Hydroxychloroquine as a pretreatment to enhance AAV delivery of broadly neutralizing monoclonal antibodies

Abstract

AAV vectors are ideally suited for long-term delivery of a combination of broadly neutralizing antibodies to achieve sterilizing immunity to HIV. Unfortunately, host immune responses to the delivered antibody have severely limited the efficacy. The TLR9 pathway has been identified in initiating adaptive immune responses against AAV and delivered bNAbs. To enhance this strategy, we validated Hydroxychloroquine, a known drug inhibitor of the TLR9 pathway, as a pretreatment to AAV delivery to avoid anti-drug antibody responses. TLR9 signaling inhibition was validated using a HEK-Blue hTLR9 reporter cell line and CpG stimulation. Hydroxychloroquine was also validated in a 3-macaque trial where AAV9-3BNC117 and AAV9-10-1074 were administered along with 3 doses of hydroxychloroquine once a week starting 1 week before AAV inoculation. Together, these data suggest that the short-term treatment of hydroxychloroquine at the time of AAV inoculation has a meaningful impact on tolerance induction to our AAV-delivered bNAbs.

Description

[0001] HYDROXYCHLOROQUINE AS A PRETREATMENT TO ENHANCE AAV DELIVERY OF BROADLY NEUTRALIZING MONOCLONAL ANTIBODIES

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] The present application claims the benefit and priority of U. S. Provisional Patent Application No. 63 / 717,425, filed on November 7, 2024, entitled “HYDROXYCHLOROQUINE AS A PRETREATMENT TO ENHANCE AAV DELIVERY OF BROADLY NEUTRALIZING MONOCLONAL ANTIBODIES”, the contents of which are hereby incorporated in their entirety.

[0004] FIELD

[0005] The present disclosure provides AAV-delivered antibody compositions and kits for treating and / or preventing infectious diseases (such as, for example Human Immunodeficiency Virus (HIV)) and methods of use thereof.

[0006] BACKGROUND

[0007] Antibody-based strategies for the treatment and / or prevention of Human Immunodeficiency Virus (HIV) have been made possible by an incredible array of monoclonal antibodies with potent neutralizing activity against a broad range of HIV isolates. While such antibodies can be administered passively, repeated expensive administrations over a prolonged period would be required for extended prevention or treatment efforts. Adeno-associated virus (AAV) vectors have a number of attractive features for prolonged delivery of such antibodies. The only protein product from such AAV vectors comes from the DNA sequences put into the vector. As long as those protein products are not viewed as foreign, very prolonged delivery can be achieved. Muscle cells essentially do not turn over and intramuscular delivery of AAV vector can result in very prolonged expression of the transgene product. However, this result is successful for a small fraction of subjects receiving AAV vector making potent broadly neutralizing anti-HIV monoclonal antibodies, known to be highly divergent from germ line. The remainder of subjects experience an anti-drug antibody (ADA) response that negates the successful delivery of the monoclonal antibody. Thus, current antibody-based strategies remain deficient in treating HIV due to intolerant immune responses to the delivered monoclonal antibodies. Given limitations of current HIV antibody-based treatment strategies, there is need to address the aforementioned problems mentioned above by developing a treatment strategy to suppress the ADA response and successfully deliver monoclonal antibodies for a very prolonged period for the treatment or prevention of HIV infection. The methods disclosed herein address these and other needs.

[0008] SUMMARY

[0009] The present disclosure provides methods and kit for the consistent and long-term delivery of antibodies and antibody-like molecules for the treatment and / or prevention of an infectious disease including, but not limited to human immunodeficiency virus (HIV).

[0010] In one aspect, disclosed herein is method of treating or preventing a human immunodeficiency virus (HIV), a hepatitis B virus (HBV), an influenza virus, or a respiratory syncytial virus (RSV) infection in a subject. The method involves administering a therapeutic regimen to a patient in need of treatment or prevention thereof. The regimen comprises a 4-aminoquinoline antimalarial drug, ideally hydroxychloroquine, but chloroquine (Aralen®), quinine / quinidine, mefloquine, primaquine, quinacrine (Atabrine®): or amodiaquine can also be used, and a viral vector encoding a broadly neutralizing antibody (including, but not limited to a HIV broadly neutralizing antibody, a HBV broadly neutralizing antibody, an influenza broadly neutralizing antibody, or a RSV broadly neutralizing antibody).

[0011] Additional 4-aminoquinoline derivatives are disclosed in Solomon, V. R., et al., “Examination of novel 4-aminoquinoline derivatives designed and synthesized by a hybrid pharmacophore approach to enhance their anticancer activities,” Sci Rep 9, 6315 (2019), the contents of which are hereby incorporated by reference. While hydroxychloroquine is the preferred compound, these additional compounds can also be used in place of hydroxychloroquine.

[0012] In some embodiments, the broadly neutralizing antibody includes, but is not limited to 3BNC117, 10-1074, and PGT145. In some embodiments, the viral vector comprises an adeno-associated viral (AAV) vector.

