Modulation of HIV viral load by antibodies present prior to infection

Abstract

Pre-infection HIV antibody reactivities were identified that correlated with post-infection VL. Pre-infection reactivity to an epitope in the 1IR2 domain of gp4I was associated with controller status and lov / er VL. Pre-infection reactivity to an epitope in the C2 domain of gpl20 was associated with non-controller status and higher VL. Different patterns of antibody reactivity were observed over time for these two epitopes.

Description

MODULATION OF HIV VIRAL LOAD BY ANTIBODIES PRESENT PRIOR TO INFECTION The present application claims the benefit of U.S. provisional application no.63 / 530,458 filed August 2, 2023, which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0001] This invention was made with government support under grants AI068613 and AI095068 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD

[0002] In general, this disclosure is directed to compositions in the prevention and treatment of human immunodeficiency virus. BACKGROUND

[0003] High HIV viral load (VL) is associated with increased transmission risk and faster disease progression. HIV controllers have low VLs without antiretroviral treatment (ART; elite controllers: <50 copies / mL; viremic controllers: <2,000 copies / mL) (1-3). HIV control develops early in infection (3, 4) and is associated with improved health outcomes (3, 5). Understanding the factors that lead to HIV control may inform the design of therapeutic HIV vaccines and antibody-based treatment strategies.

[0004] Many HIV controllers are infected with replication-competent viruses (6, 7) suggesting that host factors play a role in HIV control. Control is associated with class I HLA- B*57 and HLA-B*27 alleles (8), suggesting a role for CD8+T cell responses. CD8+T cell depletion in non-human primate models of elite control leads to viral rebound (9-11). Controllers also have more effective HIV-specific CD8+T cell responses than non-controllers (12, 13) with increased cytotoxicity toward infected cells (13-15). Humoral immunity was initially not thought to play a major role in HIV control because early research described controllers with low titers of HIV-specific antibodies (16) and neutralizing antibodies (nAb) (2, 17-19), consistent with reduced antigen exposure. However, subsequent studies demonstrated higher levels of antibodydependent cellular cytotoxicity (ADCC) (20) and potent broadly neutralizing antibody (bnAb) responses (21, 22) in a subset of controllers. Antibody isotype diversity and polyfunctionality are also associated with control (23, 24). Using a massively multiplexed antibody profiling system (VirScan), we previously identified seven primary antibody targets in HIV controllers with established infection (25).

[0005] HIV-specific antibody responses develop in some persistently uninfected persons after viral exposure. In female sex workers, these antibodies exhibit cross-clade viral neutralization activity (26-28) and may (29) or may not (30) be associated with resistance to subsequent infection. In men who have sex with men, nAbs can develop following repeated oral HIV exposure (31, 32). Pre-existing ADCC in exposed infants is associated with lower rates of HIV acquisition (33, 34) and reduced morbidity after infection (33). The role of pre-infection antibodies in HIV control has not been explored. SUMMARY

[0006] We identified pre-infection HIV antibody reactivities that correlated with post- infection VL. Pre-infection reactivity to an epitope in the HR2 domain of gp41 was associated with controller status and lower VL. Pre-infection reactivity to an epitope in the C2 domain of gp120 was associated with non-controller status and higher VL. Different patterns of antibody reactivity were observed over time for these two epitopes.

[0007] Accordingly, in certain aspects, a vaccine formulation comprises a therapeutically effective amount of one or more human immunodeficiency virus (HIV) gp41 C-terminal heptad repeat region (HR2) peptides.

[0008] In certain embodiments, the one or more HIV gp41 C-terminal heptad repeat region (HR2) peptides comprise at least a 90% sequence identity to SEQ ID NOs: 10-21, 31-42 or combinations thereof.

[0009] In certain embodiments, the one or more HIV gp41 C -terminal heptad repeat region (HR2) peptides comprise one or more peptides of SEQ ID NOs: 10-21, 31-42 or combinations thereof. In certain embodiments, the one or more HIV gp41 C -terminal heptad repeat region (HR2) peptides comprising SEQ ID NOs: 10-21, 31-42, include one or more amino acid residue insertions, deletions, substitutions or combinations thereof. In certain embodiments, the one or more HIV gp41 C -terminal heptad repeat region (HR2) peptides comprising SEQ ID NOs: 10-21, 31-42, include one or more unnatural amino acids.

[0010] In certain embodiments, the one or more HIV gp41 C -terminal heptad repeat region (HR2) peptides comprising SEQ ID NOs: 10-21, 31-42, include one or more synthetic amino acids. In certain embodiments, the one or more HIV gp41 C -terminal heptad repeat region (HR2) peptides comprise one or more peptides comprising SEQ ID NOs: 10-21, 31-41 or 42 linked to one or more peptides comprising SEQ ID NOs: 10-21, 31-41 or 42. In certain embodiments, the one or more linked peptides comprising SEQ ID NOs: 10-21, 31-41 or 42 comprise two or more linked peptides having the same peptide sequence. In certain embodiments, the one or more linked peptides comprising SEQ ID NOs: 10-21, 31-41 or 42 comprise two or more linked peptides having different peptide sequences.

[0011] In certain embodiments, the one or more linked peptides of SEQ ID NOs: 10-21, 31-41 or 42 comprise repeats of the same peptide sequences and one or more different peptide sequences. In certain embodiments, the one or more peptides comprising SEQ ID NOs: 10-21, 31-41 or 42 comprise one or more modifications.

[0012] In certain embodiments, the one or more peptides comprise glycosylation, deglycosylation, acetylation, pegylation, phosphorylation, lipidation or combinations thereof.

[0013] In certain embodiments, the vaccine formulation further comprises one or more agents linked to one or more peptides comprising SEQ ID NOs: 10-21, 31-41 or 42. In certain embodiments, the one or more agents 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.

[0014] In another aspect, a vaccine formulation comprises one or more peptides comprising SEQ ID NOs: 1-42. In certain embodiments, the vaccine formulation comprises an immunogenic carrier, such as an adjuvant.

[0015] In another aspect, a vaccine formulation further comprises one or more monoclonal antibodies, polyclonal antibodies or combinations thereof, which specifically bind to one or more HIV epitopes. In certain embodiments, the monoclonal and polyclonal antibodies specifically bind to an HIV C epitope.

[0016] In another aspect, a method of preventing or treating a human immunodeficiency virus (HIV) infection subject comprising administering to a subject, a pharmaceutical composition comprising a vector encoding one or more one or more human immunodeficiencyvirus (HIV) gp41 C-terminal heptad repeat region (HR2) peptides having at least a 90% sequence identity to SEQ ID NOs: 10-21, 31-42, or a therapeutically effective amount of one or more human immunodeficiency virus (HIV) gp41 C-terminal heptad repeat region (HR2) peptides having at least a 90% sequence identity to SEQ ID NOs: 10-21, 31-42 or combinations thereof.

[0017] In certain embodiments, one or more HIV gp41 C-terminal heptad repeat region (HR2) peptides comprise one or more peptides of SEQ ID NOs: 10-21, 31-42 or combinations thereof. 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 one or more immunotherapeutics, anti-viral agents or 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, helicase inhibitors, integrase 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 immunotherapies comprise monoclonal antibodies, polyclonal antibodies or combinations thereof which specifically bind to one or more HIV epitopes. In certain embodiments, the one or more HIV epitopes comprise C epitopes. 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.

[0018] In another aspect, a vector comprises a nucleic acid sequence encoding one or more of SEQ ID NOs: 1-42.

[0019] In another aspect, an isolated cell comprising a vector encoding one or more of SEQ ID NOs: 1-42. 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, stem cells or combinations thereof.

[0020] In another aspect, a vaccine comprises a polynucleotide encoding one or more of SEQ ID NOs: 1-42. In certain embodiments, the polynucleotide is ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimetics thereof. In certain embodiments, the polynucleotide comprises one or more modified nucleic acid bases.

[0021] In another aspect, a method of identifying pre-infection antibodies by an infectious agent, comprises incubating a sample from a subject with a library; wherein the library displays a plurality of infectious agent peptides; immunoprecipitating antibody-bound peptides; amplifying peptide encoded DNA from the immunoprecipitated antibody bound peptides; sequencing peptides bound by antibodies; and identifying pre-infection antibodies by an infectious agent. In certain embodiments, wherein the infectious agent comprises a virus, bacterium, parasite or prion. In certain embodiments, the method is a high-throughput method. In certain embodiments, wherein the library comprises phage display library, yeast display, bacterial display, mRNA display, ribosome display, MIPSA or combinations thereof.

[0022] In certain aspects, the virus comprises one or more of double-stranded DNA viruses, single-stranded DNA viruses, double-stranded RNA viruses, positive sense single- stranded RNA viruses, negative sense single-stranded RNA viruses, single-stranded RNA viruses with a DNA intermediate in their life cycle, or double-stranded DNA viruses with an RNA intermediate in their life cycle. In certain embodiments, the virus is a is a retrovirus. In certain embodiments, the virus is a human immunodeficiency virus (HIV).

