTLs”). CTLs have specificity for peptide antigens that are presented in association with proteins encoded by the major histocompatibility complex (MHC) and expressed on the surfaces of cells. CTLs help induce and promote the intracellular destruction of intracellular microbes, or the lysis of cells infected with such microbes. Another aspect of cellular immunity involves an antigen-specific response by helper T-cells. Helper T-cells act to help stimulate the function, and focus the activity of, nonspecific effector cells against cells displaying peptide antigens in association with MHC molecules on their surface. A “cellular immune response” also refers to the production of cytokines, chemokines and other such molecules produced by activated T-cells and / or other white blood cells, including those derived from CD-T and CDS6T-cells.

[0049] The terms “modified peptide sequence" or “variant peptide sequence” refers to a protein sequence that has one or more residues that differ in amino acid residue identity from another similar protein sequence. The similar protein sequence may be the natural wild type protein sequence, or another variant of the wild type sequence. Variants include proteins that have one or more amino acid residue insertions, deletions or substitutions. Variants also include proteins that have one or more post-translationally modified amino acid residues.

[0050] In the context of this disclosure, the term “oligonucleotide” refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimetics thereof, 'rhe term “oligonucleotide” also includes linear or circular oligomers of natural and / or modified monomers or linkages, including deoxyribonucleosides, ribonucleosides, substituted and alpha- anomeric forms thereof, peptide nucleic acids (PNA), locked nucleic acids (LNA), phosphorothioate, methylphosphonate, and the like. Oligonucleotides are capable of specifically binding to a target polynucleotide by way of a regular pattern of monomer-to-monomerinteractions, such as Watson-Crick type of base pairing, Hoogsteen or reverse Hoogsteen types of base pairing, or the like.

[0051] As used herein, unless otherwise indicated, the terms “peptide”, “polypeptide” or “protein” are used interchangeably herein and refer to a polymer of amino acids of varying sizes. These terms do not connote a specific length of a polymer of amino acids. Thus, for example, the terms oligopeptide, protein, and enzyme are included within die definition of polypeptide or peptide, whether produced using recombinant techniques, chemical or enzymatic synthesis, or be naturally occurring. This term also includes polypeptides that have been modified or derivatized, such as by glycosylation, acetylation, phosphorylation, and the like.

[0052] “Polypeptide fragment” refers to a polypeptide that has an amino-terminal and / or carboxy-terminal deletion, in which the remaining amino acid sequence is usually identical to the corresponding positions in the naturally-occurring sequence. Fragments typically are at least 5, 6, 8 or 10 amino acids long, at least 14 amino acids long, at least 20 amino acids long, at least 50 amino acids long, or at least 70 amino acids long.

[0053] As used herein, the term “sample” refers to a biological sample suitably obtained for the purpose of evaluation in vitro. The sample suitably may comprise a body fluid. In some embodiments, the body fluid includes, but is not limited to, whole blood, plasma, serum, lymph, breast milk, saliva, mucous, semen, cellular extracts, inflammatory fluids, cerebrospinal fluid, vitreous humor, tears, vitreous, aqueous humor, or urine obtained from the subject. In some aspects, die sample is a composite panel of two or more body fluids. In exemplary aspects, the sample comprises blood or a fraction thereof (e.g., plasma, serum, or a fraction obtained via leukapheresis).

[0054] As used herein, the term “scaffold” refers to a molecule that specifically binds to a determinant. In one embodiment, a scaffold is able to direct the entity to which it is attached, e.g., the peptides embodied herein, to a target site, e.g, the complex of a peptide with MHC. In another embodiment a scaffold is able to activate signaling through its target antigen, for example a T cell receptor complex antigen. Scaffolds include but are not limited to antibodies and fragments thereof, antigen binding domains of an antibody, comprising an antibody heavy chain variable region and an antibody light chain variable region, binding proteins comprising atleast one ankyrin repeat motif and single domain antigen binding (SDAB) molecules, aptamers, (soluble) TCRs and (modified) cells such as allogenic or autologous T cells. To assess whether a molecule is a scaffold binding to a target, binding assays can be performed. Each scafibld can comprise a labelling which provides that the bound scaffold can be detected by determining the presence or absence of a signal provided by the label For example, the scaffold can be labelled with a fluorescent dye or any other applicable cellular marker molecule. Such marker molecules are well known in the art. For example, a fluorescence-labelling, for example provided by a fluorescence dye, can provide a visualization of the bound aptamer by fluorescence or laser scanning microscopy or flow cytometry. See, for example, Dennis R. Burton, “Scaffolding to build a rational vaccine design strategy’*, October II, 2010, 107 (42) 17859-17860. doi.org / 10.1073 / pnas.1012923107, for a review on scaffolds, incorporated herein by reference in its entirety. Other examples include self-assembling peptide-, peptidomimetic-, and proteinbased biomaterials which offer a means to overcome these challenges through their inherent modularity, multivalency, and biocompatibility. See, for example, O’Neill CL et al., Peptide- based supramolecular vaccine systems. Acta Biomater. 2021 Oct 1; 133: 153- 167. doi: 10.l016 / j.actbio.2021.05.003. Epub 2021 May 16. PMID: 34010691; PMCID: PMC8497425, incorporated herein by reference in its entirety.

[0055] “Specific” binding means that the scaffold binds the peptide to the MHC-complex of interest better than other naturally occurring peptide-MHC-complexes. Tests to assess target binding are well known in the art, e.g., FRET assays. They should be performed using target cells (primary cells or cell lines) with unaltered peptide-MHC presentation, or cells loaded with peptides such that naturally occurring peptide-MHC levels are reached.

[0056] The terms “specific binding” or “specifically binding” when used m reference to the interaction of a protein and an antibody or alternative protein scaffold or peptoid or aptamers, means that the interaction is dependent upon the presence of a particular structure (i.e., toe antigenic determinant or epitope) on the protein; in other words the antibody is recognizing and binding to a specific protein structure rather than to proteins in general. Thus, an antibody that “specifically binds to” or is “specific for” a particular polypeptide or an epitope on a particularpolypeptide is one that binds to that particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope.

[0057] As used herein, the terms “subject, ” “patient,” “individual,” etc. are not intended to be limiting and can be generally interchanged. That is, an individual described as a “patient” does not necessarily have a given disease but may be merely seeking medical advice. For example, a “patient” or “subject” or “subject in need thereof” refers to a living member of the animal kingdom suffering from or who may suffer from HIV, In certain embodiments, the subject is a human.

[0058] The terms “therapeutically effective amount,” “treatment effective amount” and “effective amount” as used herein are synonymous unless otherwise indicated, and mean an amount of a compound, peptide or composition of the present disclosure that is sufficient to improve the condition, disease, or disorder being treated and / or achieved the desired benefit or goal (e.g., control of body weight). Those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject. Determination of a therapeutically effective amount, as well as other factors related to effective administration of a compound of the present disclosure to a subject of this disclosure, including dosage forms, routes of administration, and frequency of dosing, may depend upon the particulars of the condition that is encountered, including the subject and condition being treated or addressed, the severity of the condition in a particular subject, the particular compound being employed, the particular route of administration being employed, the frequency of dosing, and the particular formulation being employed. Determination of a therapeutically effective treatment regimen for a subject of this disclosure is within the level of ordinary skill in the medical or veterinarian arts. In clinical use, an effective amount may be the amount that is recommended by the U.S. Food and Drug Administration, or an equivalent foreign agency. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon die subject being treated and the particular mode of administration.

[0059] As used herein, “treating” or “treatment” of a condition, disease or disorder or symptoms associated with a condition, disease or disorder refers to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results caninclude, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of condition, disorder or disease, stabilization of toe state of condition, disorder or disease, prevention of development of condition, disorder or disease, prevention of spread of condition, disorder or disease, delay or slowing of condition, disorder or disease progression, delay or slowing of condition, disorder or disease onset, amelioration or palliation of the condition, disorder or disease state, and remission, whether partial or total “Treating” can also mean inhibiting the progression of the condition, disorder, or disease, slowing the progression of the condition, disorder or disease temporarily, although in some instances, it involves halting the progression of the condition, disorder or disease permanently.

[0060] As used herein, the terms “treaf ’ and “prevent” are not intended to be absolute terms. In various embodiments, treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in toe severity of an established disease, condition, or symptom of the disease or condition. In embodiments, a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms of toe disease in a subject as compared to a control. Thus, the reduction can be a 1034, 20%, 30%, 40%, 50%, 6034, 70%, 80%, 90%, 100%, or any percentreduction in between 10% and 100% as compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete ablation of the disease, condition, or symptoms of the disease or condition. In embodiments, references to decreasing, reducing, or inhibiting include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater as compared to a control level and such terms can include but do not necessarily include complete elimination. In embodiments, the severity of disease is reduced by at least 1034, as compared, e.g., to the individual before administration or to a control individual not undergoing treatment In some aspects the severity of disease is reduced by at least 25%, 50%, 75%, 80%, or 90%, or in some cases, no longer detectable using standard diagnostic techniques.

[0061] As used herein, an “unnatural amino acid,” “non-natural amino acid”, “synthetic amino acid”, “modified amino acid” or “chemically modified amino acid” refers to any amino acid, modified amino acid, or amino acid analogue other than the twenty genetically encoded alpha-amino acids. Unnatural amino acids have side chain groups that distinguish them from toenatural amino acids, although unnatural amino acids can be naturally occurring compounds other than the twenty proteinogenic alpha-amino acids. In addition to side chain groups that distinguish them from the natural amino acids, unnatural amino acids may have an extended backbone such as beta-amino acids. Non-limiting examples of non-natural amino acids include selenocysteine, pyrrolysine, homocysteine, an O-methyl-L-tyrosine, an L-3-(2-naphthyl)alanine, a 3-methyl- pheny lalanine, an O-4-allyl-L-tyrosine, a4-propyI-L-tyrosine, a tri-O-acetyl-GlcNAcp-serine, an L-Dopa, a fluorinated phenylalanine, an isopropyl-L-phenylalanine, a p-azido-L-phenylalanine, a p-acyl-L-phenylalanine, a p-benzoyl-L-phenylalanine, an L-phosphoserine, a phosphonoserine, a phosphonotyrosine, a p-iodo-phenylalanine, a p-bromophenylalanine, a p-amino-L- phenylabnine, an isopropyl-L-phenylalanine, an unnatural analogue of a tyrosine amino acid; an unnatural analogue of a glutamine amino acid; an unnatural analogue of a phenylalanine amino acid; an unnatural analogue of a serine amino acid; an unnatural analogue of a threonine amino acid; an alkyl, aryl, acyl, azido, cyano, halo, hydrazine, hydrazide, hydroxyl, alkenyl, alkynl, ether, thiol, sulfonyl, seleno, ester, thioacid, borate, boronate, phospho, phosphono, phosphine, heterocyclic, enone, imine, aldehyde, hydroxylamine, keto, or amino substituted amino acid, or any combination thereof; an amino acid with a photoactivatable cross-linker; a spin-labeled amino acid; a fluorescent amino acid; an amino acid with a novel functional group; an amino acid that covalently or noncovalently interacts with another molecule; a metal binding amino acid; a metal-containing amino acid; a radioactive amino acid; a photocaged and / or photoisomerizable amino acid; a biotin or biotin-analogue containing amino acid; a glycosylated or carbohydrate modified amino acid; a keto containing amino acid; amino acids comprising polyethylene glycol or polyether; a heavy atom substituted amino acid; a chemically cleavable or photocleavable amino acid; an amino acid with an elongated side chain; an amino acid containing a toxic group; a sugar substituted amino acid, e.g., a sugar substituted serine or the like; a carbon-linkedsugar-containing amino acid; a redox-active amino acid; an a-hydroxy containing acid; an amino thio acid containing amino acid; an a, a disubstituted amino acid; a p- amino acid; and a cyclic amino acid other than proline. In an embodiment of the helicases described herein, one or more amino acids of the helicase are substituted with one or more unnatural amino acids and / or one or more natural amino acids.

[0062] As used herein, “variant” of polypeptides refers to an amino add sequence that is altered by one or more amino acid residues. The variant may have “conservative” changes, wherein a substituted amino acid has similar structural or chemical properties (e.g., replacement of leucine with isoleucine). More rarely, a variant may have “nonconservative” changes (e.g., replacement of glycine with tryptophan). Analogous minor variations may also include amino acid deletions or insertions, or both. Guidance in determining which amino acid residues may be substituted, inserted, or deleted without abolishing biological activity may be found using computer programs well known in the art, for example, LASERGENE software (DNASTAR).

[0063] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. Concentrations, amounts, cell counts, percentages and other numerical values may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited.

[0064] Genbank and NCB1 submissions indicated by accession number cited herein are incorporated herein by reference.

[0065] Any compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0066] The patent or application file contains at least one drawing executed in color.Copies of this patent or patent application publication with color drawings will be provided by the Office upon request and payment of the necessary fee.

[0067] FIG. 1 shows an overview of the assessments in this report Antibody profiles were fust characterized for the study cohort Antibody responses were then evaluated at thepeptide, epitope, and aggregate levels for associations with HIV viral load, and at the epitope and aggregate levels for associations with HIV controller status.

[0068] FIG. 2 shows that antibody reactivity to peptides spanning the HIV genome. The plot shows the mean level of antibody binding to HIV peptides in the VirScan library for all 77 study participants analyzed one to two years after HIV infection. The x-axis shows the nucleotide position relative to genomic coordinates for the HIV HXB2 reference strain ( NCBI #NC 001802). The y-axis shows mean antibody binding (loglO fold change); each dot represents the mean antibody binding result for one peptide. The genomic locations of ten peptide clusters with high levels of mean antibody reactivity are indicated by vertical gray litres. Three new peptide clusters were identified in this study (cluster a: gag [p7]; cluster b: protease; cluster c: integrase). Abbreviations: Kb: kilobase.

[0069] FIG 3 (includes Panels A and B) shows the peptide-level antibody responses and HIV viral load. Tire plots show the association between the level of antibody reactivity to HIV peptides and HIV viral load as dietermined by linear regression. Data are shown for the 77 participants in the study cohort; this analysis included 1,235 HIV peptides that had significant antibody reactivity (adjusted fold change >1) for at least one participant. Panel A: The volcano plot shows the significance of the association between the level of antibody reactivity and viral load. The x-axis shows the estimated effect of antibody reactivity on viral load (estimated effect from the linear regression). Positive values indicate that higher levels of antibody reactivity were associated with higher viral loads; negative values indicate that higher levels of antibody reactivity were associated with tower viral loads. The y-axis shows the -loglO p- value for the association between the level of antibody reactivity and viral load. Each dot represents data for a single peptide; blue dots indicate peptides with a significant association. The blue dashed line indicates the highest q- value <5% (q^.OdSS); this corresponds to ap-value of 0.00158. The dotted blue line indicates the cutoff for significance using the Bonfcrroni correction (p= 0.05 / 1 ,235:::4.0 x 10-5). Panel B: The plot shows the same data and significance thresholds visualized across the viral genome. The x-axis shows nucleotide position relative to genomic coordinates for the HIV HXB2 reference strain (NCBI #NC 001802). The y-axis shows the - loglO p-value for the association between antibody reactivity and viral load. Black dots indicatepeptides for which higher antibody reacti vity was associated with higher viral loads; red dots indicate peptides for which higher antibody reactivity was associated with lower viral loads. The genomic locations of the ten peptide clusters from FIG. 2 are indicated by vertical gray line?. Abbreviations: Kb: kilobase; VL: viral load.