[0013] In some embodiments, the 4-aminoquinoline is administered one, two, three, or four weeks prior to administering the viral vector. In some embodiments, the 4-aminoquinoline is further administered 10 weeks or more following administering the viral vector. In some embodiments, the 4-aminoquinoline is administered one, two, three, four, five, six, or seven times per week. In some embodiments, it is administered by an intramuscular (i.m.) injection. In one embodiment, it is administered once a week starting 1 week before AAV inoculation, and the administration is continued once a week for two or more additional weeks.

[0014] In some embodiments, the therapeutic regimen comprises administering one or more viral vectors encoding a 3BNC117 neutralizing antibody, a 10-1074 neutralizing antibody, or a PGT145 neutralizing antibody. In some embodiments, the one or more viral vectors are individually administered. In some embodiments, the viral vector is administered by an intramuscular (i.m.) injection.

[0015] In some embodiments, the method expresses the neutralizing antibodies for more than 5 weeks. In some embodiments, the method expresses the neutralizing antibodies for more than 7 years. In some embodiments, the method expresses the neutralizing antibodies during a remainder of the subject’s life.

[0016] In some embodiments, the AAV vector comprises an AAV9 serotype. In some embodiments, the therapeutic regimen is administered in combination with an antiviral agent selected from a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, a fusion inhibitor, a CCR5 antagonist, an integrase strand transfer inhibitor, an attachment inhibitor, a post-attachment inhibitor, a capsid inhibitor, a CYP3A inhibitor, and combinations thereof.

[0017] In some embodiments, the method decreases a viral load in the subject relative to an untreated subject with a viral infection.

[0018] In one aspect, disclosed herein is a method of preventing and / or reducing an anti-drug antibody (ADA) response in a subject with a disease, wherein hydroxychloroquine, variants thereof, or similar compounds, is administered to the subject prior to administration of at least one viral vector-delivered antibody or antibody-like molecule.

[0019] In some embodiments, at least one viral vector-delivered antibody or at least one antibodylike molecule comprises two or more antibody combinations. In some embodiments, at least one viral vector-delivered antibody or at least antibody-like molecule comprises a monoclonal antibody (mAb). In some embodiments, at least one viral vector-delivered antibody or at least one antibody-like molecule comprises an adeno-associated viral (AAV) vector. In some embodiments, the AAV vector comprises an AAV9 serotype. In some embodiments, the disease comprises an infectious disease. In some embodiments, the infectious disease comprises acquired immune deficiency syndrome / human immunodeficiency virus (AIDS / HIV), malaria, hepatitis A, hepatitis B, hepatitis C, influenza, or variants thereof.

[0020] In some embodiments, the ADA response comprises an immune response wherein the subject generates an antibody targeting at least one viral vector-delivered antibody or at least one antibody-like molecule.

[0021] In one aspect, disclosed herein is a pharmaceutical kit comprising hydroxychloroquine, variants thereof, or similar compounds,, and one or more viral vectors encoding a broadly neutralizing antibody including, but not limited to 3BNC117, 10-1074, and PGT145.

[0022] In some embodiments, the 4-aminoquinoline is in a pharmaceutically acceptable carrier selected from an excipient, a diluent, a salt, a buffer, a stabilizer, a preservative, a lipid, an emulsion, and a nanoparticle.

[0023] In some embodiments, the viral vector is in a pharmaceutically acceptable carrier selected from an excipient, a diluent, a salt, a buffer, a stabilizer, a preservative, a lipid, an emulsion, and a nanoparticle.

[0024] In some embodiments, the viral vector comprises an adeno-associated viral (AAV) vector. In some embodiments, the AAV vector comprises an AAV9 serotype.

[0025] In some embodiments, the kit is combined with an antiviral agent selected from a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, a fusion inhibitor, a CCR5 antagonist, an integrase strand transfer inhibitor, an attachment inhibitor, a post-attachment inhibitor, a capsid inhibitor, a CYP3A inhibitor, and combinations thereof.

[0026] In some embodiments, the kit treats or prevents a viral infection in a subject. In some embodiments, the kit reduces viral loads in the subject with the viral infection. In some embodiments, the kit reduces viral loads in a subject with Acquired Immunodeficiency Syndrome (AIDS).

[0027] In some embodiments, the subject is a human.

[0028] BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figures 1A and IB are charts showing Anti 3BNC117 levels in macaque serum after AAVs were used to deliver 3BNC117. Figure 1 A is a chart showing the results of 4 historic control macaques that received AAV9-3BNC117 intramuscularly on day 0 without hydroxychloroquine, in terms of optical density (O. D.) over time (days). Figure IB is a chart showing the results of treatment of 3 macaques that received hydroxychloroquine orally 1 week before AAV inoculation and once a week for two weeks after AAV inoculation, in terms of O. D. over time (weeks).

[0030] Figure 2 is a chart showing Anti-10-1074 Antibody levels in macaque serum after AAVs were used to deliver 10-1074, in terms of O. D. over time (weeks). At least with respect to r21023, Anti- 10- 1074 antibody levels were essentially zero for a period of five weeks.