[0023] In another aspect, a vaccine formulation comprises a therapeutically effective amount of one or more monoclonal antibodies, polyclonal antibodies or combinations thereof, wherein the antibodies specifically bind to an HIV C epitope.

[0024] Definitions

[0025] 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).

[0026] As used herein, the singular forms “a”, “an” and “the” are intended to include the 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 eitherthe detailed description and / or the claims, such terms are intended to be inclusive in a manner similar to the term “comprising.”

[0027] 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 otherwise 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 to refer 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, and 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.

[0028] As used herein, the terms “agent” or “moiety” are 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.

[0029] 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,” “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).

[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 elements 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 anyof the listed elements or features individually or any of the recited elements or features in combination with any of the other recited elements or features. For example, the phrases “at least one 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 an unrecited feature or element is also permissible.

[0031] The term “amino acid” as used herein refers to naturally occurring and synthetic or non-naturally occurring α, β, γ, and δ 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, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleucinyl, β-prolinyl, β-phenylalaninyl, β- tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β- asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl or β-histidinyl. When the term amino acid is used, it is considered to be a specific and independent disclosure of each of the esters of α, β, γ, and δ glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine in the 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-D-methyl amino acids, C-D-methyl amino acids, E-methyl amino acids and D- or L-E-amino acids. Other non-naturally occurring amino acids include, for example, E-alanine (E-Ala), norleucine (Nle), norvaline (Nva), homoarginine (Har), 4-aminobutyric acid (J-Abu), 2-aminoisobutyric acid (Aib), 6-aminohexanoic acid (H-Ahx), ornithine (orn), sarcosine, D-amino isobutyric acid, 3-aminopropionic acid, 2,3-diaminopropionic acid (2,3-diaP), D- or L-phenylglycine, D-(trifluoromethyl)-phenylalanine, and D-p- fluorophenylalanine.

[0032] 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.

[0033] 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 characteristic(s)” of the claimed disclosure.

[0034] 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.

[0035] The term “combination therapy”, as used herein, refers to those situations in which two or more different pharmaceutical agents (e.g., SEQ ID NOs: 1-42 or variants thereof and a chemotherapeutic agent) are administered in overlapping regimens so that the 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 the agents are present in separate formulations. In another 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.

[0036] 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.), GPI-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. The 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 mannide (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 the PLURONICTMbrand products, especially L121. 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 to about 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 U.S. Patent Application Publication No. US2004 / 0213817 A1. “Adjuvanted” refers to a composition that incorporates or is combined with an adjuvant.

[0037] 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 theanimals 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.

[0038] An “antibody fragment” comprises a portion of an intact antibody, preferably the antigen binding and / or the 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 multispecific antibodies formed from antibody fragments.

[0039] 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 serve 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.

[0040] 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, 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, non-nucleoside reverse transcriptase inhibitors, purine nucleosides, chemokine receptor antagonists, interleukins, or combinations thereof. The term also refers tonon-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), analogs, variants etc.

[0041] 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 item, composition, apparatus, method, process, system, etc.

[0042] 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 the 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.

[0043] 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.

[0044] An “elite controller” or “HIV controller” is a person living with HIV who is able to maintain undetectable viral loads for at least 12 months despite not having started antiretroviral therapy (ART). Elite controllers are rare: for every two hundred people living with HIV, approximately one may be an elite controller (0.5%).

[0045] 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 translatedregions 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.

[0046] 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 full-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 of constant 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.

[0047] As used herein, the term “immune response,” means a process involving the 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 the 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 cell activity or infiltration, macrophage activity or infiltration, neutrophil activity or infiltration, and the like.

[0048] “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, andthis in turn provides for improved responses against the 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 fraction of HLA haplotypes in a population, and which elicit T-helper lymphocyte responses.

[0049] 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 CD4+and CD8+T-cells.

[0050] 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.

[0051] 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. The 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-monomer interactions, such as Watson-Crick type of base pairing, Hoogsteen or reverse Hoogsteen types of base pairing, or the like.

[0052] 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 the 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.

[0053] “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.

[0054] 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, the 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).

[0055] 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 antibodiesand 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 at least 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 scaffold 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 11, 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 protein- based 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: 10.1016 / j.actbio.2021.05.003. Epub 2021 May 16. PMID: 34010691; PMCID: PMC8497425, incorporated herein by reference in its entirety.

[0056] “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.

[0057] The terms “specific binding” or “specifically binding” when used in 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., the 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.

[0058] 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.

[0059] 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 the subject being treated and the particular mode of administration.

[0060] 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 can include, 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 the state ofcondition, 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.

[0061] As used herein, the terms “treat” 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 the 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 the disease in a subject as compared to a control. Thus, the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction 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 10%, 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.

[0062] 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 the natural 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- phenylalanine, an O-4-allyl-L-tyrosine, a 4-propyl-L-tyrosine, a tri-O-acetyl-GlcNAcβ-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- phenylalanine, 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-linked sugar-containing amino acid; a redox-active amino acid; an α-hydroxy containing acid; an amino thio acid containing amino acid; an α,α disubstituted amino acid; a β- 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.

[0063] As used herein, “variant” of polypeptides refers to an amino acid 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 besubstituted, inserted, or deleted without abolishing biological activity may be found using computer programs well known in the art, for example, LASERGENE software (DNASTAR).

[0064] 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.

[0065] Genbank and NCBI submissions indicated by accession number cited herein are incorporated herein by reference.

[0066] 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

[0067] 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.

[0068] FIGS.1A, 1B demonstrate pre-infection antibody reactivity for HIV controllers and viremic non-controllers. FIG.1A: The figure shows the size and position of open reading frames in the HIV genome. FIG.1B: The plot shows the level of pre-infection antibody binding (average z-statistic) for HIV peptides spanning the viral genome. The x-axis shows the nucleotide position in the HIV genome relative to genomic coordinates for HXB2 reference strain (NCBI #NC_001802). Each dot represents a single peptide in the VirScan library. Red dots indicate aggregate data for 13 controllers; black dots indicate aggregate data for 135 viremic non-controllers. Nine peptides had statistically significant higher antibody reactivity for viremic non-controllers; these peptides shared the V epitope. Twelve peptides had higher antibodyreactivity for controllers; these peptides shared the C epitope (see FIGS.2A, 2B and Table 2). Abbreviations: ORF: open reading frame; Kb: kilobase.

[0069] FIGS.2A, 2B show the epitopes with differential antibody reactivity in controllers and viremic non-controllers. FIG.2A: The figure shows the location of the V and C epitopes in a linear model of the HIV-1 envelope protein; a consensus sequence (sequence logo) is shown for each epitope. The V epitope is in the second constant region (C2) of gp120; the C epitope is in the C-terminal heptad repeat region (HR2) of gp41. FIG.2B: The figure shows the location of the V and C epitopes on a cryo–electron microscopy (cryo-EM) structure of the HIV- 1 envelope protein trimer (side view, PDB ID: 6VRW) (46). gp120 monomers are colored light green, light blue, and gray; gp41 monomers are colored dark green, dark blue, and gray. The V epitope is shown on all monomers in red; the C epitope is shown on all monomers in dark red.

[0070] Abbreviations: C1-5: constant regions; V1-5: variable regions; FP: fusion protein; HR1-2: heptad repeat regions; MPER: membrane-proximal external region; TMD: transmembrane domain.

[0071] FIGS.3A, 3B demonstrate the association between antibody reactivity to the C and V epitopes and HIV-1 VARscore prior to infection. VARscores are an aggregate measure of the level and breadth of antibody reactivity to all peptides spanning the viral genome. The plots show HIV-1 VARscores prior to infection for participants with and without reactivity to the C epitope (FIG.3A) and V epitope (FIG.3B). Data are shown for 148 participants (13 controllers and 135 viremic non-controllers). P-values show the significance of the association between pre- infection reactivity and HIV-1 VARscore. VARscores were calculated after excluding reactivity data for peptides containing the C (FIG.3A) and V epitope (FIG. 3B).

[0072] FIGS.4A, 4B show the antibody reactivity to the C and V epitopes before and after HIV infection. The plots show the level of antibody reactivity (log10 fold change) to the C and V epitopes at the pre-infection and follow-up visits. VirScan data were available for 86 participants at the follow-up visit (13 controllers and 73 viremic non-controllers. Tables 1 and 2). FIG.4A includes paired data for 86 participants who had reactivity to the C epitope at the pre- infection and / or follow-up visit. All 86 participants had reactivity to the C epitope at follow-up; the seven participants with reactivity to the C epitope before infection had significantly higher reactivity to this epitope at follow-up. FIG.4B includes paired data for 29 participants who had reactivity to the V epitope at the pre-infection and / or follow-up visit (data are not shown for 57participants who had no reactivity to the V epitope at either visit). Three participants who had no reactivity to the V epitope before infection developed reactivity to the V epitope at follow-up. Eleven of the 26 participants who had reactivity to the V epitope before infection no longer had reactivity to this epitope at follow-up; the remaining 15 participants did not have differential reactivity to this epitope at follow-up compared to baseline.