[0070] FIG. 4 (includes Panels A, B and C) shows the aggregate antibody responses and HIV viral load. The plots show the association between three aggregate measures of HIV antibody reactivity and HIV viral load, as determined by linear regression. Data are shown for the 77 participants in die study cohort. For each panel, each dot represents data for a single participant. The y-axes show the HIV viral load (loglO scale). The blue lines indicate die least squares regression lines. P-values indicate the significance of the associations as determined by linear regression. Grey regions show the 95% confidence bands for the mean antibody response. Panel A: Aggregate antibody reactivity was evaluated for the eight HIV epitopes shown in Table 1. The x-axis shows foe number of epitopes targeted (adjusted fold change >1). lite estimated effect indicates the change in viral load (loglO scale) associated with one additional targeted epitope. Panel B: Mean antibody reactivity was evaluated across all eight HIV epitopes shown in Table I. The x-axis shows the mean antibody reactivity (loglO fold change) across all eight epitopes. The estimated effect indicates the change in viral load (loglO scale) associated with one unit increase in mean antibody reactivity (loglO scale). Panel C: The VARscore is a composite measure of foe overall breadth and strength of antibody reactivity to all peptide targets across a viral genome, as measured by VirScan. The x-axis shows foe HIV-1 VARscore. The estimated effect indicates the change in viral load (loglO scale) associated with one unit increase in HIV-1 VARscore.

[0071] FIG. 5 (includes Panels A and B) shows foe epitope-level antibody responses in controllers vs. non-controllers. Antibody reactivity was assessed for the HIV epitopes shown in Table 1 for two participant groups: controllers (n=13; red) and non-controllers (n=64; grey). Panel Ar The plot shows the frequency of reactivity to each epitope in each group (reactive: adjusted fold change >1; not reactive: adjusted fold change = 1). P-values show the significance of the association between controller status and foe prevalence of reacti vi ty using Fisher’s exact test. Panel B: The plot shows antibody reactivity (loglO fold change) to each epitope; each dotindicates data for one participant. Mean values for each group are indicated by black crossbars. P-values show the significance of the association between controller status and the level antibody reactivity based on Wilcoxon rank-sum test statistics.

[0072] FIG. 6 (includes Panels A-F) shows foe aggregate antibody responses in controllers vs. non-controllers. Aggregate antibody reactivity was assessed for controllers (u-13; red) and non-controllers grey). Panel A: Aggregate antibody reactivity was evaluated for the eight HJV epitopes shown in Table 1. The histogram shows the number of epitopes targeted by participants based on controller status. Data were binned according to die number of epitopes targeted by each study participant. Bar heights indicate frequency. Panel B: The plot shows foe number of epitopes targeted based on controller status; each dot indicates foe number of epitopes targeted for one study participant. Mean values for each group are indicated by black crossbars. P-values show the significance of foe association between controller status and antibody reactivity based on t-statistics. Panel C: The plot shows foe mean antibody reactivity (mean loglO fold change) across all selected epitopes based on controller status; each dot indicates mean data for one study participant. Mean values for each group are indicated by black crossbars. P-values show foe significance of the association between controller status and antibody reactivity based on t-statistics. Panel D: The VARscore is a composite measure of the overall breadth and strength of antibody reactivity to all peptide targets across a viral genome, as measured by VirScan. The plot shows HIV-l VARscores for controllers (N::::13, red) and viremic non-controllers (N=64, grey); this analysis also included a group of non-controllers who were suppressed on antiretroviral therapy within the first year of HIV infection (N=36, blue; see Methods). Each dot indicates HIV-1 VARscore data for one study participant. Mean values for each group are indicated by black crossbars. P-values show the significance of foe association between controller status and HIV-l VARscore based on t-statistics. Panels E-F; The plots show VARscores for HIV-2 (Panel E) and HSV-2 (Panel F) for controllers (n=l3; red) vs. non- controllers (n=64, grey). Each dot indicates data for one participant Mean values for each group are indicated by black crossbars. P-values show foe significance of the association between controller status and foe VARscore based on t-statistics.

[0073] FIG, 7 (includes Panels A and B) shows the peptide-level antibody responses and HIV viral load in the non-controller subset. The plots show the association between the level of antibody reactivity to HIV peptides and HIV viral load as determined by linear regression. Data are shown for the subset of participants classified as non-controllers (n=64); this analysis included 1 ,183 HIV peptides that had significant antibody reactivity (adjusted fold change >1) for at least one participant in this subset. Panel At The volcano plot shows the significance of the association between the level of antibody reactivity and viral load. Hie x-axis shows the estimated effect of antibody reactivity on viral load (estimated effect from the linear regression). Positive values indicate that higher levels of antibody reactivity were associated with higher viral loads; negative values indicate that higher levels of antibody reactivity were associated with lower viral loads. The y-axis shows the -loglO p- value for the association between the level of antibody reactivity and viral load. Each dot represents data for a single peptide. Panel B: The plot shows the same data visualized across the viral genome. The x-axis shows nucleotide position relative to genomic coordinates for the HIV HXB2 reference strain (NCBI #NC .001802). The y- axis shows the -loglO p-value for foe association between antfoody reactivity and viral load. Black dots indicate peptides for which higher antibody reactivity was associated with higher viral loads; red dote indicate peptides for which higher antibody reactivity was associated with lower viral loads. The genomic locations of the ten peptide clusters from Figure 2 are indicated by vertical gray lines. Abbreviations: Kb: kilobase; VL: viral load.

[0074] FIG. 8 (includes Panels A, B and C) shows the aggregate antibody responses ami HIV viral load in the non-controller subset. The plots show the association between three aggregate measures of HIV antibody reactivity and HI V viral load, as determined by linear regression. Data are shown for the subset of participants classified as non-controllers (n~64). For each panel, each dot represents data for a single participant. The y-axes show the HIV viral load (loglO scale). The blue lines indicate the least squares regression lines. P-values indicate foe significance of foe associations as determined by linear regression. Grey regions show the 95% confidence bands for the mean antibody response. Panel A: Aggregate antibody reactivity was evaluated for the eight HIV epitopes shown in Table L The x-axis shows foe number of epitopes targeted (adjusted fold change >1 )- The estimated effect indicates foe change in viral load (logl 0scale) associated with one additional targeted epitope. Panel B' Mean antibody reactivity was evaluated across all eight HIV epitopes shown in Table 1. The x-axis shows the mean antibody reactivity (loglO fold change) across all eight epitopes. The estimated effect indicates the change in viral load (loglO scale) associated with one unit increase in mean antibody reactivity (loglO scale). Panel C: The VARscore is a composite measure of the overall breadth and strength of antibody reactivity to all peptide targets across a viral genome, as measured by VirScan. rhe x- axis shows the HIV-1 VARscore. The estimated effect indicates the change m viral load (log 10 scale) associated with one unit increase in HIV- 1 VARscore.DETAILED DESCRIPTION

[0075] This disclosure is based, in part, on the discovery of human immunodeficiency virus (HIV) antibody targets associated with lower VL and HIV controller status 1-2 years after infection. Robust aggregate responses to these targets and broad antibody reactivity across the HIV genome were also associated with lower VL and controller status. These findings provide novel insights into the relationship between humoral immunity and viral containment that could help inform the design of antibody-based approaches for reducing HIV VL.

[0076] Peptides[00077J The compositions and methods described herein provide for the incorporation of at least one modified amino acid residue into a polypeptide. In some embodiments, at least two modified amino acid residues are incorporated into a polypeptide. In some embodiments, at least three modified amino acids residues are incorporated into a polypeptide. In some embodiments, at least four modified amino acid residues are incorporated into a polypeptide. In some embodiments, at least five modified amino acid residues are incorporated into a polypeptide. In some embodiments, at least six modified amino acid residues are incorporated into a polypeptide. The modified amino acid residues may be present at any location on the polypeptide, including any terminal position or any internal position of the polypeptide. Preferably, the modified ammo acid residue does not destroy the activity and / or the tertiary structure of fee polypeptide relative to fee homologous naturally-occurring polypeptide, unless such destruction of the activity and / or tertiary structure was one of the purposes of incorporating the modified amino acid residue into the polypeptide. Further, the incotporation of the modifiedamino acid residue into the polypeptide may modify to some extent the activity (e.g., manipulating the therapeutic effectiveness of the polypeptide, improving the safety profile of the polypeptide, adjusting the pharmacokinetics, pharmacologies and / or pharmacodynamics of the polypeptide (e.g., increasing water solubility, bioavailability, increasing serum half-life, increasing therapeutic half-life, modulating immunogenicity, modulating biological activity, or extending the circulationtime), providing additional functionality to the polypeptide, incorporating a tag, label or detectable signal into the polypeptide, easing the isolation properties of the polypeptide, and any combination of the aforementioned modifications) and / or tertiary structure of the polypeptide relative to foe homologous naturally-occurring polypeptide without fully causing destruction of the activity and / or tertiary structure. Such modifications of the activity and / or tertiary structure are often one of the goals of effecting such incorporations, although the incorporation of foe modified amino acid residue into the polypeptide may also have little effect on the activity and / or tertiary structure of the polypeptide relative to the homologous naturally-occurring polypeptide. Correspondingly, polypeptides comprising modified amino acid residues, compositions comprising polypeptides with modified amino acid residues, methods for making such polypeptides and polypeptide compositions, methods for purifying, isolating, and characterizing such polypeptides and polypeptide compositions, and methods for using such polypeptides and polypeptide compositions are considered within foe scope of tiie present disclosure. Further, the polypeptides comprising modified amino acid residues described herein may also be ligated to other polypeptides (including, by way of example, a polypeptide comprising modified amino acid residues or a naturally-occurring polypeptide).