[0073] FIGS.5A, 5B demonstrates the association between pre-infection antibody reactivity to the C and V epitopes and HIV viral load. The plots show the association between the presence of antibody reactivity to the C epitope (FIG. 5A) and V epitope (FIG.5B) before infection (pre-infection visit) and log10 HIV viral load after infection (follow-up visit; infection duration: 1-2 years). Data are shown for the 87 participants who did not have antiretroviral drugs detected at follow-up and had viral load data from that visit (13 controllers and 74 viremic non- controllers, Tables 1 and 2).

[0074] FIGS.6A-6D demonstrate the correlation between the strength of antibody reactivity to the C and V epitopes after infection and HIV viral load. The plots show the Pearson correlation (R) between the strength of antibody reactivity (log10fold change) to the C epitope (FIGS. 6A and 6B) or the V epitope (FIGS. 6C and 6D) and log10 HIV viral load. VirScan data were available for 145 (98%) of 148 participants at baseline and 86 (58%) of 148 participants at follow-up (Tables 1 and 2). Each dot represents data for one participant; participants who did not have reactivity to the epitope of interest were excluded from the analysis. The blue line indicates the first principal component. FIG.6A shows data for the 143 participants who had reactivity to the C epitope at the baseline visit (infection duration: <1 year). FIG.6B shows data for the 86 participants who had reactivity to the C epitope at the follow-up visit (infection duration: 1-2 years). FIG.6C shows data for the 37 participants who had reactivity to the V epitope at the baseline visit. FIG. 6D shows data for the 18 participants who had reactivity to the V epitope at the follow-up visit.

[0075] FIGS.7A, 7B are schematics showing the identification of controllers and viremic non-controllers. Study visits were conducted during annual surveys (referred to as PC0, PC12, PC24, and PC36). The pre-infection visit was the last HIV-negative visit. The baseline visit was the first HIV-positive visit (infection duration: 0-1 year). The follow-up visit was the second HIV-positive visit (infection duration: 1-2 years). Viral load and antiretroviral drug testing were used to identify HIV controllers and viremic non-controllers.aThe 585seroconverters included two groups: (1) 360 participants were HIV negative at PC0 and HIV positive at PC12; (2) 225 participants were HIV negative at PC12 and HIV positive at PC24. The remaining 393 of 978 HPTN 071 seroconverters had different seroconversion timing and / or visit completeness and were not included.b182 participants had an additional visit at PC36. To be classified as a controller, these participants were also required to have a VL<2,000 copies / mL with no ARV drugs detected at that visit.cThe 225 seroconverters include those who were HIV negative at PC12 and HIV positive at PC24. The remaining 753 of 978 HPTN 071 seroconverters with different seroconversion timing and / or visit completeness and were not included.dOf these participants, 47 persons who were suppressed on ART at baseline (VL <400 copies / mL) and 17 non-controllers with naturally low VLs at baseline only (<2,000 copies / mL) were included in the analyses described in FIGS 8A-8C. Abbreviations: ARV: antiretroviral; N: number; VL: viral load.

[0076] FIGS.8A-8C demonstrate the pre-infection antibody reactivity for seroconverters and participants who did not acquire HIV infection during the study. The association between pre-infection antibody reactivity and infection risk was evaluated. This analysis included an expanded group of participants who acquired HIV infection during HPTN 071 (13 controllers and 135 viremic non-controllers included in the main analyses, plus 64 additional non-controllers who either had ARV drugs detected at baseline [n=47] or were naturally suppressed at baseline only [n=17]; total 212 seroconverters). This analysis also included 217 participants who were uninfected at all study visits; participants in the uninfected group reported 0-1 lifetime sexual partners and were matched to the 212 seroconverters based on gender, age, and study community. Participants in both groups had low-level antibody binding to HIV peptides across the genome prior to infection (FIG.8B). There were no differences in antibody reactivity to individual peptides between the 212 seroconverters and the 217 uninfected participants (FIG. 8C). Pre-infection HIV-1 VirScores for the 212 seroconverters and the 217 uninfected participants were also compared to explore whether HIV exposure prior to infection was associated with subsequent HIV acquisition. HIV-1 VirScores were low in both groups prior to infection with no difference between groups (seroconverters: 0.19, uninfected: 0.22 p=0.13; data not shown). This indicates that prior HIV exposure was not associated with HIV infection risk. FIG.8A: The figure shows the size and position of open reading frames in the HIV genome. FIG.8B: The plot shows the level of pre-infection antibody binding (average z-statistic) for HIVpeptides spanning the viral genome. The x-axis shows the nucleotide position in the HIV genome relative to genomic coordinates for HXB2 reference strain (NCBI #NC_001802). Each dot represents a single peptide in the VirScan library. Black dots indicate data for the 212 seroconverters (13 controllers and 199 non-controllers); red dots indicate data for the 217 uninfected participants. FIG.8C: The volcano plot shows the difference in antibody reactivity (fold change) between the two groups (x-axis) and the -log10 p value for each peptide based on t-statistics (y-axis). Positive numbers correspond to stronger antibody reactivity in seroconverters. Abbreviations: ORF: open reading frame; Kb: kilobase.

[0077] FIGS.9A, 9B demonstrate the differences in pre-infection antibody reactivity for controllers vs. viremic non-controllers. Pre-infection antibody reactivity was compared for 13 HIV controllers and 135 viremic non-controllers. FIG. 9A: The volcano plot shows the difference in pre-infection antibody reactivity (mean fold change) between the two groups (x- axis) and the -log10 p-value for each peptide based on t-statistics (y-axis). Positive numbers on the x-axis correspond to stronger antibody reactivity in controllers; negative numbers on the x- axis correspond to stronger antibody reactivity in viremic non-controllers. Red dots indicate the nine peptides that had significantly higher reactivity in viremic non-controllers compared to controllers at a false discovery rate of 5%. The blue dashed line indicates the highest q-value <5% (q=0.0418); this corresponds to a p-value of 0.000151. FIG. 9B: The plot shows the significance of the difference in pre-infection antibody reactivity for each peptide in the VirScan library for controllers vs. viremic non-controllers. The x-axis shows the position in the HIV genome for each peptide; each dot represents a single peptide. The y-axis shows the -log10 p- value based on t-statistics for each peptide. Red dots indicate peptides that had higher antibody reactivity in controllers. Black dots indicate peptides that had higher antibody reactivity in viremic non-controllers. The blue dashed line indicates the highest q-value <5% (q=0.0418); this corresponds to a p-value of 0.000151. The nine peptides with q-values <0.05 (above the blue dashed line) had significantly higher reactivity in viremic non-controllers compared to controllers. These peptides contained the V epitope. Abbreviations: Kb: kilobase. DETAILED DESCRIPTION

[0078] The present disclosure is directed to peptides in the prevention and treatment of

[0079] Peptides

[0080] 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 amino acid residue does not destroy the activity and / or the tertiary structure of the polypeptide relative to the 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 incorporation of the modified amino 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, pharmacologics 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 circulation time), 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 the 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 the 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, andmethods for using such polypeptides and polypeptide compositions are considered within the scope of the 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).

[0081] Accordingly, in certain aspects, a vaccine formulation comprises a therapeutically effective amount of one or more human immunodeficiency virus (HIV) gp41 C-terminal heptad repeat region (HR2) peptides. In certain embodiments, the one or more HIV gp41 C -terminal heptad repeat region (HR2) peptides comprise one or more peptides of SEQ ID NOs: 10-21, 31- 42 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 HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 10.

[0082] Accordingly, in certain embodiments an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 11.

[0083] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 12.

[0084] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 13.

[0085] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 14.

[0086] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 15.

[0087] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 16.

[0088] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 17.

[0089] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 18.

[0090] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 19.

[0091] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 20.

[0092] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 21.

[0093] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 31.

[0094] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 32.

[0095] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 33.

[0096] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 34.

[0097] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 35.

[0098] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 36.

[0099] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 37. [000100] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 38.[000101] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 39. [000102] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 40. [000103] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 41. [000104] In certain embodiments, an HIV gp41 C -terminal heptad repeat region (HR2) 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 SEQ ID NO: 42. [000105] In certain embodiments, the vaccine comprises any one or more HIV gp41 C- terminal heptad repeat region (HR2) peptides having at least one mutation or variation. In certain embodiments, the vaccine comprises any one or more HIV gp41 C-terminal heptad repeat region (HR2) peptides having at least one mutation. In certain embodiments, the vaccine comprises any one or more HIV gp41 C-terminal heptad repeat region (HR2) peptides having at least two mutations. [000106] In certain embodiments, the one or more HIV gp41 C -terminal heptad repeat region (HR2) peptides comprising SEQ ID NOs: 10-21, 31-42, include one or more amino acid residue insertions, deletions, substitutions or combinations thereof. In certain embodiments, the one or more HIV gp41 C -terminal heptad repeat region (HR2) peptides comprising SEQ ID NOs: 10-21, 31-42, include one or more unnatural amino acids. In certain embodiments, the one or more HIV gp41 C -terminal heptad repeat region (HR2) peptides comprising SEQ ID NOs: 10-21, 31-42, include one or more synthetic amino acids. [000107] In certain embodiments, a vaccine comprises at least one or more of SEQ ID NOs: 1-42.[000108] In some embodiments, SEQ ID NOs: 1-42 comprise one or more conservative mutations as compared to its parental counterpart. In some embodiments, the SEQ ID NOs: 1-42 variants 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 acid 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 their physicochemical 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 amino 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. [000109] In certain embodiments, a vaccine comprises one or more peptides linked together. For example, a vaccine comprises, SEQ ID NO: 10 in two or more repeating units. In another example, SEQ ID NO: 10 is linked to another peptide sequence embodied herein, such as for example SEQ ID NO: 42. These can be repetitive or associated in various combinations. For example, (SEQ ID NO: 10)-(SEQ ID NO: 12)-(SEQ ID NO: 10)-(SEQ ID NO: 12)-(SEQ ID NO: 13) and the like. 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 IA. Immunoassay Methods and their Applications in Pharmaceutical Analysis: Basic Methodology and Recent Advances. Int J Biomed Sci.2006 Sep;2(3):217-35. PMID: 23674985; PMCID: PMC3614608.[000110] In certain embodiments, the vaccine comprising any one of SEQ ID NOs: 1-42, 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. [000111] In certain embodiments, the one or more HIV gp41 C -terminal heptad repeat region (HR2) peptides comprising SEQ ID NOs: 10-21, 31-42, include one or more amino acid residue insertions, deletions, substitutions or combinations thereof. In certain embodiments, the one or more HIV gp41 C -terminal heptad repeat region (HR2) peptides comprising SEQ ID NOs: 10-21, 31-42, include one or more unnatural amino acids. In certain embodiments, the one or more HIV gp41 C -terminal heptad repeat region (HR2) peptides comprising SEQ ID NOs: 10-21, 31-42, include one or more synthetic amino acids. [000112] 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’)2 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. [000113] 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”), polyoxyethylated 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 hasat 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 the polymer to optimize or confer the desired biological activity. PEG is useful in biological applications 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 pharmacokinetic 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. [000114] In certain embodiments, the 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 the 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 (13C,15N,2H,125I,123I,99Tc,43K,52Fe,67Ga,68Ga,111In and the like). Other useful moieties are known in the art. [000115] 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.[000116] 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 reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, purine nucleosides, chemokine receptor antagonists, interleukins, or combinations thereof. [000117] 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, MIP-1beta, 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, PD-1, VISTA, B7-H2, B7-H3, PD-L1, 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). “Anti-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 receptor(s); 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 checkpointinhibitor proteins and its natural receptor(s); 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 receptor(s); nucleic acid molecules that block immune checkpoint inhibitor nucleic acid transcription or translation; and the like. Such agents can directly block the interaction between the one or more immune checkpoint inhibitors and its natural receptor(s) (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 receptor(s) 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-L1 antibodies, and anti-CTLA-4 antibodies, either alone or used in combination. [000118] In certain embodiments, the peptides are conjugated via a linker to each other or to the 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. [000119] 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-succinimidyl-3-(2- pyridyldithio) propionate (SPDP), succinimidyl-4-(N-maleimidomethyl) cyclohexane-1- carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), 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)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4- dinitrobenzene). The linker may be a “cleavable linker” facilitating release of the effector entityupon 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. [000120] 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: 1-42 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 the two molecules to be conjugated to include a reactive group (as non- limiting 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 the art (i.e., photocrosslinking, see, e.g., Zatsepin et al. Russ. Chem. Rev.74: 77-95 (2005)). [000121] Nucleic Acids [000122] Also provided herein are nucleic acids encoding the peptides comprising any one of SEQ ID NOs: 1-42, 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 form of nucleotides of any length, either ribonucleotides or desoxyribonucleotides. Thus, this term includes, but is not limited to, single-, double- or multi- stranded DNA or RNA, genomic DNA, cDNA, DNA-RNA hybrids, or a polymer comprising purine and pyrimidine bases, or other natural, chemically or biochemically modified, non-natural, or derivatized nucleotide bases. [000123] The nucleic acids encoding the encoding the peptides comprising any one of SEQ ID NOs: 1-42, variants or functional fragments thereof disclosed herein may be, e.g., DNA, cDNA, RNA, synthetically produced DNA or RNA, or a recombinantly 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 SEQ ID NOs: 1-42 variants or functional fragments thereof disclosed herein described herein operablylinked to expression control sequences suitable for expression in a eukaryotic and / or prokaryotic host cell. [000124] 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 art 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 picornavirus 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 leukosis- sarcoma, mammalian C-type, B-type viruses, D type viruses, HTLV-BLV group, lentivirus, and spumavirus. [000125] A variety of expression vectors have been developed for the efficient synthesis polypeptides such as encoding the peptides comprising any one of SEQ ID NOs: 1-42, 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 SEQ ID NOs: 1-42, variants or functional fragments thereof disclosed herein. [000126] The encoding the peptides comprising any one of SEQ ID NOs: 1-42, variants or functional fragments thereof are typically produced by recombinant expression. For example, a nucleic acid encoding any one of SEQ ID NOs: 1-42, 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. [000127] 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). [000128] The expression of the encoding the peptides comprising any one of SEQ ID NOs: 1-42, 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. [000129] E. coli 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, Serratia, and various Pseudomonas species. [000130] Other microbes, such as yeast, are also useful for expression of the encoding the peptides comprising any one of SEQ ID NOs: 1-42, 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 of replication, 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.[000131] Further, by use of, for example, the yeast ubiquitin hydrolase system, in vivo synthesis of ubiquitin-transmembrane polypeptide fusion proteins can be accomplished. The fusion proteins so produced can be processed in vivo or purified and processed in vitro, allowing synthesis of encoding the peptides comprising any one of SEQ ID NOs: 1-42, 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). [000132] 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 in mediums rich in glucose can be utilized to obtain recombinant HIV gp41 C -terminal heptad repeat region (HR2) antibodies or peptides of the present disclsoure. 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. [000133] Production of encoding the peptides comprising any one of SEQ ID NOs: 1-42, 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. [000134] In addition to microorganisms, mammalian tissue culture may also be used to express and produce encoding the peptides comprising any one of SEQ ID NOs: 1-42, variants or functional fragments thereof disclosed herein. See Winnacker, 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, RNA 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 the like. See Co et al., J. Immunol.148:1149 (1992). [000135] Alternatively, nucleotide sequences encoding encoding the peptides comprising any one of SEQ ID NOs: 1-42, variants or functional fragments thereof disclosed herein can be incorporated in transgenes for introduction into the genome of a transgenic animal and subsequent expression in the 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 of SEQ ID NOs: 1-42, 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. [000136] 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 of SEQ ID NOs: 1-42, 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. [000137] 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, and microinjection (see generally, Sambrook et al., 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. [000138] Once expressed, the encoding the peptides comprising any one of SEQ ID NOs: 1- 42, 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 generallyScopes, Protein Purification (Springer-Verlag, 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. [000139] 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 lines, 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. [000140] 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. [000141] 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 cells (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 the context of cell therapy, e.g., adoptive cell therapy, samples from autologous and allogeneic sources. [000142] Methods of Treating [000143] In embodiments, the methods disclosed herein are useful for preventing HIV infection and / or treating subjects infected with HIV. [000144] 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 one or more anti-viral agents. In certain embodiments, the one or more antiviralagents 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, 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. [000145] In embodiments, a therapeutically effective amount of the SEQ ID NOs: 1-42 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 the 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 preferred. 