[0078] Accordingly, in certain aspects, a vaccine formulation comprises a therapeutically effective amount of one or more immunogenic human immunodeficiency virus (HIV) peptides comprise one or more peptides comprising any one of SEQ ID NOs: 1 *43, or combinations thereof, having at least a 60%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, sequence identity to its corresponding sequence. That is, for example, an immunogenic HIV peptide comprises a peptide having at least a 60%, 70%,75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, sequence identity to peptides comprising SEQ ID NOs: 1-43.[000121] QQLIXilWGCSGKLICTTAVPWNASWSNKSLEDIWDNMTWMQWEREIDN YTNTIYTL (SEQ ID NO: 42);[000122] WGCSGKLICTTAVPWNSSWSNRSQEDIWNNMTWMQWDREISNYTNTIY RLLEDSQN (SEQ ID NO: 43).[000123] In certain embodiments, antibodies which specifically bind to peptides comprising any one of SEQ ID NOs: 1 -43 are generated.[000124] In certain embodiments, the vaccine comprises any one or more HIV peptides comprising SEQ ID NOs: 1 -43 having at least one mutation or variation. In certain embodiments, the vaccine comprises any one or more HIV peptides comprising SEQ ID NOs: M3 having at least one mutation. In certain embodiments, tire vaccine comprises any one or more HIV peptides comprising SEQ ID NOs: 1-43 having at least two mutations.[000125] In certain embodiments, the one or more HIV peptides comprising SEQ ID NOs: 1 -43, include one or more amino acid residue insertions, deletions, substitutions or combinations thereof. In certain embodiments, the one or more HIV peptides comprising SEQ ID NOs: M3 include one or more unnatural amino acids. In certain embodiments, the one or more HIV peptides comprising SEQ ID NOs: 1-43 include one or more synthetic amino acids.[000126] In certain embodiments, a vaccine comprises at least one or more HIV peptides comprising SEQ ID NOs: M3.[000127] In some embodiments, the HIV peptides comprising SEQ ID NOs; M3 comprise one or more conservative mutations as compared to its parental counterpart. In some embodiments, the HIV variants of peptides comprising SEQ ID NOs: 1 -43 comprise 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative mutations as compared to its parental counterpart (or a relevant portion of the parental counterpart). As used herein, the terms “conservative amino acid substitutions” and “conservative modifications” refer to amino acid modifications that do not significantly affect or alter the function and / or activity of the presently disclosed proteins comprising the amino add sequence. Such conservative modifications include amino acid substitutions, additions., and deletions. Modifications can be introduced into the proteins of this disclosure by standard techniques known in the art, such as site-directed mutagenesis and PCR- mediated mutagenesis. Amino acids can be classified into groups according to theirphysicochemical properties such as charge and polarity. Conservative amino acid substitutions are ones in which the amino acid residue is replaced with an amino acid within the same group. For example, amino acids can be classified by charge: positively-charged ammo acids include lysine, arginine, histidine, negatively-charged amino acids include aspartic acid, glutamic acid, neutral charge amino acids include alanine, asparagine, cysteine, glutamine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In addition, amino acids can be classified by polarity : polar amino acids include arginine (basic polar), asparagine, aspartic acid (acidic polar), glutamic acid (acidic polar), glutamine, histidine (basic polar), lysine (basic polar), serine, threonine, and tyrosine; non-polar amino acids include alanine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, tryptophan, and valine.[000128] In certain embodiments, a vaccine comprises one or more peptides linked together. For example, a vaccine comprises, any one or more HIV peptides comprising SEQ ID NOs: 1 -43 wherein the same peptides are linked in two or more repeating units, to another example, a peptide comprising SEQ ID NOs: 1 -43 is linked to another peptide sequence embodied herein. These can be repetitive or associatedin various combinations. Various combinations of linked peptides as suitable vaccine combinations can be identified by immunoassays, e.g., radioimmunoassays, ELISAs, Enzyme immunoassays, in vivo animal experiments etc. See, for example, Darwish I A. Immunoassay Methods and their Applications in Pharmaceutical Analysis: Basic Methodology and Recent Advances, tat J Biomed Sci. 2006 Sep;2(3):217-35. PMID: 23674985; PMCID: PMC3614608.[000129] In certain embodiments, the vaccine comprising any one of HIV peptides comprising SEQ ID NOs: 1-43, including variants, homologues and analogues thereof, can be covalently linked, with or without a spacer, to a peptide containing a sequence known to contain one or more B cell epitopes or T cell epitopes. The linked peptides can offer enhanced immunogenicity over the equivalent immunogens that are not covalently linked to B or T cell epitope peptides. In some embodiments, the vaccine is a multivalent long peptide vaccine, a multi-peptide vaccine, a peptide cocktail vaccine, a hybrid peptide vaccine, or a peptide -pulsed dendritic cell vaccine.[000136] In certain embodiments, the one or more HIV peptides comprising SEQ ID NOs: 1-43, include one or more amino acid residue insertions, deletions, substitutions or combinations thereof. In certain embodiments, the one or more HIV peptides comprising SEQ ID NOs: 1 -43 include one or more unnatural amino acids. In certain embodiments, the one or more HI V peptides comprising SEQ ID NOs; 1-43 include one or more synthetic amino acids.[000131] In certain embodiments, the peptides are conjugated to one or more agents or moieties. As used herein, the term “agent” or “moiety” is meant to encompass any molecule, chemical entity, composition, drug, therapeutic agent, chemotherapeutic agent, or biological agent capable of preventing, ameliorating, or treating a dysfunction or other medical condition. The term includes small molecule compounds, detectable labels, cytotoxic moieties, antisense oligonucleotides, siRNA reagents, antibodies, antibody fragments bearing epitope recognition sites, such as Fab, Fab’, F(ab’): fragments, Fv fragments, single chain antibodies, antibody mimetics (such as DARPins, affibody molecules, affilins, affitins, anticalins, avimers, fynomers, Kunitz domain peptides and monobodies), peptoids, aptamers; enzymes, peptides organic or inorganic molecules, natural or synthetic compounds and the like.[000132] In another embodiment, the moiety is a polyalkylene glycol moiety, for example, a PEG moiety and preferably a PEG-maleimide moiety. Pegylation moieties (or related polymers) can be, for example, polyethylene glycol (“PEG”), polypropylene glycol (“PPG”), polyoxyetbylated glycerol (“POG”) and other polyoxyethylated polyols, polyvinyl alcohol (“PVA”) and other polyalkylene oxides, polyoxyethylated sorbitol, or polyoxyethylated glucose. The polymer can be a homopolymer, a random or block copolymer, a terpolymer based on the monomers listed above, straight chain or branched, substituted or unsubstituted as long as it has at least one active sulfone moiety . The polymeric portion can be of any length or molecular weight, but these characteristics can affect the biological properties. Polymer average molecular weights particularly useful for decreasing clearance rates in pharmaceutical applications are in the range of 2,000 to 35,000 Daltons. In addition, if two groups are linked to the polymer, one at each end, the length of the polymer can impact upon the effective distance, and other spatial relationships, between the two groups. Thus, one skilled in the art can vary the length of foe polymer to optimize or confer the desired biological activity. PEG is useful in biologicalapplications for several reasons. PEG typically is clear, colorless, odorless, soluble in water, stable to heat, inert to many chemical agents, does not hydrolyze, and is nontoxic. Pegylation can improve phar macokinetic performance of a molecule by increasing the molecule's apparent molecular weight. The increased apparent molecular weight reduces the rate of clearance from the body following subcutaneous or systemic administration. In many cases, pegylation can decrease antigenicity and immunogenicity. In addition, pegylation can increase the solubility of a biologically-active molecule.[000133] In certain embodiments, die peptides are linked to one or more detectable moieties. Examples of detectable moieties include fluorescent moieties or labels, imaging agents, radioisotopic moieties, radiopaque moieties, and the like, e.g., detectable labels such as biotin, fluorophores, chromophores, spin resonance probes, or radiolabels. Exemplary fluorophores include fluorescent dyes (e.g., fluorescein, rhodamine, and die like;) and other luminescent molecules (e.g., luminal). A fluorophore may be environmentally-sensitive such that its fluorescence changes if it is located close to one or more residues in the modified protein that undergo structural changes upon binding a substrate (e.g., dansyl probes). Exemplary radiolabels include small molecules containing atoms with one or more low sensitivity nuclei (nC,l5N,2H,l25I,,:3I, "Tc, ^K,52Fe,<?Ga,68Ga,11’in and the like). Other useful moieties are known in the art.[000134] Examples of diagnostic moieties include detectable moieties suitable for revealing the presence of a disease or disorder. Typically, a diagnostic moiety allows for determining the presence, absence, or level of a molecule, for example, a target peptide, protein, or proteins, that is associated with a disease or disorder. Such diagnostics are also suitable for prognosing and / or diagnosing a disease or disorder and its progression.[000135] Examples of therapeutic moieties include, for example, anti-viral agents. An antiviral agent includes, without limitation: antibodies, aptamers, adjuvants, anti-sense oligonucleotides, chemokines, cytokines, gene-editing agents, immune stimulating agents, immune modulating agents, B-cell modulators, T-cell modulators, NK cell modulators, antigen presenting cell modulators, enzymes, siRNA’s, ribavirin, protease inhibitors, helicase inhibitors, polymerase inhibitors, helicase inhibitors, neuraminidase inhibitors, nucleoside reversetranscriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, purine nucleosides, chemokine receptor antagonists, interleukins, or combinations thereof.[000136] In certain embodiments, the peptides are conjugated to one or more agents comprising immunomodulatory agents. Immunomodulatory agents include tumor necrosis factor; interferon alpha, beta, and gamma; IL-2 and other cytokines; F42K and other cytokine analogs; or MIP-1 , MlP-lbeta, MCP-1, RANTES, checkpoint inhibitors, and other chemokines. The term “checkpoint inhibitor” means a group of molecules on the cell surface of CD4* and / or CD8* T cells that fine-tune immune responses by down-modulating or inhibiting an anti-tumor immune response. Immune checkpoint proteins are well known in the art and include, without limitation, CTLA-4, PM, VISTA, B7-H2, B7-H3, PD-LI, B7-H4, B7-H6, 2B4, ICOS, HVEM, PD-L2, CD160, gp49B, PIR-B, KIR family receptors, TIM-1, TIM-3, TIM-4, LAG-3, BTLA, SIRPalpha (CD47), CD48, 2B4 (CD244), B7.1, B7.2, ILT-2, ILT-4, TIGIT, and A2aR (see, for example, WO 2012 / 177624).klAnti-immune checkpoint inhibitor therapy” refers to the use of agents that inhibit immune checkpoint inhibitors. Inhibition of one or more immune checkpoint inhibitors can block or otherwise neutralize inhibitory signaling to thereby upregulate an immune response in order to more efficaciously treat HIV. Exemplary agents useful for inhibiting immune checkpoint inhibitors include antibodies, small molecules, peptides, peptidomimetics, natural ligands, and derivatives of natural ligands, that can either bind and / or inactivate or inhibit immune checkpoint proteins, or fragments thereof; as well as RNA interference, antisense, nucleic acid aptamers, etc. that can downregulate the expression and / or activity of immune checkpoint inhibitor nucleic acids, or fragments thereof. Exemplary agents for upregulating an immune response include antibodies against one or more immune checkpoint inhibitor proteins block the interaction between the proteins and its natural receptors); a non-activating form of one or more immune checkpoint inhibitor proteins (e.g., a dominant negative polypeptide); small molecules or peptides that block the interaction between one or more immune checkpoint inhibitor proteins and its natural receptors); fusion proteins (e.g. the extracellular portion of an immune checkpoint inhibition protein fused to the Fe portion of an antibody or immunoglobulin) that bind to its natural receptors); nucleic acid molecules that block immune checkpoint inhibitor nucleic acid transcription or translation; and the like. Such agents can directly block dieinteraction between the one or more immune checkpoint inhibitors and its natural receptors) (e.g., antibodies) to prevent inhibitory signaling and upregulate an immune response. Alternatively, agents can indirectly block the interaction between one or more immune checkpoint proteins and its natural receptors) to prevent inhibitory signaling and upregulate an immune response. For example, a soluble version of an immune checkpoint protein ligand such as a stabilized extracellular domain can binding to its receptor to indirectly reduce the effective concentration of the receptor to bind to an appropriate ligand. In one embodiment, anti-PD-1 antibodies, anti-PD-Ll antibodies, and anti-CTLA-4 antibodies, either alone or used in combination.[000137] In certain embodiments, the peptides are conjugated via a linker to each other or to die one or more agents. Single chain peptide linkers, comprised of from one to twenty amino acids joined by peptide bonds, can be used. In certain embodiments, the amino acids are selected from the twenty naturally-occurring amino acids. In certain other embodiments, one or more of the amino acids are selected from glycine, alanine, proline, asparagine, glutamine and lysine. In other embodiments, the linker is a chemical linker. In certain embodiments, said linker is a single chain peptide with an amino acid sequence with a length of at least 25 amino acids, or with a length of 32 to 50 amino acids.[000138] Conjugation may be performed using a variety of chemical linkers. For example, the monovalent binding entity or the fusion protein and the brain effector entity may be conjugated using a variety of bifunctional protein coupling agents such as N-succinimidy1-3-(2- pyridyldithio) propionate (SPDP), succinimidyl-4-(N-maleinridomethyl) cyclohexane- 1- carboxylate (SMCC), iminothiolane ( IT), bifunctional derivatives of imidoestera (such as dimethyl adipimidate HC1), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis- diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylencdiamine), diisocyanates (such as toluene 2 ,6-di isocyanate), and bis-active fluorine compounds (such as 1 ,5-difluoro-2,4- dinitrobenzene). The linker may be a “cleavable linker” facilitating release of die effector entity upon delivery to the brain. For example, an acid-labile linker, peptidase-sensitive linker,photolabile linker, dimethyl linker or disulfide-containing linker (Chari et al, Cancer Res. 52: 127-131 (1992); U.S. Pat. No. 5,208,020) may be used.|G00139] Covalent conjugation can either be direct or via a linker. In certain embodiments, direct conjugation is by construction of a protein fusion (i.e., by genetic fusion of the two genes encoding the peptides and / or the one or more agents expressed as a single protein). In certain embodiments, direct conjugation is by formation of a covalent bond between a reactive group on the SEQ ID NOs: 1-43 variants or functional fragments thereof and a corresponding group or acceptor on the agent. In certain embodiments, direct conjugation is by modification (i.e., genetic modification) of one of foe two molecules to be conjugated to include a reactive group (as nonlimiting examples, a sulfhydryl group or a carboxyl group) that forms a covalent attachment to the other molecule to be conjugated under appropriate conditions. As one non-limiting example, a molecule (i.e., an amino acid) with a desired reactive group (i.e., a cysteine residue) may be introduced. Methods for covalent conjugation of nucleic acids to proteins are also known in tire art (Le., photocrosslinking, see, e.g., Zatsepin et al. Russ. Chern. Rev. 74: 77-95 (2005)).[000140] Nucleic Acids[000141] Also provided herein are nucleic acids encoding the peptides comprising any one of HIV peptides comprising SEQ ID NOs: 1-43 variants or functional fragments thereof disclosed herein, as well as vectors, host cells, and expression systems. The term “nucleic acid” as used herein refers to a polymeric fonn of nucleotides of any length, either ribonucleotides or desoxyribonucleotides. Thus, this term includes, but is not limited to, single-, double- or multistranded DNA or RNA, genomic DNA, cDNA, DNA-RNA hybrids, or a polymer comprising purine and pyrimidine bases, or other natural, chemically or biochemically modified, nonnatural, or deri vatized nucleotide bases.[000142] The nucleic acids encoding the encoding foe peptides comprising any one of HIV peptides comprising SEQ ID NOs: 1-43, variants or functional fragments thereof disclosed herein may be, e.g., DNA, cDNA, RNA, synthetically produced DNA or RNA, or a recombniantly produced chimeric nucleic acid molecule comprising any of those polynucleotides either alone or in combination. For example, provided is an expression vector comprising a polynucleotide sequence encoding HIV peptides comprising SEQ ID NOs: 1-43 variants or functional fragmentsthereof disclosed herein described herein operably linked to expression control sequences suitable for expression in a eukaryotic and / or prokaryotic host cell,[000143] The term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. A “vector” includes, but is not limited to, a viral vector, a plasmid, an RNA vector or a linear or circular DNA or RNA molecule which may consists of a chromosomal, non-chromosomal, semi-synthetic or synthetic nucleic acids. In some embodiments, the employed vectors are those capable of autonomous replication (episomal vector) and / or expression of nucleic acids to which they are linked (expression vectors). Large numbers of suitable vectors are known to those of skill in the an and commercially available. Viral vectors include retrovirus, adenovirus, parvovirus (e.g., adeno associated viruses, AAV), coronavirus, negative strand RNA viruses such as orthomyxovirus (e.g., influenza virus), rhabdovirus (e. g„ rabies and vesicular stomatitis virus), paramyxovirus (e.g., measles and Sendai), positive strand RNA viruses such as picomavirus and alphavirus, and double-stranded DNA viruses including adenovirus, herpesvirus (e.g., Herpes Simplex virus types 1 and 2, Epstein-Barr virus, cytomegalovirus), and poxvirus (e.g., vaccinia, fowlpox and canarypox). Other viruses include Norwalk virus, togavirus, flavivirus, reoviruses, papovavirus, hepadnavirus, and hepatitis virus, for example. Examples of retroviruses include avian leukosissarcoma, mammalian C-type, B-type viruses, D type viruses, HTLV-BLV group, lentivirus, and spumavirus.[000144] A variety of expression vectors have been developed for the efficient synthesis polypeptides such as encoding the peptides comprising any one of HIV peptides comprising SEQ ID NOs: 1 -43, variants or functional fragments thereof in prokaryotic cells such as bacteria and in eukaryotic systems, including but not limited to yeast and mammalian cell culture systems have been developed. The vectors can comprise segments of chromosomal, non-chromosomal and synthetic DNA sequences. Also provided are cells comprising expression vectors for the expression of the encoding the peptides comprising any one of HIV peptides comprising SEQ ID NOs: 1-43, variants or functional fragments thereof disclosed herein.[00014S] The encoding the peptides comprising any one of HIV peptides comprising SEQ ID NOs: M3, variants or functional fragments thereof are typically produced by recombinantexpression. For example, a nucleic add encoding any one of HIV peptides comprising SEQ ID NOs: 1-43, variants or functional fragments thereof are inserted into an expression vector and operatively linked to an expression control sequence. Expression control sequences include, but are not limited to, promoters (e.g., naturally-associated or heterologous promoters), signal sequences, enhancer elements, and transcription termination sequences. Preferably, the expression control sequences are eukaryotic promoter systems in vectors capable of transforming or transfecting eukaryotic host cells. Once the vector has been incorporated into the appropriate host, the host is maintained under conditions suitable for high level expression of the nucleotide sequences, and the collection and purification of the cross-reacting antibodies.[000146] These expression vectors are typically replicable in the host organisms either as episomes or as an integral part of the host chromosomal DNA. Commonly, expression vectors contain selection markers (e.g., ampicillin-resistance, hygromycin-resistance, tetracycline resistance or neomycin resistance) to permit detection of those cells transformed with the desired DNA sequences (see, e.g;, Itakura et al., U.S. Pat. No. 4,704,362).[000147] The expression of die encoding the peptides comprising any one of HIV peptides comprising SEQ ID NOs: 1-43, variants or functional fragments thereof disclosed herein can occur in either prokaryotic or eukaryotic cells. Suitable hosts include bacterial or eukaryotic hosts, including yeast, insects, fungi, bird and mammalian cells either in vivo, or in situ, or host cells of mammalian, insect, bird or yeast origin. The mammalian cell or tissue can be of human, primate, hamster, rabbit, rodent, cow, pig, sheep, horse, goat, dog or cat origin, but any other mammalian cell may be used.[000148] E, eoli is one prokaryotic host particularly useful for cloning the polynucleotides (e.g., DNA sequences) disclosed herein. Other microbial hosts suitable for use include bacilli, such as Bacillus subtilus, and other enterobacteriaceae, such as Salmonella, Senatia, and various Pseudomonas species.[000149] Other microbes, such as yeast, are also useful for expression of the encoding die peptides comprising any one of HIV peptides comprising SEQ ID NOs: 1 -43, variants or functional fragments thereof disclosed herein. Saccharomyces and Pichia are exemplary yeast hosts, with suitable vectors having expression control sequences (e.g., promoters), an origin ofreplication, termination sequences and the like as desired. Typical promoters include 3- phosphoglycerate kinase and other glycolytic enzymes. Inducible yeast promoters include, among others, promoters from alcohol dehydrogenase, isocytochrome C, and enzymes responsible for methanol, maltose, and galactose utilization.[000150] Further, by use of, for example, the yeast ubiquitin hydrolase system, in viva synthesis of ubiquitin-transmembrane polypeptide fusion proteins can be accomplished. The fusion proteins So produced can be processed in viva or purified and processed w vi / TO, allowing synthesis of encoding the peptides comprising any one of HI V peptides comprising SEQ ID NOs: 1-43 , variants or functional fragments thereof with a specified amino terminus sequence.Moreover, problems associated with retention of initiation codon-derived methionine residues in direct yeast (or bacterial) expression maybe avoided. Sabin et al, 7 Bio / Technol. 705 (1989); Miller et al, 7 Bio / Technol. 698 (1989).[000151] Any of a series of yeast gene expression systems incorporating promoter and termination elements from the actively expressed genes coding for glycolytic enzymes produced in large quantities when yeast is grown to mediums rich in glucose can be utilized to obtain recombinant HIV antibodies or peptides of the present disclosure. Known glycolytic genes can also provide very efficient transcriptional control signals. For example, the promoter and terminator signals of the phosphoglycerate kinase gene can be utilized.[000152] Production of encoding the peptides comprising any one of H IV peptides comprising SEQ ID NOs: 1 -43, variants or functional fragments thereof disclosed herein in insects can be achieved. For example, by infecting the insect host with a baculovirus engineered to express a transmembrane polypeptide by methods known to those of skill. See Ausubel et al., 1987, 1993,[000153] In addition to microorganisms, mammalian tissue culture may also be used to express and produce encoding the peptides comprising any one of HIV peptides comprising SEQ ID NOs: M3, variants or functional fragments thereof disclosed herein. See Whmacker, From Genes to Clones, VCH Publishers, N.Y., N.Y. (1987). Eukaryotic cells can actually be preferred, because a number of suitable host cell lines capable of secreting heterologous proteins have been developed in the art, and include CHO cell lines, various COS cell lines, HeLa cells, 293 cells.myeloma cell lines, transformed B-cells, and hybridomas. Expression vectors for these cells can include expression control sequences, such as an origin of replication, a promoter, and an enhancer (Queen et al., Immunol. Rev. 89:49 (1986)), and necessary processing information sites, such as ribosome binding sites, RN A splice sites, polyadenylation sites, and transcriptional terminator sequences. Preferred expression control sequences are promoters derived from immunoglobulin genes, SV40, adenovirus, bovine papilloma virus, cytomegalovirus and die like. See Co et al, J. Immunol. 148:1149 (1992).[000154] Alternatively, nucleotide sequences encoding die peptides comprising any one of HIV peptides comprising SEQ ID NOs: M3, variants or functional fragments thereof disclosed herein can be incoiporated in transgenes for introduction into the genome of a transgenic animal and subsequent expression in die milk of the transgenic animal (see, e.g., Deboer et al., U.S. Pat. No. 5,741,957, Rosen, U.S. Pat No. 5,304,489, and Meade et al., U.S. Pat. No. 5,849,992). Suitable transgenes include coding sequences for any one HIV peptides comprising SEQ ID NOs: 1 -43, variants or functional fragments thereof in operable linkage with a promoter and enhancer from a mammary gland specific gene, such as casein or beta lactoglobulin.[000155] Additionally, plants have emerged as a convenient, safe and economical alternative main-stream expression systems for polypeptide production, which are based on large scale culture of microbes or animal cells, encoding the peptides comprising any one HIV peptides comprising SEQ ID NOs: M3, variants or functional fragments thereof disclosed herein can be expressed in plant cell culture, or plants grown conventionally. The expression in plants may be systemic, limited to sub-cellular plastids, or limited to seeds (endosperms). See, e.g., U.S. Patent Pub. No. 2003 / 0167531; U.S. Patent Nos. 6,080,560 and 6,512,162; and WO 0129242.[000156] The vectors containing the polynucleotide sequences of interest can be transferred into the host cell by well-known methods, which vary depending on the type of cellular host. For example, calcium chloride transfection is commonly utilized for prokaryotic cells, whereas calcium phosphate treatment, electroporation, lipofection, biolistics or viral-based transfection may be used for other cellular hosts, (See generally Sambrook et al., Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Press, 2nd ed., 1989). Other methods used to transform mammalian cells include the use of polybrene, protoplast fusion, liposomes, electroporation, andmicroinjection (see generally, Sambrook et at, supra). For production of transgenic animals, transgenes can be microinjected into fertilized oocytes, or can be incorporated into the genome of embryonic stem cells, and the nuclei of such cells transferred into enucleated oocytes.[000157] Once expressed, the encoding the peptides comprising any one of HI V peptides comprising SEQ ID NOs: M3, variants or functional fragments thereof disclosed herein can be purified according to standard procedures of the art, including ammonium sulfate precipitation, affinity columns, column chromatography, HPLC purification, gel electrophoresis and the like (see generally Scopes, Protein Purification (Springer-Veriag, N.Y., (1982)). Substantially pure immunoglobulins of at least about 90 to 95% homogeneity are preferred, and 98 to 99% or more homogeneity most preferred, for pharmaceutical uses.[000158] In certain embodiments, the isolated cell comprises an autologous cell, an allogeneic cell, a haplotype matched cell, a haplotype mismatched cell, a haplo-identical cell , a xenogeneic cell, cell lines or combinations thereof. In some embodiments, the cells are derived from cell tines, e.g., T cell lines. The cells in some embodiments are obtained from a xenogeneic source, for example, from mouse, rat, non-human primate, or pig.[000159] Accordingly, the cells in some embodiments are primary cells, e.g., primary human cells. The samples include tissue, fluid, and other samples taken directly from the subject, as well as samples resulting from one or more processing steps, such as separation, centrifugation, genetic engineering (e.g. transduction with viral vector), washing, and / or incubation. The biological sample can be a sample obtained directly from a biological source or a sample that is processed. Biological samples include, but are not limited to, body fluids, such as blood, plasma, serum, cerebrospinal fluid, synovial fluid, urine and sweat, tissue and organ samples, including processed samples derived therefrom.[000166] In some aspects, the sample from which the cells are derived or isolated is blood or a blood-derived sample or is or is derived from an apheresis or leukapheresis product Exemplary samples include whole blood, peripheral blood mononuclear ceils (PBMCs), leukocytes, bone marrow, thymus, tissue biopsy, tumor, leukemia, lymphoma, lymph node, gut associated lymphoid tissue, mucosa associated lymphoid tissue, spleen, other lymphoid tissues, liver, lung, stomach, intestine, colon, kidney, pancreas, breast, bone, prostate, cervix, testes,ovaries, tonsil, or other organ, and / or cells derived therefrom. Samples include, in die context of cell therapy, e.g., adoptive cell therapy, samples from autologous and allogeneic sources. [0 00161] Antibodies{000162] Also provided herein are antibodies which specifically bind to any one or more peptides comprising SEQ ID NOs; M3,{000163] Accordingly, in one aspect, the disclosure pertains to antibodies, e.g., monoclonal antibodies or fragments thereof, which specifically bind any one or more peptides comprising SEQ ID NOs: M3.{000164] In one aspect, die disclosure pertains to antibodies or fragments thereof, wherein the antibodies or fragments thereof are monoclonal antibodies, polyclonal antibodies. In one embodiment, the antibodies or fragments thereof are human or humanized antibodies. In one embodiment, the antibodies or fragments thereof are chimeric antibodies. In one embodiment, the antibodies or fragments thereof comprise a human heavy chain constant region and a human light chain constant region. In one embodiment, the antibodies or fragments thereof are an IgG isotype. In another embodiment, the antibodies can be of any isotype (e.g., IgG, IgE, IgM, IgD, and IgA), dass (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or derivative s thereof. In one embodiment, the antibodies or fragments thereof are selected from the group consisting of a Fab, F(ab2)', F(ab)2' and scFV. In one embodiment, the antibodies or fragments thereof are selected from the group consisting of a monoclonal antibody, a polyclonal antibody, a chimeric antibody, a humanized antibody, and a synthetic antibody. In one embodiment, the antibody or fragment thereof is a human or humanized antibody.{000165] Methods of Treating[000166] In embodiments, the methods disclosed herein are useful for preventing HIV infection and / or treating subjects infected with HIV.[000167] In certain embodiments, the peptides are used to generate antibodies which specifically bind to any one or more peptides comprising SEQ ID NOs: .1 -43. These antibodies can be administered to a subject either alone or in combination with the peptides.[000168J In certain embodiments, the one or more peptides induce an immune response to HIV. In certain embodiments, the method further comprises administering one or moresecondary therapeutic agents. In certain embodiments, the one or more secondary therapeutic agents comprise one or more anti-viral agents. In certain embodiments, the one or more antiviral agents comprise antibodies, aptamers, adjuvants, anti-sense oligonucleotides, chemokines, cytokines, gene-editing agents, immune stimulating agents, immune modulating agents, B-cell modulators, T-cell modulators, NK cell modulators, antigen presenting cell modulators, enzymes, siRNA’s, ribavirin, protease inhibitors, helicase inhibitors, polymerase inhibitors, helicase inhibitors, neuraminidase inhibitors, nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, purine nucleosides, chemokine receptor antagonists, interleukins, or combinations thereof. In certain embodiments, the one or more peptides are formulated with a pharmaceutical carrier, a delivery vehicle or combinations thereof,[000169] In certain embodiments, a therapeutically effective amount of the HIV peptides comprising SEQ ID NOs: 1-43, variants or functional fragments thereof herein is administered to a subject in need thereof. A therapeutically effective amount as used herein would also include an amount sufficient to delay the development of a symptom of the disease, alter the course of a symptom of disease (for example but not limited to, slow the progression of a symptom of the disease), or reverse a symptom of disease. Thus, it is not possible to specify the exact “therapeutically effective amount” that is effective for all patients and all conditions. However, for any given case, an appropriate “therapeutically effective amount” can be determined by one of ordinary skill in the art using only routine experimentation. Effective amounts, toxicity, and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining die LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dosage can vary depending upon the dosage form employed and the route of administration utilized. The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50 / ED50. Compositions and methods that exhibit large therapeutic indices are prefared. A therapeutically effective dose can be estimated initially from cell culture assays. Also, a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (Le„ the concentration of foe agenlfs) which achieves a half-maximal inhibition of symptoms) as determined in cell culture, or in an appropriate animal model. Levelsin plasma can be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay. The dosage can be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment[000170] The HIV peptides comprising SEQ ID NOs: 1 -43, variants or functional fragments thereof described herein can be isolated agents, meaning that the agents are substantially pure and are essentially free of other substances with which they may be found in nature or in vivo systems to an extent practical and appropriate for their intended use. In particular , die agents are sufficiently pure and are sufficiently free from other biological constituents of their host cells so as to be useful in, for example, producing pharmaceutical preparations. Because an isolated agent may be admixed with a pharmaceutically acceptable carrier in a pharmaceutical preparation, the agents may comprise only a small percentage by weight of the preparation.[000171] In some embodiments, the HIV peptides comprising SEQ ID NOs: 1-43, variants or functional fragments thereof described herein are administered to a subject by any mode of administration that delivers the agent systemically or to a desired surface or target, and can include, but is not limited to, injection administration and infusion instillation. “Injection” includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intracerebro spinal, and mtrastemal injection and infusion.[000172] The phrases “parenteral administration” and “administered parenterally” as used herein, refer to modes of administration other than enteral and topical administration, usually by injection. The phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” as used herein refer to the administration of an agent other than directly into a target site, tissue, or organ, such that it enters the subject’s circulatory system and, thus, is subject to systemic metabolism and other like processes.[000173] In certain embodiments, a dose of one or more HIV peptides comprising SEQ ID NOs: 1-43, variants or functional fragments thereof disclosed herein is administered to a subject every day, every other day, every couple of days, every third day, once a week, twice a week,three times a week, once every two weeks, or once a month. In other embodiments, two, three or four doses of one or more HIV peptides comprising SEQ ID NOs: M3, variants or functional fragments thereof disclosed herein is administered to a subject every day, every couple of days, every third day, once a week, once every two weeks or once a month. In some embodiments, a dose(s) of one or more HIV peptides comprising SEQ ID NOs; M3, variants or functional fragments thereof disclosed herein is administered for 2 days, 3 days, 5 days, 7 days, 14 days, 21 days or 28 days. In certain embodiments, a dose of a compound or a composition is administered for 1 month, 1.5 months, 2 months, 2.5 months, 3 months, 4 months, 5 months, 6 months or more.[000174] For the clinical use of the methods described herein, administration of one or more HIV peptides comprising SEQ ID NOs: M3, variants or functional fragments thereof can include formulation into pharmaceutical compositions or pharmaceutical formulations for parenteral administration, e.g., intravenous or other mode of administration. In some embodiments, one or more HIV peptides comprising SEQ ID NOs: 1-43, variants or functional fragments thereof can be administered along with any pharmaceutically acceptable carrier compound, material, or composition which results in an effective treatment in the subject. Thus, a pharmaceutical formulation for use in the methods described herein can contain any one of one or more HIV peptides comprising SEQ ID NOs: 1 -43, variants or functional fragments thereof as described herein in combination with one or more pharmaceutically acceptable ingredients.