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 (i.e., the concentration of the agent(s) which achieves a half-maximal inhibition of symptoms) as determined in cell culture, or in an appropriate animal model. Levels in 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.[000146] The SEQ ID NOs: 1-42 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, the 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. [000147] In some embodiments, the SEQ ID NOs: 1-42 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 intrastemal injection and infusion. [000148] 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. [000149] In certain embodiments, a dose of a SEQ ID NOs: 1-42 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 SEQ ID NOs: 1-42 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 SEQ ID NOs: 1-42 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. [000150] For the clinical use of the methods described herein, administration of SEQ ID NOs: 1-42 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, SEQ ID NOs: 1-42 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 SEQ ID NOs: 1-42, variants or functional fragments thereof as described herein in combination with one or more pharmaceutically acceptable ingredients. [000151] Provided herein is a pharmaceutical composition comprising SEQ ID NOs: 1-42 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 are, 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), or solvent encapsulating material, involved in maintaining the stability, solubility, or activity of, an agent. Each carrier 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 andethyl 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 l2 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 drug delivery system. See, for example, Urquhart, et al., 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 defenses against 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 the disclosure are well known to those skilled in the art. Examples include, 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.[000152] The pharmaceutical compositions provided herein comprising SEQ ID NOs: 1-42 variants or functional fragments thereof and a pharmaceutically acceptable carrier may comprise SEQ ID NOs: 1-42 variants or functional fragments thereof at various concentrations. For example, the compositions may comprise SEQ ID NOs: 1-42 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 SEQ ID NOs: 1-42, 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. [000153] In some embodiments, the compositions comprising the SEQ ID NOs: 1-42 variants or functional fragments thereof and the pharmaceutically acceptable carrier are lyophilized and provided in a composition for reconstitution prior to administration. [000154] In one aspect, the SEQ ID NOs: 1-42 variants or functional fragments thereof is administered with an additional therapeutic agent. Such 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 anti-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-1beta, MCP-1, RANTES, and other chemokines. [000155] The administration of SEQ ID NOs: 1-42 variants or functional fragments thereof and the additional therapeutic agent may be concurrently or consecutively. The administration of SEQ ID NOs: 1-42 variants or functional fragments thereof and the additional therapeutic agent may be separately or as a mixture.[000156] 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. [000157] 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 the context excludes that possibility), and the method can include one or more other steps which are carried 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). [000158] See also Grant McAuley W, et al. Front Immunol. 2023; 14:1178520. doi: 10.3389 / fimmu.2023.1178520. eCollection 2023. Comprehensive profiling of pre-infection antibodies identifies HIV targets associated with viremic control and viral load, which is incorporated herein by referenced in its entirety. EXAMPLES [000159] Logistical barriers have hampered efforts to define the role of pre-existing HIV immunity in HIV control. HIV control is typically identified in persons with established infection (3, 6, 8). Most studies include small numbers of controllers and lack pre-infection samples from controllers. A very large longitudinal study is required to identify a cohort of seroconverters who meet the criteria for HIV control and have pre-infection samples available for analysis. [000160] The HPTN 071 (PopART) trial enrolled >48,000 participants in Zambia and South Africa (35). Participants were followed for up to three years with annual HIV testing and sample storage; 978 seroconverters were identified in the enrolled cohort (36). In this report, we used VirScan to compare pre-infection antibody reactivity in HIV controllers and viremic non- controllers in HPTN 071. [000161] METHODS[000162] Source of Samples [000163] This study used samples and data from HPTN 071 (PopART) (NCT 019000977) (35). The trial was conducted in 21 urban communities in Zambia and South Africa (35), where HIV subtype C is predominant (37). The trial enrolled a population cohort of >48,000 adults (ages 18-44), randomly selected from each community, and demonstrated that population-level delivery of a combination HIV prevention package that included universal HIV testing, linkage to care and immediate offer of ART, was associated with reduced HIV incidence (35). Plasma samples were collected at annual visits from enrolled participants. VirScan was used to analyze antibody profiles in a subset of the 978 seroconverters identified in this trial. Antibody profiles were also characterized for a subset of participants who were uninfected at all study visits; participants in this group reported 0-1 lifetime sexual partners and were matched to the seroconverter group based on gender, age, and study community. [000164] Laboratory Methods [000165] Laboratory testing was performed at the HPTN Laboratory Center (Johns Hopkins University, Baltimore, MD). HIV status was determined at each study visit (36). Pre-infection samples additionally had no RNA detected using an assay with a limit of detection (LOD) of 400 copies / mL (36); the same assay was used to measure VL in samples collected at HIV-positive visits. VL values for HIV-positive samples with no RNA detected or RNA detected below the LOD were set at 399 copies / mL. Samples were analyzed for the presence of ARV drugs using a qualitative assay that detects 22 ARV drugs in five classes (LOD: 2 ng / mL or 20 ng / mL, depending on the drug) (38). [000166] Samples were also analyzed using VirScan (39, 40). VirScan is a multiplexed phage-display assay that provides quantitative data for antibody binding to displayed peptides (56 amino acids long with 28 amino acid overlaps) (39, 40). The VirScan library includes peptides that span the genomes of >200 viruses that infect humans, including >3,300 peptides from multiple HIV subtypes and strains (39, 40). After sample incubation with the phage library, antibody-bound phage were immunoprecipitated using magnetic beads coated with protein A and protein G. Peptide-encoding DNA present in immunoprecipitated phage was amplified by polymerase chain reaction (PCR) using primers with sample-specific barcodes. PCR products were sequenced using the NovaSeq 6000 instrument with the S2 flowcell (Illumina, San Diego, CA) to determine the amino acid sequences of peptides bound by antibodies in study samples.[000167] VirScan Data Analysis [000168] Longitudinal samples for each participant were included on the same 96-well immunoprecipitation plate. Each plate included 7-8 mock reactions (beads only; negative controls) and a positive control sample in triplicate (pooled plasma from 10 HPTN 071 participants with infection duration >2 years and VL >2,000 copies / mL). Antibody reactivity data for individual peptides were reported as raw read counts, fold change values (compared to read counts in observed mock reactions), and associated p-values. Raw read counts for each peptide were determined via exact matching of the first 50 nucleotides of peptide coding DNA, with one added read count for each peptide. Fold changes and p-values were determined using the exact test for the negative binomial distribution implemented in the edgeR package (41, 42). Fold change values were set at one under the following conditions: read count <15, fold change <3, and / or p-value >0.001. After adjustment, fold change values >1 indicated significant antibody binding. Z-statistics were calculated by transforming p-values. [000169] Viral aggregate reactivity scores (VARscores) are a measure of the overall level and breadth of antibody reactivity across a viral genome. In this study, VARscores and associated p-values were calculated by comparing mean log2 fold change values for virus specific peptides to distributions of expected mean log2 fold change values for randomly selected peptides in VirScan (43). Viruses that had a VARscore greater than an empirically defined cutoff and a p-value below a Bonferroni-corrected cutoff were considered significant targets of an antibody response. Scores were calculated iteratively; in each iteration, peptides from all viruses in genera with a significantly targeted virus were removed from the pool of peptides used to generate random distributions. This process was performed a maximum of 10 iterations or until no new viruses met the reactivity thresholds. When comparing VARscores for participants with reactivity to specific peptides, those peptides were excluded from the calculation. HIV-1 VARscores were calculated as the mean VARscore across all HIV-1 subtypes. [000170] Statistical Methods [000171] Statistical analysis of