[000175] Provided herein is a pharmaceutical composition comprising one or more HIV peptides comprising SEQ ID NOs: 1-43 , variants or functional fragments thereof disclosed herein and a pharmaceutically acceptable excipient. The phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which ate, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit-risk ratio. The phrase*’ “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, media, encapsulating material, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), orsolvent encapsulating material, involved in maintaining the stability, solubility, or activity of, an agent Each earner must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically -acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose, microcrystalline cellulose and cellulose acetate; ( 4) powdered tragacanth; (5) malt; (6) gelatin; (7) excipients, such as cocoa butter and suppository waxes; (8) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil ; (9) glycols, such as propylene glycol; (10) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol (PEG); (11) esters, such as ethyl oleate and ethyl laurate; (12) agar, (13) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (14) alginic acid; (15) pyrogen-free water; (16) isotonic saline; (17) Ringer's solution; (19) pH buffered solutions; (20) polyesters, polycarbonates and / or polyanhydrides; (21) bulking agents, such as polypeptides and amino acids (22) serum components, such as serum albumin, HDL and LDL; (23) C2-C 12 alcohols, such as ethanol; and (24) other non-toxic compatible substances employed in pharmaceutical formulations. Release agents, coating agents, preservatives, and antioxidants can also be present in the formulation. The terms such as “excipient”, “carrier”, “pharmaceutically acceptable carrier” or the like are used interchangeably herein. The agents described herein can be specially formulated for administration of the compound to a subject in liquid form, including those adapted for parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; Additionally, the polypeptide agent can be implanted into a patient or injected using a dreg delivery system. See, for example, Urquhart, et at, Ann. Rev. Pharmacol. Toxicol. 24: 199-236 (1984); Lewis, ed. “Controlled Release of Pesticides and Pharmaceuticals” (Plenum Press, New- York, 1981); U.S. Pat. No. 3,773,919; and U.S. Pat. No. 353,270,960. Parenteral dosage forms of an agent can also be administered to a subject by various routes, including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Since administration of parenteral dosage forms typically bypasses the patient's natural defensesagainst contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, controlled- release parenteral dosage forms, and emulsions. Suitable vehicles that can be used to provide parenteral dosage forms of die disclosure are well known to those skilled in the art. Examples inchide, without limitation: sterile water; water for injection USP; saline solution; glucose solution; aqueous vehicles such as but not limited to, sodium chloride injection, Ringer's injection, dextrose Injection, dextrose and sodium chloride injection, and lactated Ringer's injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and propylene glycol; and non-aqueous vehicles such as, but not limited to, com oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.[000176] lire pharmaceutical compositions provided herein comprising one or more HIV peptides comprising SEQ ID NOs: 1-43, variants or functional fragments thereof and a pharmaceutically acceptable carrier may comprise one or more HIV peptides comprising SEQ ID NOs: 1-43, variants or functional fragments thereof at various concentrations. For example, the compositions may comprise one or more HIV peptides comprising SEQ ID NOs: 1-43, variants or functional fragments thereof at 10 mg / ml to 200 mg / ml, 25 mg / ml to 130 mg / ml, 50 mg / ml to 125 mg’ ml, 75 mg / ml to 110 mg / ml, or 80 mg / ml to 100 mg / ml. The compositions also may comprise any one of one or more HIV peptides comprising SEQ ID NOs: M3, variants or functional fragments thereof at about 10 mg / ml, 20 mg / ml, 30 mg / ml, 40 mg / ml, 50 mg / ml, 60 mg / ml, 70 mg / ml, 80 mg / ml, 90 mg / ml, 100 mg / ml, 110 mg / ml, 120 mg / ml, 130 mg / ml, 140 mg / ml, or 150 mg / ml[000177] In some embodiments, the compositions comprising the one or more HIV peptides comprising SEQ ID NOs: 1 -43, variants or functional fragments thereof and the pharmaceutically acceptable carrier are lyophilized and provided in a coneposition for reconstitution prior to administration.[000178] In one aspect, the one or more HIV peptides comprising SEQ ID NOs: 1-43, variants or functional fragments thereof is administered with an additional therapeutic agentSuch additional agents include, but are not limited to, a surgical therapy, chemotherapy, radiation therapy, cryotherapy, hyperthermia treatment, phototherapy, radioablation therapy, hormonal therapy, immunotherapy, small molecule therapy, receptor kinase inhibitor therapy, anti- angiogenic therapy, cytokine therapy or a biological therapies such as monoclonal antibodies, siRNA, miRNA, antisense oligonucleotides, ribozymes or gene therapy. Without limitation the biological therapy may be an anti-viral therapy, gene therapy a cell death protein gene therapy, a cell cycle regulator gene therapy, a cytokine gene therapy, a toxin gene therapy, an immunogene therapy, a suicide gene therapy, a prodrug gene therapy, an ami-cellular proliferation gene therapy, an enzyme gene therapy, or an anti-angiogenic factor gene therapy. Immunomodulatory agents include tumor necrosis factor; interferon alpha, beta, and gamma; IL-2 and other cytokines; checkpoint inhibitors; F42K and other cytokine analogs; or MIP-1, MIP-1 beta, MCP- 1 , RANTES, and other chemokines.[000179] lite administration of one or more HIV peptides comprising SEQ ID NOs: 1 -43, variants or functional fragments thereof and the additional therapeutic agent may be concurrently or consecutively. The administration of one or more HIV peptides comprising SEQ ID NOs: 1- 43, variants or functional fragments thereof and the additional therapeutic agent may be separately or as a mixture.{000180] It is to be understood that this invention is not limited to the particular molecules, compositions, methodologies, or protocols described, as these may vary. Any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention. It is further to be understood that the disclosure of the invention in this specification includes all possible combinations of such particular features. For example, where a particular feature is disclosed in the context of a particular aspect or embodiment of the invention, or a particular claim, that feature can also be used, to the extent possible, in combination with and / or in the context of other particular aspects and embodiments of the invention, and in the invention generally.[000181] Where reference is made herein to a method comprising two or more defined steps, the defined steps can be carried out in any order or simultaneously (except where fee context excludes that possibility), and fee method can include one or more other steps which arecarried out before any of the defined steps, between two of the defined steps, or after all the defined steps (except where the context excludes those possibilities).EXAMPLES[000182] EXAMPLE 1 : IDENTIFICATION OF ANTIBODY TARGETS ASSOCIATED WITH LOWER HIV VIRAL LOAD AND VIREMIC CONTROL[000183] VirScan is a massively multiplexed assay that can be used to quantify antibody responses to peptide targetsF across die HIV genome (47, 63). In prior study that included longitudinal samples collected from 14 days to 8.7 years after HIV infection, itwas found that antibody breadth (i.e., the number of unique epitopes targeted) increased early in infection and then declined or stabilized. Persons who had a decline in antibody breadth 9 months to 2 yearn after were more likely to start antiretroviral treatment (ART). In addition , a faster decline in antibody breadth was associated with a shorter time to ART initiation (44).[000184] In a subsequent study, VirScan twas used to characterize the fine specificity of HIV antibody responses in persons with established HIV infection (64). That study identified seven clusters of homologous peptides that represented the primary antibody targets in both viremic controllers and non-controllers who were not on ART (64). The study also found that higher levels of antibody reactivity to a target in gag p !7 were associated with reduced plasma viral load (64). The participants evaluated in that study had HIV infection of unknown duration. Because antibody titer, avidity, and breadth vary in persons infected for different periods of time (2, 47), differences in infection duration among the study participants may have confounded the results of that study.[000185] In this report, we extended our prior work by characterizing antibody responses in a cohort of PWH who were known to be infected for 1-2 years and explored whether specific patterns of antibody reactivity were associated with low viral load and HIV control. This cohort included viremic controllers and non-controllers who acquired HIV infection during the HIV Prevention Trials Network (HPTN) 071 (PopART) trial (65). This report used an unbiased approach to identify peptides that are more frequently targeted in HIV controllers and persons with lower viral loads. Findings from this study could support future research evaluating whether specific HIV antibodies play a causative role in viral containment.[600186] Results[000187] Study cohort[000188] This report evaluated a subset of the 978 participants who acquired HIV infection during the HPTN 071 trial (65). The study cohort included 77 seroconverters (13 controllers [viral load <2,000 copies / mL with no ARV drugs detected at two annual study visits], 64 non-controllers [viral load >2,000 copiesrml. with no ARV drugs detected at two annual study visits]). VirScan testing was performed using samples collected at die second HIV-positive study visit (infection duration: 1-2 years). The mean viral load at this visit was 802 copies / mL for the controller group (interquartile range [IQR]; 399, 1 , 180) and 101 ,393 copies / mL for the non-contrnller group (IQR: 7,110, 80,098). There was no significant difference between groups for biological sex, age, or study country (Table 2).[060189] Figure 1 provides an overview of the analyses in this report. Antibody responses were first characterized for the study cohort and were then evaluated at the peptide level (reactivity to a single peptide from the VirScan library), epitope level (reactivity to a common amino acid sequence shared by overlapping peptides), and aggregate level for associations with HIV viral load and HIV controller status.[000196] HIV antibody reactivity in the study cohort[000191] VirScan was used to characterize antibody responses to HIV peptides in the 77 study participants (Figure 2). Ten clusters of HIV peptides had high levels of antibody reactivity (defined as having two or more peptides with mean antibody reactivity [log 10 fold change] >0.5). Seven of these clusters were identified in a prior report that evaluated antibody responses among HIV controllers and non-controllers with unknown duration of infection (cluster 1: gag [pl 7; N- terminus); cluster 2: gag [p24; Oterminus]; cluster 3: integrase (C-terminusj; cluster 4: vpu [N- terminus]; cluster 5: envelope [gpl20; V3 loop and CD4 binding loop]; cluster 6: envelope [gpl20 / gp41; V5 and fusion peptide]; cluster 7: envelope [gp4l; C-terminal heptad repeat region, HR2]) (64). The three additional peptide clusters identified in this report had high levels of antibody reactivity to the following targets: cluster a: the first zinc finger region of the nucleocapsid protein, gag p7; cluster b: the bi -terminus of protease, including the active site; and cluster c; the N-tenninus of integrase.[000192] Associations between antibody reactivity and HIV viral load[000193] Peptide-level responses: We next evaluated whether antibody reactivity to individual peptides was associated with HIV viral load (Figure 3). This analysis included die 1 ,235 HIV peptides with significant antibody reactivity (adjusted fold change >1) that were detected in samples from one or more participants. Antibody reactivity to 43 peptides was significantly associated with viral load after multiple testing correction to control for the false discovery rate (q<0.05, p<0.00158). Using the Bonferroni correction method, antibody reactivity to one peptide remained significantly associated with viral load (p=3.1 x IO"6; Peptide ID: 18306). For all 43 peptides, higher levels of antibody reactivity were associated with lower viral loads.[000194] The 43 peptides were located in the six clusters of homologous peptides that had high levels of mean antibody reactivity for the cohort (Figure 1, Table 3). Twenty-six peptides were located in gag (four in foe N-terminal region of pl 7 [cluster I J, five in the C-terminal region of p24 [cluster 2] and 17 in foe C-terminal region of p7 [cluster a]). Three peptides were located in the C-terminal region of integrase (cluster 3). The remaining 14 peptides were located in env (seven in the region spanning foe V5 loop of gpl 20 and fusion peptide of gp41 [cluster 6] and seven in the HR2 of gp41 [cluster 7J).[000195] Epitope-level responses; The program eptiopeffndr (75) was used to identify common epitopes for foe peptides in each cluster (Table 1). The number of peptides with each epitope ranged from two to 17. Clusters 1, 2, 3, and 7 each contained one common epitope shared by peptides in foe cluster, while Clusters a and 6 each contained two common epitopes. The association between antibody reactivity and HIV viral load remained statistically significant when the analysis was performed at the epitope level for each of foe eight epitopes. Estimated effect for the association ranged from -1.430 to -0.520; this measure indicates foe change m viral load (loglO scale) associated with one unit increase in antibody reactivity (loglO scale) (i.e., if foe estimated effect were -0.5, then when comparing two participants that differ tenfold in antibody reactivity, we would expect foe participant with higher reactivity to have a 32% [104*5] lower viral load).[000196] Table 1. HIV antibody epitopes associated with lower HIV viral load.[000197] The table shows the features of the eight epitopes where higher antibody reactivity was associated with lower viral load. These epitopes were identified from 43 peptides located m six clusters (Figure 3; Table 3). HIV gene and protein locations were determined based on full- length peptides. Sequence logos were generated using ggseqlogo vOJ (76). Estimated effect and associated p-vahies were calculated using simple linear regression between antibody reactivity and viral load. The estimated effect indicates the change in viral load (log 10 scale) associated with a unit increase in antibody reactivity (loglO scale). Negative values indicate that a unit increase in antibody reactivity was associated with a decrease in viral load. Abbreviations: gp: glycoprotein; HR: helical region; 95% Cl: 95% confidence intervals.[000198] Aggregate responses: We next evaluated whether aggregate antibody reactivity to the epitopes described in Table 1 was associated with HIV viral load (Figure 4). We found a significant association between the total number of epitopes targeted and HIV viral load (estimated effect: -0.15, 95% CI: -0.26, -0.04, p::=0.008); here, estimated effect indicates die change in viral load (loglO scale) associated with one additional targeted epitope. There was also a significant association between participant mean antibody reactivity (fold change) across all eight epitopes and HIV viral load (estimated effect: -1.76, 95% CI: -2.38, -1.15, p<0.001 ); here, estimated effect indicates the change in viral load (loglO scale) associated with one unit increase in mean antibody reactivity (login scale).[000199] The VARscore is a composite value that combines VitScan data for all peptide targets across a viral genome; this provides an aggregate measure of the overall breadth and strength of antibody reactivity to a virus (73). We next evaluated whether HIV-1 VARscore wasassociated with HIV viral load (Figure 4). There was a significant association between HIV-1 VARscore and HIV viral load (estimated effect: -0.37, 95% CI: -0.59, -0.15, p=0.001); here, estimated effect indicates the change in viral toad (loglO scale) associated with one unit increase in HIV- 1 VARscore.[000200] Associations in the non-controller participant subset: We next evaluated whether die associations between antibody reactivity and HIV viral load were still observed when data from the 13 controllers were removed from the analysis. At the peptide level, we analyzed the 1,1.83 HIV peptides that had significant antibody reactivity in samples from one or more of the 64 noncontrollers (Figure 7); this analysis did not identify any peptides where antibody reactivity was significantly associated with viral load after multiple testing correction. At the epitope-level, associations between antibody reactivity and viral load were still observed when the 13 controllers were excluded (Table 3). The association remained statistically significant for five of the eight epitopes (epitopes 2.1, 3.1, 6.1, 6.2, and 7.1; estimated effect range: <0.977 to -0.352); the association between epitope-level antibody reactivity to the other three epitopes (1.1 , a, 1 and a.2) and viral load was not significant.[000201] As a final step in this portion of the analysis, we evaluated whether aggregate antibody reactivity was associated with viral load when the 13 controllers were excluded (Figure 8). In this analysis, the association between the number of epitopes targeted (adjusted fold change >1 ) and viral load was not significant (estimated effect: -0.08, 95% CI: -0.17, 0.01 , p:::0.094); here, estimated effect indicates the change tn viral load (loglO scale) associated with one additional targeted epitope. In contrast, we still observed a significant association between participant mean antibody reactivity (fold change) across all eight epitopes and viral load for the non-controller group (estimated effect: -1.17, 95% CT; -1.79, -0.54; p<0.001); here, estimated effect indicates the change in viral load (loglO scale) associated with one unit increase in mean antibody reactivity (loglO scale). The association between HIV-1 VARscore and viral load also remained significant for the non-controller subset (estimated effect: -0.24, 95% CI: -0.44, -0.05; p:::0.016); here, estimated effect indicates the change in viral toad (loglO scale) associated with one unit increase in HIV-1 VARscore.[000202 ] Associations between antibody reactivity and HIV controller status[000203] Epitope-level responses[000204] We next compared antibody reactivity to each of die eight epitopes in controllers (n=::I3) vs. non-controllers (n::s64) (Figure 5). Panel A shows the frequency of antibody reactivity (adjusted fold change >1) to each of the epitopes in the two groups. Antibody reactivity to two epitopes was observed more frequently among controllers than nou-conttollers (epitope a J : 13 / 13 [100.0%] vs. 42 / 64 [65.6%], p-0.015; epitope a.2; 13 / 13 [100.0%] vs.45 / 64 [70.3%], p-0.03); for the remaining epitopes, there was no significant difference in the prevalence of antibody reactivity between groups. Panel B shows mean antibody reactivity (fold change) to each of the eight epitopes in the two groups. Mean antibody reactivity to seven epitopes was higher among controllers than non-controllers (epitope 1.1: 24.7 vs. 9.3, p:::0.001; epitope 2.1: 22.2 vs. 10.3, p=0.009; epitope a.1: 27.2 vs. 9.2, p=0.001; epitope a.2: 28.4 vs. 10.1, p=0.001; epitope 3.1: 27.4 vs. 17.4, p-0.007; epitope 6.2: 16.4 vs 9.0, p=0.017; epitope 7.1: 38.2 vs. 28.1, p=0.025); there was no significant difference in mean antibody reactivity to epitopes 6.1 between the two groups (which may be due to low power; epitope 6.1. only had two peptides, the lowest among all epitopes).[000205] Aggregate responses[000206] We next compared aggregate antibody reactivity to the eight epitopes for controllers vs. non-controllers (Figure 6, Panels A-C). The number of epitopes targeted ranged from five to eight for controllers and from two to eight for non-controllers. The mean number of epitopes targeted was higher among controllers vs. non-controllers (7.15 vs. 6.19, p=0.015). The participant mean antibody reactivity (fold change) across all eight epitopes was also higher for controllers vs. non-controllers (21.31 vs. 10.70, p<0.001). Both measures indicate that controllers reacted more broadly across the eight epitopes than non-controllers.[000207] We then compared HIV- 1 VARscores for controllers vs. non-controllers (Figure 6, Panel D); this analysis included an additional group of 36 participants who were vitally suppressed on ART (viral load <400 copies / mL with ARV drugs detected at both HIV-positive study visits). Mean HIV- 1 VARscores were higher for controllers than non-controllers (3.03 vs. 2.47, p==0.043), indicating that controllers had stronger overall HIV-1 specific antibody responses than non- controllers. Mean HIV-1 VARscores were lower for participants suppressed on ART titancontrollers (1.56 vs. 3.03, p<0.001) and iron-controllers (1.56 vs. 2.47, p<0.001); this finding is consistent with prior studies that demonstrate a down-regulation of HIV antibody expression in persons who are vitally suppressed on ART (47-50).[000208] As a final step, we compared VARscores for two other viruses to assess whether the findings in Figure 5 were specific for HIV-1. This analysis was performed for HIV-2, which was expected to be uncommon in this cohort, and HSV-2, which was expected to be highly prevalent in this cohort. For both viruses, mean VARscores were similar for controllers and noncontrollers (HIV -2: 0.66 vs. 0.69, p-0.80; HSV-2: 2.32 vs. 1.90, p-0.25). This indicates that the observed differences in HIV-1 VARscores were HIV-1 virus-specific and did not reflect general differences in the breadth and strength of the antibody response in controllers vs. non-controllers,[000209] Table. 2. Study cohort.Legend for Table 2. The table shows viral load and demographic data for the study cohort and for each study group (controllers, non-controllers).Footnotes:1Participants classified as controllers had viral loads <2,000 copies / mL with no ARV drugs detected at two annual study visits.2Participants classified as non-controllers had viral loads >2,000 copies / mL with no ARV drugs detected at two annual study visits.3Viral load data (HIV RNA copies / mL) are shown for the second HIV-positive study visit (infection duration 1-2 years).4This P-value was not determined because viral load was used to identify controllers.Abbreviations. ARV; antiretroviral; IQR; interquartile range; NDt not determined.[000210] Table 3. Characteristics of peptides where higher antibody reactivity was associated with lower viral load.8{00021 II Legend for Table 3, The table shows the features of the 43 peptides where higher antibody reactivity was associated with lower viral load. The following information is provided for each peptide; peptide identifier; HIV gene location; HIV protein location; HXB2 genomic coordinates (NCB1 #NC_00.l 802); Un.iP.rot identifier; cluster designation; epitope designation(s); amino acid sequence. Epitope sequences are shown in red font.[000212] Abbreviations: gp; glycoprotein; HR: helical region; ID: identifier.[000213] Table 4: Epitope-level antibody responses and HIV viral load in the non-controller subset.[0 00214] We evaluated whether an association between antibody reactivity and HIV viral load was observed at the epitope level for the subset of participants classified as non-controllers (11=64). The table shows the association between the level of antibody reactivity (logni fold change) to the HIV epitopes described in Table 1 and HIV viral load as determined by linear regression. Estimated effect and associated p-values were calculated using simple linear regression between antibody reactivity and viral load. The estimated effect indicates the change in. viral load (logte scale) associated with a unit increase in antibody reactivity (log™ scale). Negative values indicate that an increase in antibody reactivity was associated with a decrease in viral load. Statistically significant p-vaiues are shown in bold font. [0 00215] Discussion [0 00216] In this report, we used VirScan to characterize HIV antibody responses associated with viral load and controller status among persons who had been living with HIV for one to two years. These persons were enrolled in a coramunity-randomized trial that recruited participants from the general population in Zambia and South Africa, We identified ten peptide clusters that served as the primary targets of HIV antibodies in this cohort (three in env, three in gag, two in integrase, and one each in protease and vpu), Seven of these clusters (clusters 1-7) overlapped with clusters identified in our previous study (64). This was consistent with the findings from our earlier report in an independent cohort with a different prevalent HIV subtype (prior study: subtype B; current study; subtype C). Three new peptide clusters (clusters a-c) were also identified in thisreport. The new clusters could represent epitopes that are more commonly targeted in subtype € HIV. High-level reactivity to these targets could also be more common in the first 1-2 years of HIV infection (47) or could reflect other differences in the cohorts used for analysis in this report and our prior report (64).[000217] We found that higher levels of antibody reactivity to 43 HIV peptides representing 8 unique epitopes were associated with lower HIV viral loads. All eight epitopes were located in the clusters commonly targeted by both controllers and non-controllers, suggesting that more robust antibody responses to standard HIV targets, rather than responses to unique targets, may play a role in controlling viral replication. HIV controllers reacted more frequently to two of these epitopes (a.1 and a.2) and had higher mean antibody reactivity to seven of these epitopes (1,1 , 2.1, a.1, a.2, 3.1, 6.2, and 7.1). Three of these seven epitopes and 26 (72.2%) of the 36 corresponding peptides are located in gag. These findings me consistent with prior studies that found robust controller antibody responses to broad gag targets (55, 60-62).[000218] When antibody reactivity to all eight HIV epitopes was assessed as a composite measure, both the number of epitopes targeted and the mean reactivity across the eight epitopes was associated with lower viral load. Higher reactivity to targets across the HIV genome (HIV- 1 VARscore (73)) was also associated with lower viral load. These associations remained significant when we compared reactivity in controllers and non-controllers. HIV controllers targeted more of the eight epitopes, had higher mean reactivity across all eight targets, and had significantly higher mean HIV-1 VARscores than non-controllers. These findings are consistent with general differences in foe breadth of the antibody response that we observed in our prior study of controllers vs. non-controllers with unknown duration of infection (64). Taken together, our findings suggest that broad, robust antibody responses to standard HIV targets may contribute to viral containment and HIV controller status.[000219] In this study, 7 / 13 (54%) of the controllers had a vital load below the limit of quantification (400 copies / mL) and were assigned a viral load value of 399 copies / mL. Using fols conservative approach, we identified 43 peptides where the level of antibody reactivity was significantly associated with viral load; for all of these peptides, higher levels of antibody reactivity were associated with tower viral loads (Figure 3). Using the largest possible value below the limitof quantification for "censored” participants assured that the type I error was actually an upper bound and that we could be confident in the significance of the association with viral load. Since this approach might increase the number of false negative results, we conducted additional sensitivity analyses. When we used an assigned value of 200 copies / mL or more, we did not observe large numbers of additional peptides showing significance. Only when the imputed vial load value was consistently below 200 copies / mL for each of the seven censored participants did we observe a somewhat larger increase in the number of significant peptides. In all simulation scenarios, the 43 peptides remained significantly associated with viral load.[000220] To our knowledge, none of foe bnAbs currently under investigation for HIV treatment and prevention target epitopes located in the same regions of the corresponding HIV proteins as the peptides identified in this study (79-81). Notably, one of these epitopes (7.1) overlaps with an HR2 epitope that we previously demonstrated was preferentially targeted prior to infection in persons who were able to control infection after HIV acquisition (68). We did not identify any peptides or epitopes where higher levels of antibody reactivity were associated with higher HIV viral load or non-controller status. This was unexpected, since viral suppression from ART generally leads to a reduction in antibody titer due to reduced antigen exposure (47-50), which was consistent with our findings of tower HIV- 1 VARscores in persons on ART as compared to both controllers and non-controllers.[000221] Viral suppression on ART can improve health outcomes for PWH and reduce risk of HIV-related mortality (8-15). HPTN 071 and global health programs have also demonstrated that reducing viral load at foe community level with “universal testing and treatment'’ strategies can significantly reduce HIV incidence (66, 82). These findings led UNAIDS to establish “95-95- 95” Fast-Track targets based on mathematical models indicating that achieving 95% success in each step of the HIV care cascade (diagnosis, linkage to care, viral suppression on ART) would effectively curb the epidemic (83). Unfortunately, significant structural barriers to universal ART delivery still remain in some resource-limited settings (84, 85).[000222] Significant reductions in HIV incidence may still be achieved with more modest levels of community-wide viral load reduction. A modeling study found that lower viral loads in North America vs. sub-Saharan Africa (difference of -0.5 loglO viral load) may significantlycontribute to observed geographic differences in HIV incidence (86). Other studies have demonstrated that similar reductions in population-level viral load were associated with reduced HIV incidence (87-89). The findings in this report suggest that enhancing the depth and breadth of HIV antibody responses (potentially with pre-infection Or therapeutic vaccination (90-93)) could help lower community-level viral load and reduce HIV incidence. This approach may offer advantages in settings with barriers to universal ART delivery. Further research could evaluate whether the epitopes identified in this report might be useful targets for immune-based interventions for modulating HIV viral load.[000223] This study has several limitations. First, despite the large size of the HPTN 071 trial (>48,000 persons enrolled and followed), we were only able to identify 13 controllers with known duration of infection. Second, the HPTN 071 cohort only included participants from Zambia and South Africa, where the vast majority of infections are caused by subtype C infection HIV; the HPTN 071 cohort also included a disproportionate number of women (74%). These factors may limit the generalizability of our findings. Third, the viral load assay that was used in HPTN 071 had a LOQ of <400 copies / mL (66); the plasma samples stored in this trial did not have sufficient volume for testing with a more sensitive viral load assay. For this reason, we were not able to evaluate factors associated with elite control of HIV infection. Fourth, the VirScan assay measures IgG binding to unglycosylated, linear epitopes; therefore, we were not able to assess reactivity for other antibody isotypes or against glycosylated or conformational epitopes. Fifth, the measure of antibody reactivity provided by the VirScan assay reflects both antibody titer and avidity; therefore, we were not able to assess whether the observed associations between antibody reactivity, viral load, and controller status were driven by differences in antibody titer, antibody avidity, or a combination of both factors. Sixth, CD4 cell count data was not collected in HPTN 071, cellular samples were not stored, and consent was not obtained for host genetic testing; therefore, we were not able to evaluate the association of viral load and HIV control with other factors, such as host HLA type (69) and cellular immune responses (94-97)). Seventh, the viral loads were too low in most controllers for HIV genotyping; this limited our ability to evaluate viral factors associated with viral load and controller status (98, 99). Eighth, we assessed antibody profiles at a single timepoint (infection duration: 1-2 years); further research in cohorts with knownduration and longer post-infection follow-up could be used to evaluate the evolution of these responses and their association with viral load over the full HIV disease course. Finally, it is possible that the higher levels of antibody reactivity that we observed in persons with lower viral loads could be a consequence of HIV control (rather than the cause), reflecting more robust immune systems among those with a greater capacity for viral containment. If the findings from this study are confirmed in other cohorts, further studies could be performed to determine whether enhancing reactivity to the HTV epitopes identified in this study (e.g„ with vaccination or passive immunization) results in a reduction in HIV viral load.[000224] Conclusion[000225] We identified HIV antibody targets that are associated with lower viral load and HIV controller status one to two years after infection. We also demonstrated feat robust aggregate responses to these targets and broad antibody reactivity across fee HIV genome were associated with these outcomes. These findings provide novel insights into fee relationship between humoral immunity and viral containment, which could help inform the design of antibody-based approaches for HIV treatment and prevention. [0 00226] EXAMPLE 2: METHODS USED IN EXAMPLE 1 [000227] Source of samples [000228] Samples and data were obtained from the HPTN 071 trial (NOT 019000977), which demonstrated feat universal delivery of a comprehensive HIV prevention package was associated wife lower HIV incidence (66). Plasma samples were collected annually from >48,000 adult participants from 21 communities in Zambia and South Africa (66) where most HIV infections are caused by subtype C HIV (67). Ibis report evaluated a subset of fee 978 participants who acquired HIV infection during the trial (seroconverters) (65) and had controller status determined based on viral load and antiretroviral (ARV) drug testing (68). Participants included in this report had samples and data available from at least three consecutive annual visits (one negative, two positive). Participants classified as controllers had viral loads <2,000 copies / mL wife no ARV drugs detected at both HIV-positive visits; this method for identifying controllers is consistent with methods used in prior studies (29, 31 , 69). Participants classified as non-controlfers had viral loads >2,000 copies / mL wife no ARV drags detected at both HIV-positive visits. VirScan testing wasperformed using samples collected at the second HIV-positive study visit (1-2 years after HIV acquisition). The analysis of HIV’ 1 VARscores included additional participants who were vitally suppressed on antiretroviral therapy (ART; viral loads <400 copies / mL with ARV drugs detected at both HIV-positive visits).[000229] Laboratory methods[000230] Laboratory testing was performed at the HPTN Laboratory Center (Johns Hopkins University, Baltimore, MD). HIV viral load was measured with the RealTime HIV- 1 Viral Load assay (Abbott Molecular, Des Plaines, IL) using a validated dilution method (limit of quantification [LOQ]: 400 copies / mL); a viral load value of 399 copies / mL was assigned for samples with no RNA detected or RNA < LOQ, ARV drugs were detected using a qualitative assay that detects 22 drugs in five classes (limit of detection [LOD]: 2 ng / mL or 20 ng / mL, depending on the drug) (70).[000231] HIV antibody profiling was performed using the VirScan assay, as described previously (47, 63). This assay uses phage display to quantify antibody binding to a library of overlapping peptides spanning the expressed genomes of >200 viruses, including >3,300 HIV peptides representing multiple HIV subtypes and strains (47, 63). In this assay, plasma is incubated with die phage library and antibody-bound phage are immunocaptured using beads coated with protein A and protein G. Primers with sample-specific barcodes are used to amplify the peptide- encoding DNA in immunocaptured phage; the amplified DNA is then sequenced to determine the amino acid sequences of peptides bound by the antibodies in each sample. In this study, sequencing was performed using the NovaSeq 6000 with the S2 flowcell (Illumina, San Diego, CA).[000232] VirScan data analysis[000233] Each immunoprecipitation plate included 7-8 negative controls (beads only) and 3 positive controls (pooled plasma from other study participants infected >2 years with viral loads >2,000 copies / mL), Raw read counts from the VirScan assay were based on exact matching of the initial 50 nucleotides for each read. Fold change values and associated p-values were determined by comparing observed read counts to those in negative control reactions using the exact test for the negative binomial distribution in the edgeR package (71, 72). Fold change values were adjusted by setting the value to one under the following conditions: read count <15, fold change <3, and / orp-value >0.001. Adjusted fold change values >1 represented significant antibody reactivity. VARscore values were calculated from VirScan data using the ARscore package vO.2.0 (73).[000234] Statistical methods[000235] Peptide clusters with high levels of antibody reactivity at the cohort-level were identified based on having two or more peptides with cohort-level mean antibody reactivity (log 10 fold change) >0.5 (i.e., adjusted fold change >3.16). Viral load and antibody reactivity (fold change) values were loglO-transformed prior to statistical analysis. Analysis of associations between antibody reactivity to HIV peptides and HIV viral load was performed using simple linear regression; tins analysis was limited to HIV peptides that had significant antibody reactivity (adjusted fold change >1) for one or more participants. Multiple comparisons correction was performed using two methods: a) q-values calculated from observed p-values to control the false discovery rate (where q-values <5% indicated statistical significance) (74), and b) the Bonferroni method. Epitopes in overlapping peptides associated with lower HIV viral load were identified with epitopefindr vl.1.30 (75). Epitope logos were generated using ggseqlogo vO.l (76). Epitopelevel reactivity was determined by selecting the maximum fold change value for any peptide containing that epitope. HIV-1 VARscore values refer to the mean VARscore value across all HIV- 1 subtypes. Analysis of associations between two continuous variables was performed using simple linear regression. Between-group comparisons for categorical variables were performed using Fisher's exact test Between-group comparisons for continuous variables were performed using the Wilcoxon rank-sum test. Statistical analyses were performed using the statistical environment R (77). Data were visualized using base R and ggplot2 (78).[000236] Informed consent[000237] HPTN 071 participants provided written informed consent before study enrollment. HPTN 071 was approved by the institutional review boards and ethics committees of the London School of Hygiene and Tropical Medicine, the University of Zambia, and Stellenbosch University. Data and samples used for this work were accessed between 1 / 1 / 2020 and 12 / 312023. The authors did not have access to information that could be used to identify individual study participants.