peptide-level antibody reactivity between participant groups was performed using t-tests. Observed p-values were used to calculate multiple comparison corrected q-values to control the false discovery rate; q-values <5% were considered statistically significant (44). Alternatively, peptides of interest were selected from a cluster of peptides withobserved differential reactivity (mean z-statistic for group A >1, mean z-statistic for group B <1, mean z-statistic for group A >2x that for group B). Likely antibody epitopes represented by overlapping peptides with differential reactivity were identified with epitopefindr v1.1.30 (45). Epitope reactivity was determined by selecting the maximum reactivity to any peptide with the epitope. Epitope visualization on the env trimer structure (PDB ID: 6VRW) (46) was performed with PyMOL v2.0 (47); epitope sequences from UniProt ID P04583 were aligned to the 6VRW sequence to define epitope position on the structure. VL and fold change values were log10- transformed prior to statistical analysis. Univariate analyses were performed using Fisher’s exact test for categorical variables or the t-test for continuous variables; paired t-tests were used for longitudinal analysis of continuous variables. Correlation analyses were performed using Pearson’s method. Statistical analyses were performed using R v4.1.2 (48). Data were visualized using ggplot2 v3.3.6 (49). [000172] Informed Consent [000173] HPTN 071 (PopART) study participants provided written informed consent prior to enrollment. The study was approved by the institutional review boards and ethics committees at the London School of Hygiene and Tropical Medicine, the University of Zambia, and Stellenbosch University. [000174] RESULTS [000175] Study Cohort [000176] Previous analyses identified 978 seroconverters in the HPTN 071 trial (36). The approach used to identify participants for inclusion in this report is shown in FIGS. 7A, 7B. Viral load and ARV drug testing were used to determine controller status for a subset of seroconverters selected based on seroconversion timing and visit completeness. Participants were classified as controllers if they had a VL <2,000 copies / mL with no ARV drugs detected at the first HIV-positive visit (baseline; infection duration 0-1 years) and the second HIV-positive visit (follow-up; infection duration 1-2 years). This approach for classifying controllers is consistent with criteria used in prior studies (2, 8, 50). Participants were classified as viremic non- controllers if they had a VL ≥2,000 copies / mL with no ARV drugs detected at baseline. The final cohort for the main analyses described in this report included 148 seroconverters, including 13 controllers and 135 viremic non-controllers. Analyses described in FIGS.8A-8C included an additional 47 participants who were suppressed on ART at baseline (VL <400 copies / mL), 17non-controllers with natural suppression at baseline only (VL <2,000 copies / mL, no ARV drugs detected), and a matched control group of 217 participants who remained uninfected throughout the study. [000177] Association between pre-infection antibody reactivity and HIV controller status [000178] VirScan was used to compare pre-infection antibody reactivity for the 13 controllers and 135 viremic non-controllers. Both groups had low-level antibody binding to HIV peptides across the genome (FIGS.1A, 1B). Two clusters of peptides were identified that had differential reactivity in these two participant groups. One cluster of nine overlapping peptides had higher levels of antibody reactivity in viremic non-controllers (V cluster); each of the individual peptides in this cluster had significantly higher mean antibody reactivity in the viremic non-controller group (q<0.05; p<0.000151; FIGS.9A, 9B). A second cluster of 12 overlapping peptides had higher mean levels of antibody reactivity in controllers (C cluster). The individual peptides in this cluster did not have significantly different antibody binding in the two groups after multiple testing correction, but had higher antibody reactivity in the controller group when the analysis was based on observed differences in z-statistics; this likely reflected the small number of controllers included in the analysis who had reactivity to these peptides. [000179] The peptides in each cluster contained a common epitope (FIGS. 2A, 2B and Table 2). Peptides in the C cluster shared an epitope in the C-terminal heptad repeat region (HR2) of gp41 (C epitope). Peptides in the V cluster shared an epitope in the second constant (C2) region of gp120 (V epitope). Pre-infection reactivity to the C epitope (adjusted fold change >1) was observed more frequently among controllers vs. viremic non-controllers (3 / 13 [23.1%] vs.5 / 135 [3.7%], p=0.023). Pre-infection reactivity to the V epitope was not observed among controllers but was common among viremic non-controllers (0 / 13 [0.0%] vs.43 / 135 [31.9%], p=0.011). We did not find any sequences with homology to the C or V epitopes using BLAST, aside from HIV-1 and simian immunodeficiency virus (SIV) sequences (51). [000180] Association between broad pre-infection antibody reactivity to HIV peptides and HIV controller status [000181] The depth and breadth of antibody reactivity to HIV peptides across the viral genome in the 13 controllers and 135 viremic non-controllers was compared. This analysis was performed using an aggregate measure of antibody reactivity (VARscore); higher VARscores(generally >1) indicate prior viral exposure (52). Mean HIV-1 VARscores were low in both groups (controllers: 0.24, viremic non-controllers: 0.18, p=0.533; data not shown), consistent with their HIV-uninfected status. [000182] Association between broad pre-infection antibody reactivity to HIV and C or V epitope reactivity [000183] Pre-infection HIV-1 VARscores were compared for participants with vs. without pre-infection reactivity to the C or V epitope (adjusted fold change >1 vs. adjusted fold change = 1; FIGS.3A, 3B). For this analysis, HIV-1 VARscores were calculated after removing VirScan data for peptides with the relevant epitope (C or V). First, VARscores were compared for participants with (n=8) vs. without (n=140) pre-infection reactivity to the C epitope. Participants with pre-infection reactivity to the C epitope had higher mean HIV-1 VARscores (reactive: 0.75, not reactive: 0.15, p=0.0063); this provides evidence that reactivity to the C epitope may have been induced by prior HIV exposure. Next, VARscores were compared for participants with (n=43) vs. without (n=105) pre-infection reactivity to the V epitope. HIV-1 VARscores were low in both groups with no difference between groups (reactive: 0.23, not reactive: 0.15, p=0.058); this suggests that reactivity to the V epitope may not have been induced by prior HIV exposure. [000184] Changes in antibody reactivity to the C and V epitopes after HIV infection [000185] Antibody reactivity to the C and V epitopes at the pre-infection visit and the first HIV-positive visit (baseline, infection duration 0-1 year) was compared. VirScan data were available at baseline for 145 / 148 participants, including 7 / 8 participants with pre-infection reactivity to the C epitope and 42 / 43 participants with pre-infection reactivity to the V epitope. (Table 3). VirScan data were available at follow-up for 86 / 148 participants, including 7 / 8 participants with pre-infection reactivity to the C epitope and 26 / 43 participants with preinfection reactivity to the V epitope. [000186] At baseline, almost all participants (143 / 145 [98.6%]) had C epitope reactivity; this included all seven participants with pre-infection reactivity to this epitope. Reactivity to this epitope (mean fold change) increased at baseline for the seven participants with pre-infection reactivity (pre-infection: 10.3, baseline: 29.1, p=0.0041). Mean baseline reactivity was similar for participants with vs. without pre-infection reactivity (reactive at pre-infection: 29.1, not reactive at pre-infection: 22.2, p=0.059). We then evaluated reactivity to the C epitope at follow- up (infection duration 1-2 years) when infection was more established. At follow-up, all 86participants had reactivity to the C epitope, including all seven participants with pre-infection reactivity (FIGS.4A, 4B). Mean reactivity was higher at follow-up than pre-infection for participants with pre-infection reactivity (pre-infection: 10.3, follow-up: 42.5, p=0.00036). Mean reactivity was also higher at follow-up for those with vs. without pre-infection reactivity (reactive at pre-infection: 42.5, not reactive at pre-infection: 25.9, p=0.0088). The findings from analysis of data from the baseline and follow-up visits are consistent with results from the VARscore analysis, indicating that HIV exposure induces and boosts expression of C epitope antibodies. [000187] Different patterns of antibody reactivity were observed for the V epitope. Only 37 / 145 (25.5%) participants had reactivity to the V epitope at baseline (data not shown); most (32 / 37 [86.5%]) of these participants also had pre-infection reactivity to this epitope. Ten additional participants with pre-infection reactivity to the V epitope were no longer reactive to this epitope at baseline. There was no increase in V epitope reactivity (mean fold change) after infection for the 32 participants who had V epitope reactivity at both visits (pre-infection: 6.4, baseline: 6.1, p=0.33). We also observed no difference in mean baseline reactivity for participants with vs. without pre-infection reactivity (reactive at pre-infection: 6.1, not reactive at pre-infection: 6.8, p=0.68). Furthermore, only 18 / 86 (20.9%) participants had reactivity to the V epitope at follow-up, including 15 participants with pre-infection reactivity (FIGS.4A, 4B). An additional 11 participants with pre-infection reactivity did not have reactivity to this epitope at follow-up. Mean reactivity was unchanged at follow-up (vs. pre-infection) for the 15 participants with reactivity at both visits (pre-infection: 6.5, follow-up: 7.3, p=0.68), and there was no difference in mean follow-up reactivity for participants with vs. without pre-infection reactivity (reactive at pre-infection: 7.3, not reactive at pre-infection: 7.2, p=0.58). These findings are consistent with results from the VARscore analysis, indicating that expression of V epitope antibodies is not induced or boosted by HIV exposure or HIV infection. [000188] Association between antibody reactivity to the C and V epitopes and viral load [000189] It was evaluated whether pre-infection reactivity to the C and V epitopes was associated with VL after infection. Participants with pre-infection reactivity to the C epitope had lower mean VLs at baseline than those without pre-infection reactivity, but the difference was not statistically significant (reactive at pre-infection: 23,969 copies / mL, not reactive at pre-infection: 98,982 copies / mL, p=0.16; data not shown). A significant difference was observed for mean VL at follow-up (reactive at pre-infection: 4,594 copies / mL, not reactive at pre-infection: 81,124 copies / mL, p=0.014; Figure 5). These findings indicate that the pre-infection reactivity to the C epitope is associated with lower VLs in established infection. [000190] The opposite association was observed for the V epitope. Participants with pre- infection reactivity to the V epitope had higher mean VLs at baseline but the difference was not statistically significant (reactive at pre-infection: 119,243 copies / mL, not reactive at pre- infection: 84,969 copies / mL, p=0.068). A significant difference was observed for mean VL at follow-up (reactive at pre-infection: 150,647 copies / mL, not reactive at pre-infection: 42,709 copies / mL, p=0.0016). These findings indicate that the pre-infection reactivity to the V epitope is associated with higher VLs in established infection. [000191] Also evaluated was whether the strength of antibody reactivity to the C and V epitopes at baseline or follow-up was correlated with VL at the same visit (FIGS. 6A-6D). In persons with C epitope reactivity, the strength of reactivity was inversely correlated with VL at baseline (R= -0.17, p=0.039) and follow-up (R= -0.25, p=0.019). There was no observed correlation between the strength of reactivity to the V epitope and VL at either visit. [000192] Association between pre-infection antibody reactivity and infection risk [000193] As a final step, it was evaluated whether pre-infection antibody reactivity was associated with subsequent HIV infection (FIGS.8A-8C). There were no differences in mean antibody reactivity for 212 seroconverters vs.217 uninfected participants to any HIV peptides in the VirScan library, including those with the C or V epitopes. Mean pre-infection HIV-1 VARscores were also low with no difference between groups (seroconverters: 0.186, uninfected: 0.217 p=0.134).n i sye:tide;)it dit 20e8poti V V V V V V V V VC C C C C C Cviptepe1pEcp p0aee h 0rnic _ tr 8 0 2 2 7yNaeC oe Z 3N rP 8Z4630 09Y 94 0Z Y Q 972877 41 38ib B5d4 B 1281 42 B59 B B S548533 754o.)iero#I .t.sr nmUuQN90 QQP 9 1 41 QQ O OP 91 QQP 9QQ9QQ90 0 0 Q90QP P PQPbtpfBno ellnotaidef po edi C fvNdol rotQnEQSEDI (S QENI(KISETNY EI DIIQE I EM SWYREDIN NTG YTsCor,lp2Bbonc II-IEEDKSV TNTS( R(ITNSWEIYENNESRI IN N DKASR RSMIQRR NE ERNI SIe inDT KM Dveltnereffidyltnacifingisdahtahtseditpep12eh tfoscitsiret vp 5 5c l ell po w oc 6 6 6 6 6 6 6 656 7575757575757a eo V trwra t I ip sedh Tc .nse r oH;e;ritdiec- non 0hiebpecaooit808080808088080806 6 4 4 4 4 4i2-2 2 2 2 2 3 3 316164646464646tllnoonta m pfni so5-25-5-5-5-5-3-3-3-1-1-9-9- - -222222 2 2 5 5 5 6 6 8 8989898srtccoun om Ap 2 2 2 2 2 2 5 5 5 5 5 5 5wonho i ltscsci - meernoertPsi ni 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2enlo iv g in retet nbn oroitC; C0; C0; C0; C C C C CR R R R R R R 0;0;0;0;0;0H;H;H;H;H;H;H;atciniVIU;car p aVc2o12p12p12p12p12p12 2 2 1 1 1 1 1 1 1p1p1p1p4p4p4p4p4p4p4pemy eh etiHa IHl g g g g g g g g g g g g g g g gT rivvi ;cn h] .t rcei efiuCq: 2enneoi v v v v v v v v4 s aetesd gta n n n n n n n nvnvnvnvnvnvnvnvn9 v1srrr nede e e e e e e e e e e e e e e ei nVI cHol0eedic a0l0lhg e a1[orithdi ose ent n l dit 3 2 2 1 8 5 9 7 3 0 2 5 6 0 8D83029 6 9 6 3 8 9 5 4 2 2 1 051od p i bpe I7732274772186112378752372772781304129623cahePmaa7 2 2 2 7 2TPC C771887 7 45805813359ylP0P3P0P1Pg:14YIL NNpS YI YLgTV IL TY EE,YQSINT TT LL noDIYNiENR SE VWEKQ DM WW ET LMWNTN MWIK DDDWLISDSKQNSSKW NS SA WNSWSPNVTWT PT VNCILTPKCGIISK C) GS))C) 4G7W 1C81SC9G1S 0I1 :5F :G:G C2LK2 0GO: : :WL NIO NWIO NGOGO21LQDGWILLDG ILLDIINSNGDCDpL I G IgQQQQQQLQ WQ ;DEKS(QEQEQE I E nDS(DS(QS(GLS(ietor ) )p1) )32) )7)333 )8)0)45)3633:3:)94142003 3 6 5 :O: :3707070717 eNOO: : :OO3: :O:4:OOON NONOO7-7-7-7-7 p D N NN N N DID N N N2353538-374 olIDIDIDID I DIQIDID I DIDI5757575757 ev QnEQEQEQ Qe S(S(S(E EQEQSES Q Q(S((ESQE(E EQS S(S(ES1.-nEoiMEQS( QQ(EE EMMEEQ(EWMM WWIMM WWWWTWLM WMM444 4 4 464 V-64I g T T T T T TMTWT TWTWT9-64-64-6-89 9 9 9HerM NMMMMMNMMMMM NNNNNNNN N NKNNN585858585 :v tane ) )3)4) )6)7) )9)N 0WN W NNDWIWD WDN ep 22;e 2: :2: 52 2 2: 82 2:3I:EIWEIWIEWIWIEDIDWI IQWIWIOOO: :O OON:OEONOWEM QN EQ D LELDLLSDLDSDD EKD2 2 2 2 2rreidN N Na DIDIDIN N NDIDIDIND DIDISKSLKSKSKSNKSKRSQMLNKS S SLNK K KSKR R R R Rf tQQ QI QN N N N NS SN N N NH;H1;H41;H1;H1; i1tnp Qp4gp4gp4gp4gpgee EEEQQ EESQ E QS Sdh SS S EWWS SWS SWWWWS S S SW (( S( ES (S((IES ((IS(S SW SS S S SSSW S W SSW Si:laIIII IMIIIIRVII IVI SNSNA SNA SNANS A A TEIE M KIEIDVE IEVE M K N NN NNNN WWWWWWWPW WWWDnIi e EEEEEEEEEE G EEEEEEEPVPV P:mrcn AVPVPVPVVPW FV PPVPVPLALALALALALALALALNTNTTTTTATNTT VTTNT AVTv v v v veS S S S S S S S S TTTT T T Tn n n n n s eo tuGGT T T T TCICP T T Te e e e e ni -q N NG NG NG NG NG NGGCICICICICICIHIL CtICICICIaCesLLLLLLLLLLLLLN N L L L H L LLL L K K K K K K K KIKLKLKLKi:di LQLQLQLQL L LLLLLGSGSGSGSGSG GSSGSGSGSGSGS6 6 5 0 9 v2R2caTQQQQQ STSTSTSTSTST T TCCCCCCC GC GCCCC3 9 9 4 9 eeo S S SGGGGGGW GGGG9 9 8 1 8 rH l niV V V V V V V V V WWW W3232142253bb ;1bamVAPVKPVPVPVPVPVPVPVPIGIGIWGIWGIWGIGM GFWGIWGIWGIWGIG A4 T K K K K K K K K L L L L L L L L L L L L[000195] Table 3: The table shows the number of participants with data from VirScan and viral load testing by HIV controller status and study visit.[000196]aThree viremic non-controllers were not included in the analysis of VirScan data at baseline due to assay failure. This included one participant with pre-infection reactivity to the C epitope and one participant with pre-infection reactivity to the V epitope. [000197]bSixty-two viremic non-controllers were not included in the analysis of VirScan data at follow-up for the following reasons: no follow-up visit (N=27), on antiretroviral therapy (N=34), assay failure (N=1). This included one participant with pre-infection reactivity to the C epitope and 17 participants with pre-infection reactivity to the V epitope. [000198]cSixty-one viremic non-controllers were not included in the analysis of viral load at follow-up for the following reasons: no follow-up visit (N=27), on antiretroviral therapy (N=34). This included one participant with pre-infection reactivity to the C epitope and 17 participants with pre-infection reactivity to the V epitope. [000199] DISCUSSION [000200] Previous studies demonstrated that HIV-specific pre-existing antibody responses can be protective in non-controllers (26-29, 31-34) but did not include a comprehensive evaluation of reactivity to all expressed HIV peptides. In this study, VirScan was used to compare pre-infection antibody profiles in controllers and viremic non-controllers in HPTN 071. All participants, independent of controller or infection status, had low-level antibody binding to HIV peptides across the viral genome prior to infection; this may reflect a combination of HIV- specific and non-specific binding to target peptides. A subset of participants had pre-infection antibodies to the C and V epitopes; this reactivity was associated with HIV controller status and VL after infection. Neither of these epitopes is targeted by bnAbs under investigation for HIV treatment and prevention (53, 54). 161222925[000201] It was found that the C epitope (gp41, HR2) was targeted more frequently prior to infection in controllers vs. viremic non-controllers (23.1% vs.3.7%). Pre-infection reactivity to this epitope was also associated with higher overall HIV-specific antibody responses prior to infection, suggesting that production of C epitope antibodies was stimulated by HIV exposure without infection. At follow-up (infection duration: 1-2 years), pre-infection responses were boosted and all participants had reactivity to this epitope. Pre- and post-infection reactivity to the C epitope were also associated with lower VL after infection. [000202] The 12 peptides with the C epitope overlap with an HR2 epitope that was targeted in controllers with established HIV infection in our prior study. HR2 plays a critical role in viral fusion; antibodies targeting this region may impair hairpin formation and viral entry (55). NAbs targeting HR2 have been described in slow progressors (56) and controllers (57), while non- neutralizing HR2 antibodies with robust ADCC activity were found in a non-controller (58). This report demonstrates that pre-infection antibody reactivity to the C epitope is associated with controller status and lower VL after infection, consistent with antibody-mediated suppression of viral replication. [000203] Antibodies to V epitope (gp120, C2) were only present prior to infection in viremic non-controllers. In contrast to the C epitope, pre-infection reactivity to this epitope was not associated with pre-infection reactivity to other HIV peptides, suggesting that production of V epitope antibodies was triggered by a mechanism other than HIV exposure. Changes in reactivity to the V epitope over time were also different from those observed for the C epitope. At follow-up, pre-infection responses to the V epitope were not boosted or consistently maintained, and only three participants developed V epitope reactivity after infection. Overall, these data suggest that V epitope reactivity was triggered by an unidentified, non-HIV antigen. [000204] The nine peptides with the V epitope (C2 target) did not overlap with epitopes identified in our previous work. In the RV144 trial (NCT00223080; Thailand), vaccine-induced antibodies targeting C2 were associated with higher levels of ADCC and reduced HIV acquisition risk (59). However, in our study, reactivity to the V epitope was not protective. In antibody dependent enhancement (ADE), pre-existing non-neutralizing or cross-reactive antibodies can facilitate viral entry by interacting with complement and / or the Fc receptor (60). In HIV infection, ADE allows rapid viral trafficking to lymph node resident CD4+ T cells following mucosal transmission, enhancing early processes required to establish robust infection 161222925(61-64). Infection-enhancing antibodies targeting env have been associated with HIV transmission risk (65) and higher VL after infection (66). We find that pre-infection reactivity to the V epitope is associated with non-controller status and higher VL after infection. Taken together, our findings suggest that V epitope reactivity might modulate VL via ADE in early infection. [000205] In summary, two env epitopes were identified that were targeted in some persons prior to infection. Reactivity to one epitope was associated with natural control of HIV infection and appeared to reduce VL via antibody-mediated suppression of viral replication. In contrast, reactivity to the other epitope was not present in HIV controllers and appeared to increase VL, possibly via ADE early in infection. 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OTHER EMBODIMENTS [000207] 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 the following claims. [000208] All 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 indicated to 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. 161222925