[000238] References1. Fauci AS, Desrosiers RC. Pathogenesis of HIV and SIV. In; Coffin JM, Hughes SH, Varmus HE, editors. Retroviruses. Cold Spring Harbor (NY)1997.2. Fiebig EW, Wright DI, Rawal BD, Garrett PE, Schumacher RT, Peddada L, et al. Dynamics of HIX' viremia and antibody seroconversion in plasma donors: imputations for diagnosis and staging of primary HIV infection. AIDS. 2003;l7(I3):I871-9.3. Coffin J, Swanstrom R. HIV pathogenesis: dynamics and genetics of viral populations and infected cells. Cold Spring Harb Perspect Med. 2013;3(l):a012526.4. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995;373(6510): 123-6.5. Perelson AS, Neumahn AU, Markowitz M, Leonard JM, Ho DD. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science. 1996;271(5255):1582-6.6. Robb ML, EUer LA, Kibuuka H, Rono K, Maganga L, Nitayaphan S, et al. Prospective Study of Acute HIV-1 Infection in Adults in East Africa and Thailand. N Engl J Med. 2016;374(22):2120-30.7. Boutwell CL, Rolland MM, Herbeck JT, Mullins JI, Allen TM. Viral evolution and escape during acute HIV- 1 infection. J Infect Dis. 2010,202 Suppl 2:5309-14.8. de Wolf F, Spijkerman 1, Schelfekens PT, Langendam M, Kuiken C, Bakker M, et at AIDS prognosis based on HIV-1 RNA, CD4+ T-cell count and function: markers with reciprocal predictive value overtime after seroconversion. AIDS. 1997;ll(15):1799-806.9. Katzenstein TL, Pedersen C, Nielsen C, Lundgren JD, Jakobsen PH, Gerstoft J. Longitudinal serum HIV RNA quantification: correlation to viral phenotype at seroconversion and clinical outcome. AIDS. 1996;10(2):167-73.10. Mellors JW, Rinaldo CR, Jr., Gupta P, White RM, Todd JA, Kingsley LA. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science. 1996;272(5265):1167-70,11. Sterling TR, Vlahov D, Astemborski J, Hoover DR, Margolick JB, Quinn TC. Initial plasma HIV-1 RNA levels and progression to AIDS in women and men, N Engl J Med. 2001;344(10):720-5.12. Fraser C, Hollingsworth TD, Chapman R, de Wolf F, Hanage WP. Variation in HIV-1 setpoint viral load: epidemiological analysis and an evolutionary hypothesis. Proc Natl Acad Sci U S A. 2007; 104(44): 17441 -6.13. Mellors JW, Kingsley LA, Rinaldo CR, Jr, Todd JA, Hoc BS, Kokka RP, et al. Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion. Ann Intern Med. 1995;122(8):573-9,14. Goujard C, Bonarek M, Meyer L, Bonnet F, Chaix ML, Deveau C, et al. CD4 cell count and HIV DNA level are independent predictors of disease progression after primary HIV type 1 infection in untreated patients. Clin Infect Dis. 2006;42(5):709-15.15. Lavreys L, Baeten JM, Chohan V, McClelland RS, Hassan WM, Richardson BA, et al. Higher set point plasma viral load and more-severe acute HIV type 1 (HlV-1) illness predict mortality among high-risk HIV-l-infected African women. Clin Infect Dis. 2006;42(9): 1333-9.16. Quinn TC, Wawer MJ, Sewankambo N, Serwadda D, Li C, Wabwire-Mangen F. et al Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med. 2000;342(13):921-9.17. Fideli US, Allen SA, Musonda R, Trask S, Hahn BH, Weiss H, et al. Virologic and immunologic determinants of heterosexual transmission of human immunodeficiency virus type 1 in Africa. AIDS Res Hum Retroviruses. 2001;17(10).901-10.18. Autran B, Carcelain G, Li IS, Blanc C, Mathez D, Tubiana R, et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science. 1997;277(5322): 112-6.19. Palella FJ, Jr., Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338(13):853-60.20. Rodger AJ, Lodwick R, Schechter M, Decks S, Amin J, Gilson R, et al. Mortality in well controlled HIV in the continuous antiretroviral therapy arms of the SMART and ESPRIT trials compared with the general population. AIDS. 2013;27(6):973-9.21. van Sighem Al, Gras LA, Reiss P, Brinkman K, de Wolf F, study Anoc. Life expectancy of recently diagnosed asymptomatic HIV-infected patients approaches that of uninfected individuals. AIDS. 2010;24(10):1527-35.22. Vittinghoff E, Scheer S, O’Malley P, Colfax G, Holmberg SD, Buchbinder SP. Combination antiretroviral therapy and recent declines in AIDS incidence and mortality. J Infect Dis. 1999;! 79(3): 717-20.23. Samji H, Cescon A, Hogg RS, Modur SP, Althoff KN, Buchacz K, et al. Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada. PUS One. 2013;8(12):e81355.24. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al. Antiretroviral Therapy for the Prevention of HIV-1 Transmission. N Engl J Med. 20I6;375(9):830-9.25. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al. Prevention of HIV-I infection with early antiretroviral therapy. N Engl J Med. 2011 ;365(6):493- 505.26. Bavinton BR, Pinto AN, Phanuphak N, Grinsztejn B, Prestage GP, Zablotska-Manos IB, et al. Viral suppression and HIV transmission in serodiscordant male cotpies: an international, prospective, observational, cohort study. Lancet HIV. 2018;5(8)re438-e47.27. Rodger AJ, Cambiano V, Bruun T, Vemazza P, Collins S, Degen O, et al Risk of HIV transmission through condomless sex tn serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study. Lancet. 2019;393(l0r89):2428-38.28. Rodger AJ, Cambiano V, Bruun T, Vemazza P, Collins S, van Lunzen J, et al. Sexual Activity Without Condoms and Risk of HIV Transmission in Serodifferent Couples When die HIV-Positive Partner Is Using Suppressive Antiretroviral Therapy. JAMA. 2016;316(2): 171 -81.29. Pereyra F, Addo MM, Kaufmann DE, Liu Y, Miura T, Rathod A, et al. Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy. J Infect Dis. 2008;197(4);563-71.30. Okulicz JF, Marconi VC, Landrum ML, Wegner S, Weintrob A, Ganesan A, et al. Clinical outcomes of elite controllers, viremic controllers, and long-term nonprogressors in the US Department of Defense HIV natural history study. J Infect Dis. 2009;200(11): 1714-23.31. Olson AD, Meyer L, Ptins M, Thiebaut R, Gurdasani D, Guiguet M, et al. An evaluation of HIV elite controller definitions within a large seroconverter cohort collaboration. PLoS One. 2014;9(l):e86719.32. Decks SG, Walker BD. Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity. 2007;27(3):406-16.33. O’Brien TR, Blattner WA, Waters D, Eyster E, Hilgartner MW, Cohen AR, et al. Serum HIV-1 RNA levels and time to development of AIDS in the Multicenter Hemophilia Cohort Study. JAMA. 1996;276( 2): 105-10.34. Giorgi JV, Lyles RH, Matud JL, Yamashita TE, Mellors JW, Hultin LE, et al. Predictive value of immunologic and virologic markers after long or short duration of HIV- 1 infection. J Acquir Immune Defic Syndr. 2002;29(4):346-55.35. Gray RH, Wawer MJ, Brookmeyer R, Sewankambo NK, Serwadda D, Wabwire-Mangen F, et al. Probability of HIV-1 transmission per coital act in monogamous, heterosexual, H1V-1- discordant couples in Rakai, Uganda. Lancet, 2001 ;357(9263): 1149-53.36. Morley D, Lambert JS, Hogan LE, De Gascun C, Redmond N, Rutishauser RL, et al. Rapid development of HIV elite control in a patient with acute infection. BMC Infect Dis. 2019;19(l):815.37. Goujard C, Chaix ML, Lambotte O, Deveau C, Sinet M, Guergnon J, et al. Spontaneous control of viral replication during primary HIV infection: when is "HIV controller” status established? Clin Infect Dis. 2009;49(6):982-6.38. Madec Y, Boufassa F, Porter K, Meyer L, Collaboration C, Spontaneous control of viral load and CD4 ceil count progression among HIV-1 seroconverters. AIDS. 2005,19(17):2001-7.39. Altfeld M, Addo MM, Rosenberg ES, Hecht EM, Lee PK, Vogel M, et at Influence of HLA-B57 on clinical presentation and viral control during acute HIV-1 infection. AIDS. 2003;17(18):2581-91.40. Gonzalo-Gil E, Ikediobi U, Sutton RE. Mechanisms of Virologic Control and Clinical Characteristics of H1V+ Elite / Viremic Controllers. Yale J Biol Med. 2017;90(2).245-59.41. Margolis DM, Koup RA, Ferrari G. HIV antibodies for treatment of HIV infection. Immunol Rev. 2017;275(l):313-23.42. Bailey JR, Lassen KG, Yang HC, ()uinn TC, Ray SC, Blankson JN, et al. Neutralizing antibodies do not mediate suppression of human immunodeficiency virus type 1 in elite suppressors or selection of plasma virus variants in patients on highly active antiretroviral therapy. J Virol. 2006,80(10):4758-70.43. Lambotte O, Ferrari G, Moog C, Yates NL, Liao HX, Parks RJ, et al. Heterogeneous neutralizing antibody and antibody-dependent cell cytotoxicity responses in HIV-1 elite controllers. AIDS. 2009;23(8)i897-906.44. Doria-Rose NA, Klein RM, Daniels MG, O'Dell S, Nason M, Lapedes A, et al. Breadth of human immunodeficiency virus-specific neutralizing activity in sera: clustering analysis and association with clinical variables. J Virol. 2010;84(3).i631-6.45. Laeyendecker O, Rothman RE, Henson C, Home BJ, Ketlogetswe KS, Kraus CK, et al. The effect of viral suppression on cross-sectional incidence testing in die Johns hopkins hospital emergency department J Acquir Immune Defic Syndr. 2008;48(2)<.2I 1-5.46. Pereyra F, Palmer S, Miura T, Block BL, Wiegand A, Rofechild AC, et al. Persistent low- level viremia in HIV-1 elite controllers and relationship to immunologic parameters. J Infect Dis. 2009;200(6):984-90.47. Eshleman SH, Laeyendecker O, Kammers K, Chen A, Sivay MV, Kottapalli S, et al. Comprehensive Profiling of HIV Antibody Evolution. Cell Rep. 2019;27(5): 1422-33 e4.48. Keating SM, Pilcher CD, Jain V, Lebedeva M, Hampton D, Abdel-Mohsen M, et al. HIV Antibody Level as a Marker of HIV Persistence and Low-Level Viral Replication. J Infect Dis. 2017;216(l):72-8L49. Mitchell JL, Pollara J, Dietze K, Edwards RW, Nohara J, N'Guessan K F, et a). Anti-HIV antibody development up to 1 year after antiretroviral therapy initiation in acute HIV infection. J Clin Invest. 2022;132(I).50. Wendel SK, Mullis CE, Eshleman SH, Blankson JN, Moore RD, Keruly JC, et al. Effect of natural and ARV-induced viral suppression and viral breakthrough on anti-HIV antibody proportion and avidity in patients wife HIV-1 subtype B infection. PLoS One. 2013;8(2):e55525.51. Lambotte O, Pollara J, Boufassa F, Moog C, Venet A, Haynes BF, et al. High antibodydependent cellular cytotoxicity responses are correlated wife strong CDS T cell viral suppressive activity but not wife B57 status in HIV-1 elite controllers. PLoS One. 20I3;8(9):e74855.52. Freund NT, Wang H, Scharf L, Nogueira L, Horwitz JA, Bar-On Y, et al. Coexistence of potent HIV-1 broadly neutralizing antibodies and antibody-sensitive viruses in a viremic controller. Sci Transl Med. 2017;9(373).53. Scheid JF, Mouquet H, Feldhahn N, Seaman MS, Velinzon K, Pietzsch J, et al Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals. Nature. 2009;458(7238):636-40.54. Scheid JF, Mouquet H, Ueberiieide B, Diskin R, Klein F, Oliveira TY, et al. Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science. 2011 ;333(6049): 1633-7,55. Alter G, Dowell KG, Brown EP, Suseovich TJ, Mikhailova A, Mahan AE, et al. High- resolution definition of humoral immune response correlates of effective immunity against HIV. Mol Syst Biol. 2018;14(3):e788I.56. Nabi R, Moldoveanu Z, Wei Q. Golub ET, Durkin HG, Greenblatt RM, et al. Differences in serum IgA responses to HIV-1 gp41 in elite controllers compared to viral suppressors on highly active antiretroviral therapy. PLoS One. 2017;1.2(7):e0180245.57. Ngo-Giang-Huong N, Candotti D, Goubar A, Auttan B, Maynatt M, Sicard D, et al. HIV type 1 -specific IgG2 antibodies; markers of helper T cell type 1 response and prognostic marker of long-term nonprogression. AIDS Res Hum Retroviruses. 2001 : 17(15): 1435-46.58. Ackerman ME, Mikhailova A, Brown EP, Dowell KG, Walker BD, Bailey-Kellogg C, et al. Polyfunctional HIV-Specific Antibody Responses Are Associated with Spontaneous HIV Control. PLoS Pathog. 2016;12(l):el0053l5.59. Klingler J, Paul N, Laumond G, Schmidt S, Mayr LM, Decoville T, etal. Distinct antibody profiles in HLA-B *57+, HLA-B *57- HIV controllers and chronic progressors. AIDS. 2022;36(4):487-99.60. French MA, Center RJ, Wilson KM, Fleyfel I, Fernandez S, Schorcht A, et al. Isotype- switched immunoglobulin G antibodies to HIV Gag proteins may provide alternative or additional immune responses to ‘protective* human leukocyte amigen-B alleles in HIV controllers. AIDS. 2013;27(4);519-28.61. Tjiam MC, Morshidi MA, Sariputra L, Martin JN, Decks SG, Tan DBA, et al. Association of HI V-1 Gag-Specific IgG Antibodies With Natural Control of HIV-1 Infection in Individuals Not Carrying HLA-B*57: 01 Is Only Observed in Viremic Controllers. J Acquit Immune Defic Syndr. 2017;76(3):e90-e2.62. Tjiam MC, Sariputra L, Armitage ID, Taylor IP, Kelleher AD, Tan DB, et al. Control of early HIV- 1 infection associates with plasmacytoid dendritic cell-reactive opsonophagocytic IgG antibodies to HIV-1 p24. AIDS, 2016;30(18):2757-65.63. Xu GJ, Kula T, Xu Q, Li MZ, Vernon SD, Ndung'u T, et al Viral immunology. Comprehensive serological profiling of human populations using a synthetic human virome. Science. 2015;348(6239):aaa0698.64. Kammers K, Chen A, Monaco DR, Hudelson SE, Grant-McAuley W, Moore RD, et al. HIV Antibody Profiles in HIV Controllers and Persons With Treatment-Induced Viral Suppression. Front Immunol. 2021; 12:740395.65. Eshleman SH, Piwowar-Manning E, Wilson EA, Lennon D, Fogel JM, Agyei Y, et al. Determination of HIV status and identification of incident HIV infections in a large, community- randomized trial: HPTN 071 (PopART). J fat AIDS Soc. 2020;23(2):e25452.66. Hayes RJ. Donnell D, Floyd S, MandlaN, Bwalya J, Sabapathy K, et al. Effect of Universal Testing and Treatment on HIV Incidence - HPTN 071 (PopART). N Engl J Med. 2019;381 (3);207- 18.67. Bbosa N, Kaleebu P, Ssemwanga D. HIV subtype diversity worldwide. Curr Opin HIV AIDS. 2019; 14(3): 153-60.68. Grant-McAuley W, Morgenlander W, Hudelson SB, Thakar M, Piwowar-Manning E, Clarke W, et al. Comprehensive profiling of pre-infection antibodies identifies HIV targets associated with viremic control and viral load. Submitted for Publication. 2023.69. International HIVCS, Pereyra F, Jia X, McLaren PJ, Telemi A, de Bakker PI, et al The major genetic determinants of HIV- 1 control affect HLA class I peptide presentation. Science. 2010;330(6010);1551-7.70. Marzinke MA, Breaud A, Parsons TL, Cohen MS, Piwowar-Manning E, Eshleman SH, et al. The development and validation of a method using high-resolution mass spectrometry (HRMS) for the qualitative detection of antiretroviral agents in human blood. Clin Cbim Acta. 2014;433:157-68.71. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(l):l 39-40.72. Chen A, Kammers K, Lamian HB, Scharpf RB, Ruczinski I. Detecting antibody reactivities in Phage ImmunoPrecipitation Sequencing data. BMC Genomics. 2022;23(l):654.73. Morgenlander, WR and Larman, HB. R package 'ARscore'. 2022. Available from; https: / / github.com / wmorgenl / ARscore / .74. Storey JD, Tibshirani R. Statistical significance for genomewide studies. Proc Natl Acad Sci U S A. 2003;100(16);9440-5.75. Sie, B. epitopefindr: Minimal Overlaps from BLAST Alignments. R package Version 1.1.30. 2022. Available from GitHub: https: / / brandonsie.gitliub.io / epitopefindr / .76. Wagih, Omar, ggseqlogo: a versatile R package for drawing sequence logos. Bioinformatics (2017). https: / / doi.org / 10.1093foioinformatics / btx469.77. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2013. Available from: httpJ7www.R-project.org / .78. Wickham fit. ggplot2; Elegant Graphics for Data Analysis. New York; Springer-Verlag; 2016.79. Walsh SR, Seaman MS. Broadly Neutralizing Antibodies for HIV-1 Prevention. Front Immunol. 2021 ; 12:712122.80. Caskey M. Broadly neutralizing antibodies for the treatment and prevention of HIV infection. Curr Opin HIV AIDS. 2020;! 5(I):49-55.81. Awan SF, Happe M, Hofstetter AR, Gama L . Broadly neutralizing antibodies for treatinent and prevention of HIV- 1 infection. Curr Opin HIV AIDS. 2022;17(4):247-57.82. Havlir D, Lockman S, Ayles H, Larmarange J, Chamie G, Gaolathe T, et al. What do the Universal Test and Treat trials tell us about the path to HIV epidemic control? J Int AIDS Soc. 2020;23(2):e25455.83. UNAIDS / WHO. 2015. Understanding Fast-Track: Accelerating Action to End the AIDSEpidemic by 2030. https: / / www.unaids.org / sites / defeult / files / media_asset / 201506_JC2743_Understanding_FastTrac k_en.pdf. Geneva, Switzerland: Accessed July 2023.84. I^ofgren SM, Tsui S, Atuyambe L, Ankunda L, Komuhendo R, Wamala N, et al. Barriers to HIV care in Uganda and implications for universal test-and-treat. a qualitative study. AIDS Care. 2022;34(5):597-605.85. Mnyaka OR, Mabunda SA, Chitha WW, Nomatshila SC, Ntlongweni X. Barriers to the Implementation of the HIV Universal Test and Treat Strategy in Selected Primary Care Facilities in South Africa's Eastern Cape Province. J Prim Care Community Health. 2021;12:21501327211028706.86. Abu-Raddad LJ, Barnabas RV, Janes H, Weiss HA, Kublin JG, Longini IM, Jr., et al. Have the explosive HIV epidemics in sub-Saharan Africa been driven by higher community viral load? AIDS. 2013;27(6):981-9.87. Das M, Chu PL, Santos GM, Scheer S, Vittinghoff E, McFarland W, et al. Decreases in communitv viral load are accompanied by reductions in new HIV infections in San Francisco. PLoS One' 2010;5(6):e11068.88. Farahani M, Radin E, Saito S, Sachathep KK, Hladik W, Voetsch AC, et at Population Viral Load, Viremia, and Recent HIV-1 Infections: Findings From Population-Based HIV Impact Assessments (PHIAs) in Zimbabwe, Malawi, and Zambia. J Acquit Immune Defic Syndr. 2021;87(Suppl 1):S81-S8.89. Montaner JS, Lima VD, Barrios R, Yip B, Wood E, Kerr T, et al. Association of highly active antiretroviral therapy coverage, population viral load, and yearly new HIV diagnoses in British Columbia, Canada; a population-based study. Lancet. 2010;376(9740):532-9.90. Bobardt M, Kuo J, Chatletji U, Wiedemann N, Vuagniaux G, Gallay P. The inhibitor of apoptosis proteins antagonist Debio 1143 promotes the PD-1 blockade-mediated HIV load reduction in blood and tissues of humanized mice. PLoS One. 2020;15(l):e0227715.91. Mu Z, Haynes BF. Cain DW. HIV niRNA Vaccines-Progress and Future Paths. Vaccines (Basel). 2021;9(2).92. Mylvaganam GH, Sil vestri G, Amara RR. HIV therapeutic vaccines: moving towards a functional cure. Curr Opin Immunol. 2015;35:1-8.93. Stephenson KE. Therapeutic vaccination for HIV: hopes and challenges. Curr Opin HIV AIDS. 2018;13(5):408-15,94. Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, Abraham J, et al. HIV nonprogressors preferentially maintain highly functional HIV -specific CDS* T cells. Blood. 2006;I07(12):4781-9.95. Lecuroux C, Girault I, Cheret A, Versmisse P, Nembot G, Meyer L, et al. CDS T-cells from most HIV-infected patients lack ex vivo HIV-suppressive capacity during acute and early infection. PLoS One. 2013;8(3).'e59767.96. Migueles SA, Laborico AC. Shupert WL, Sabbaghian MS, Rabin R, Hallahan CW, et al. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol. 2002;3(l 1):[061-8.97. Saez-Cirion A, Lacabaratt C, Lambotte O, Versmisse P, Urrutia A, Boofassa F, et al. HIV controllers exhibit potent CDS T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc Natl Acad Sci U S A. 2007;104(16):6776-8198. Fraser C, Lythgoe K, Leventhal GE, Shtrreff G, Hollingsworth I'D, Alizon S, et al. Virulence and pathogenesis of HIV-1 infection: an evolutionary perspective. Science. 2014;343(6177): 1243727.99. Hollingsworth TD, Laeyeudecker O, Shirreff G, Donnelly CA, Serwadda D, Wawer MJ, et al. HIV- 1 transmitting couples have similar viral load set-points in Rakai, Uganda. PLoS Pathog. 20l0;6(5):el000876.OTHER EMBODIMENTS[000239] From the foregoing description, it will be apparent that variations and modifications may be made to the disclosure described herein to adopt it to various usages and conditions. Such embodiments are also within the scope of die following claims.[000240] AH citations to sequences, patents and publications in this specification are herein incorporated by reference to the same extent as if each independent patent and publication was specifically and individually indicatedto be incorporated by reference. By their citation of various references in this document, Applicants do not admit any particular reference is “prior art” to their disclosure.