Claims

What is claimed:

1. A vaccine formulation comprising a therapeutically effective amount of one or more human immunodeficiency virus (HIV) gp41 C-terminal heptad repeat region (HR2) peptides.

2. The vaccine formulation of claim 1, wherein the one or more HIV gp41 C-terminal heptad repeat region (HR2) peptides comprise at least a 90% sequence identity to SEQ ID NOs: 10-21, 31-42 or combinations thereof.

3. The vaccine formulation of claim 2, wherein the one or more HIV gp41 C -terminal heptad repeat region (HR2) peptides comprise one or more peptides of SEQ ID NOs: 10-21, 31- 42 or combinations thereof.

4. The vaccine formulation of any one of claims 1-3, wherein the one or more HIV gp41 C - terminal heptad repeat region (HR2) peptides comprising SEQ ID NOs: 10-21, 31-42, include one or more amino acid residue insertions, deletions, substitutions or combinations thereof.

5. The vaccine formulation of claim 4, wherein the one or more HIV gp41 C -terminal heptad repeat region (HR2) peptides comprising SEQ ID NOs: 10-21, 31-42, include one or more unnatural amino acids.

6. The vaccine formulation of claim 4, wherein the one or more HIV gp41 C -terminal heptad repeat region (HR2) peptides comprising SEQ ID NOs: 10-21, 31-42, include one or more synthetic amino acids.

7. The vaccine formulation of any one of claims 1-6, wherein the one or more HIV gp41 C - terminal heptad repeat region (HR2) peptides comprise one or more peptides comprising SEQ ID NOs: 10-21, 31-41 or 42 linked to one or more peptides comprising SEQ ID NOs: 10-21, 31-41 or 42.

8. The vaccine formulation of claim 7, wherein the one or more linked peptides comprising SEQ ID NOs: 10-21, 31-41 or 42 comprise two or more linked peptides having the same peptide sequence. 1612229259. The vaccine formulation of claim 8, wherein the one or more linked peptides comprising SEQ ID NOs: 10-21, 31-41 or 42 comprise two or more linked peptides having different peptide sequences.

10. The vaccine formulation of claim 8, wherein the one or more linked peptides of SEQ ID NOs: 10-21, 31-41 or 42 comprise repeats of the same peptide sequences and one or more different peptide sequences.

11. The vaccine formulation of any one of claims 1-10, wherein the one or more peptides comprising SEQ ID NOs: 10-21, 31-41 or 42 comprise one or more modifications.

12. The vaccine formulation of any one of claims 1-10, wherein the one or more comprises glycosylation, deglycosylation, acetylation, phosphorylation, pegylation, lipidation or combinations thereof.

13. The vaccine formulation of any one of claims 1-12, further comprising one or more agents linked to one or more peptides comprising SEQ ID NOs: 10-21, 31-41 or 42.

14. The vaccine formulation of claim 13, wherein the one or more agents 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.

15. The vaccine formulation of any one of claims 1-13, further comprising one or more monoclonal antibodies, polyclonal antibodies or combinations thereof, which specifically bind to one or more HIV epitopes.

16. The vaccine formulation of claim 15, wherein the monoclonal and polyclonal antibodies specifically bind to an HIV C epitope.

17. A vaccine formulation comprising one or more peptides of SEQ ID NOs: 1-42.

18. The vaccine formulation of claim 15, wherein the one or more peptides comprise a scaffold, wherein the scaffold increases immunogenicity as compared to a peptide without a scaffold. 16122292519. A method of preventing or treating a human immunodeficiency virus (HIV) infection subject comprising administering to a subject, a pharmaceutical composition comprising a vector encoding one or more one or more human immunodeficiency virus (HIV) gp41 C-terminal heptad repeat region (HR2) peptides having at least a 90% sequence identity to SEQ ID NOs: 10- 21, 31-42, or a therapeutically effective amount of one or more human immunodeficiency virus (HIV) gp41 C-terminal heptad repeat region (HR2) peptides having at least a 90% sequence identity to SEQ ID NOs: 10-21, 31-42 or combinations thereof.

20. The method of claim 19, wherein one or more HIV gp41 C-terminal heptad repeat region (HR2) peptides comprise one or more peptides of SEQ ID NOs: 10-21, 31-42 or combinations thereof.

21. The method of claims 19 and 20, wherein the one or more peptides induce an immune response to HIV.

22. The method of any one of claims 19-21, further comprising administering one or more secondary therapeutic agents.

23. The method of claim 22, wherein the one or more secondary therapeutic agents comprise immunotherapies, one or more anti-viral agents and combinations thereof.

24. The method of claim 23, 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.

25. The method of any one of claims 19-24, wherein the one or more peptides are formulated with a pharmaceutical carrier, a delivery vehicle or combinations thereof. 16122292526. The method of any one of claims 19-25, wherein the one or more peptides are formulated with a scaffold.

27. The method of claims 23, wherein the immunotherapies comprise monoclonal antibodies, polyclonal antibodies or combinations thereof which specifically bind to one or more HIV epitopes.

28. The method of claim 27, wherein the monoclonal and polyclonal antibodies specifically bind to an HIV C epitope.

29. A vector comprising a nucleic acid sequence encoding one or more of SEQ ID NOs: 1-42.

30. An isolated cell comprising a vector encoding one or more of SEQ ID NOs: 1-42.

31. A vaccine comprising a polynucleotide encoding one or more of SEQ ID NOs: 1-42.

32. The vaccine of claim 31, wherein the polynucleotide is ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimetics thereof.

33. The vaccine of claim 32, wherein the polynucleotide comprises one or more modified nucleic acid bases.

34. A method of identifying pre-infection antibodies by an infectious agent, comprising: incubating a sample from a subject with a library wherein the library displays a plurality of peptides; immunoprecipitating antibody-bound peptide; amplifying peptide encoded DNA from the immunoprecipitated antibody bound peptides; sequencing peptides bound by antibodies; and, identifying pre-infection antibodies by an infectious agent.

35. The method of claim 34, wherein the infectious agent comprises a virus, bacterium, parasite or prion.

36. The method of claim 34, wherein the virus comprises one or more of double-stranded DNA viruses, single-stranded DNA viruses, double-stranded RNA viruses, positive sense single- 161222925stranded RNA viruses, negative sense single-stranded RNA viruses, single-stranded RNA viruses with a DNA intermediate in their life cycle, or double-stranded DNA viruses with an RNA intermediate in their life cycle.

37. The method of claim 36, wherein the virus is a is a retrovirus.

38. The method of claim 38, wherein the virus is a human immunodeficiency virus (HIV).

39. The method of claim 34, wherein the method is a high-throughput method.

40. The method of claim 34, wherein the library comprises phage display library, yeast display, bacterial display, mRNA display, ribosome display, MIPSA or combinations thereof.

41. A method of preventing or treating a subject at risk of or has been infected with human immunodeficiency virus (HIV) comprising: administering a therapeutically effective amount of one or more monoclonal antibodies, polyclonal antibodies or combinations thereof, wherein the antibodies specifically bind to an HIV C epitope.

42. A vaccine formulation comprising a therapeutically effective amount of one or more monoclonal antibodies, polyclonal antibodies or combinations thereof, wherein the antibodies specifically bind to an HIV C epitope. 161222925

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