Claims

1. What is claimed:

1. A vaccine formulation comprising a therapeutically effective amount of one or more immunogenic human immunodeficiency virus (HIV) peptides.

2. The vaccine formulation of claim 1 , wherein the peptides induce a post- HIV infection immune response.

3. The vaccine formulation of claim 1 or 2, wherein the peptides derived from one or more HIV peptide clusters comprise cluster I : gag [pl7; N-terminus]; cluster 2: gag [p24; C-terminusJ; cluster 3: integrase [C-terminus]; cluster 4; vpu [N-terminusJ; clusters*, envelope [gpI20; V3 loop and CD4 binding loop); cluster 6: envelope (gpl20 / gp41; VS and fusion peptide); cluster 7: envelope [gp41 ; C-terminal heptad repeat region, (HR2), cluster a (first zinc finger region of the nucleocapsid protein, gag p7); cluster b (N-terminus of protease), cluster c (N-terminus of integrase) or combinations thereof4. The vaccine formulation of claim 3, wherein die peptides derived from one or more HIV peptide clusters comprise peptides comprising cluster a (first zinc finger region of the nucleocapsid protein, gag p7); cluster b (N-terminus of protease), cluster c (N-terminus of integrase) or combinations thereof.

5. The vaccine formulation of any one of claims 1 to 4, wherein the one or more peptides comprise at least a 90% sequence identity to peptides set forth in Tables 1 , 2 or combinations thereof6. The vaccine formulation of claim 5, wherein the one or more peptides comprise peptides set forth in Tables 1, 2 or combinations thereof.

7. The vaccine formulation of any one of claims 1 to 6, wherein the one or more HIV peptides comprising SEQ ID NOs: 1 -43 further comprise one or more amino acid residue insertions, deletions, substitutions or combinations thereof.

8. The vaccine formulation of claim 7, wherein the one or the one or more HIV peptides comprising SEQ ID NOs: 1-43 further comprise one or more unnatural amino acids.

9. The vaccine formulation of claim 8, wherein the one or more HIV peptides comprising SEQ ID NOs: 1 -43 further comprise one or more synthetic amino acids.

10. The vaccine formulation of any one of claims 1 to 9, wherein the one or more HIV peptides comprising SEQ ID NOs: 1-43 further comprise amino acid modifications comprising glycosylation, deglycosylation, acetylation, phosphorylation, pegylation, lipidation or combinations thereof.

11. The vaccine formulation of claims I to 10, wherein the one or more HIV peptides comprising SEQ ID NOs: 1-43 further comprise one or more of a scaffold, an immunogenic carrier, an adjuvant, an antibody, antibody fragments, an immunoglobulin Fc region, an aptamer, a detectable label, a ligand, a therapeutic agent, a cytotoxic agent, a receptor or fragments thereof.

12. A vaccine formulation comprising one or more peptides comprising SEQ ID NOs: 1-43,13. The vaccine formulation of claim 12, whereto the one or more peptides comprise a scaffold, wherein tire scaffold increases immunogenicity as compared to a peptide without a scaffold.

14. A method of treating a subject infected with a human immunodeficiency virus (HIV) infection, comprises administering to the subject, a pharmaceutical composition comprising a vector encoding one or more one or more HIV peptides having at least a 90% sequence identity to peptides comprising SEQ ID NOs: 1 -43; or a pharmaceutical composition comprising a therapeutically effective amount of one or more HIV peptides having at least a 90% sequence identity to peptides comprising SEQ ID NOs: 1-43.15, The method of claim 14, whereto the one or more HIV peptides comprise one or more peptides comprising SEQ ID NOs: 1-43.

16. The method of claims 14 or 15, wherein the pharmaceutical composition Comprising a vector encoding one or more one or more HIV peptides comprising SEQ ID NOs: 1 -43, or a pharmaceutical composition comprising a therapeutically effective amount of one or more HIV peptides comprising SEQ ID NOs: M3, are administered post-infection.

17. The method of any one of claims 14 to 16, wherein the one or more peptides induce an immune response to HIV.

18. The method of any one of claims 14 to 17, further comprising administering one or more secondary therapeutic agents.

19. The method of claim 18, wherein the one or more secondary therapeutic agents comprise immunotherapies, one or more anti-viral agents and combinations thereof.

20. The method of claim 19, wherein the one or more antiviral agents comprise antibodies, aptamers, adjuvants, anti-sense oligonucleotides, chemokines, cytokines, gene-editing agents, immune stimulating agents, immune modulating agents, B-cell modulators, T-cell modulators, NK cell modulators, antigen presenting cell modulators, enzymes, siRNA’s, ribavirin, protease inhibitors, helicase inhibitors, polymerase inhibitors, integrase inhibitors, helicase inhibitors, neuraminidase inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, purine nucleosides, chemokine receptor antagonists, interleukins, or combinations thereof.

21. The method of any one of claims 14 to 20, wherein the one or more peptides are formulated with a pharmaceutical carrier, a delivery vehicle or combinations thereof.

22. The method of any one of claims 14 to 20, wherein the one or more peptides are formulated with a scaffold.

23. A vector comprising a nucleic acid sequence encoding one or more peptides comprising SEQ ID NOs: 1-43.

24. An isolated cell comprising a vector encoding one or more peptides comprising SEQ ID NOs: 1-43.

25. A vaccine comprising a polynucleotide encoding one or more peptides comprising SEQID NOs: M3.

26. An antibody which specifically binds to any one peptide having at least a 90% sequence identity to peptides comprising SEQ ID NOs: M3.

27. The antibody of claim 27, wherein the antibody specifically binds to any one peptide comprising SEQ ID NOs: M3.

28. The antibody of claims 26 or 27, wherein the antibody comprises monoclonal antibodies, polyclonal antibodies, multispecific antibodies, or fragments thereof29. A method of treating a subject infected with a human immunodeficiency virus (HIV) infection, comprises administering to the subject, a pharmaceutical composition comprising an antibody which specifically binds to any one peptide having at least a 90% sequence identity to peptides comprising SEQ ID NOs: M3.

30. The method of claim 29, wherein the antibody specifically binds to any one peptide comprising SEQ ID NOs: M3.

31. The method of claims 29 or 30, wherein one or more peptides comprising SEQ ID NOs: M3 are administered to the subject in combination with one or more antibodies which specifically bind to SEQ ID NOs: M3.

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