[0031] Figure 3 A is a chart showing 3BNC117 levels in macaque serum in control macaques receiving no hydroxychloroquine, in terms of ug / ml 3BNC117 / day.

[0032] Figures 3B-D are charts 3BNC117 levels in macaque serum in macaques that received hydroxychloroquine orally 1 week before AAV inoculation and once a week for two weeks after AAV inoculation.

[0033] Figures 4A-C show the results where 3 treatment macaques received hydroxychloroquine orally 1 week before AAV inoculation and once a week for two weeks after AAV inoculation with AAV9-10-1074, in terms of 10-1074 levels (ug / ml) over time (weeks).

[0034] DETAILED DESCRIPTION

[0035] The following description of the disclosure is provided as an enabling teaching of the disclosure in its best, currently known embodiment(s). To this end, those skilled in the relevant art will recognize and appreciate that many changes can be made to the various embodiments of the invention described herein, while still obtaining the beneficial results of the present disclosure. It will also be apparent that some of the desired benefits of the present disclosure can be obtained by selecting some of the features of the present disclosure without utilizing other features. Accordingly, those who work in the art will recognize that many modifications and adaptations to the present disclosure are possible and can even be desirable in certain circumstances and are a part of the present disclosure. Thus, the following description is provided as illustrative of the principles of the present disclosure and not in limitation thereof. Reference will now be made in detail to the embodiments of the invention, examples of which are illustrated in the drawings and the examples. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

[0036] Terminology

[0037] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs.

[0038] The term “comprising” and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consisting essentially of’ and “consisting of’ can be used in place of “comprising” and “including” to provide for more specific embodiments and are also disclosed. As used in this disclosure and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly dictates otherwise.

[0039] The following definitions are provided for the full understanding of terms used in this specification.

[0040] The terms "about" and "approximately" are defined as being “close to” as understood by one of ordinary skill in the art. In one non-limiting embodiment the terms are defined to be within 10%. In another non-limiting embodiment, the terms are defined to be within 5%. In still another non-limiting embodiment, the terms are defined to be within 1%.

[0041] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that when a value is disclosed that “less than or equal to” the value, “greater than or equal to the value” and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “10” is disclosed the “less than or equal to 10”as well as “greater than or equal to 10” is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point 15 are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0042] As used herein, the terms "may," "optionally," and "may optionally" are used interchangeably and are meant to include cases in which the condition occurs as well as cases in which the condition does not occur. Thus, for example, the statement that a formulation "may include an excipient" is meant to include cases in which the formulation includes an excipient as well as cases in which the formulation does not include an excipient.

[0043] “Composition” refers to any agent that has a beneficial biological effect. Beneficial biological effects include both therapeutic effects, e.g., treatment of a disorder or other undesirable physiological condition, and prophylactic effects, e.g., prevention of a disorder or other undesirable physiological condition. The terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of beneficial agents specifically mentioned herein, including, but not limited to, a vector, polynucleotide, cells, salts, esters, amides, proagents, active metabolites, inhibitors, isomers, fragments, analogs, and the like. When the term “composition” is used, then, or when a particular composition is specifically identified, it is to be understood that the term includes the composition per se as well as pharmaceutically acceptable, pharmacologically active vector (such as, for example, a viral vector or an AAV vector), polynucleotide, salts, esters, amides, proagents, conjugates, active metabolites, isomers, fragments, analogs, etc.

[0044] A “therapeutic composition” refers to at least one substance, molecule, or compound suitable for administering to a subject, wherein the composition further includes a pharmaceutical carrier. A non-limiting example include a therapeutic composition comprises an inhibitor or an antibodies. As used herein, the term “agent” or “therapeutic agent” refers to a living organism or biological substance, such as a virus, chemical, toxin, or antibody, that can be designed to purposefully fulfill a biological function or action.

[0045] As used herein, a “therapeutic regimen” refers to a structured treatment plan or strategy designed to improve and maintain health. Generally, a therapeutic regimen will be designed, prescribed, and / or administered by a licensed medical practitioner. The therapeutic regimen generally specifies the treatment dosage, the treatment scheduling, and the duration of the treatment. In some embodiments, the therapeutic regimen comprises one or more therapeutic compositions. In some embodiments, the therapeutic regimen comprises one or more therapeutic agents. In some embodiments, the therapeutic regimen comprises any combination of therapeutic compositions and therapeutic agents, such as for example the combination of an inhibitor and an antibody. In some embodiments, a therapeutic regimen comprises modifying, continuing, and / or initiating at least one therapeutic agent and / or therapeutic composition. In some embodiments, a therapeutic regimen comprises treating and / or preventing a disease, disorder, and / or condition.

[0046] The term “comprising”, and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consisting essentially of’ and “consisting of’ can be used in place of “comprising” and “including” to provide for more specific embodiments and are also disclosed.

[0047] An "increase" can refer to any change that results in a greater amount of a symptom, disease, composition, condition, or activity. An increase can be any individual, median, or average increase in a condition, symptom, activity, composition in a statistically significant amount. Thus, the increase can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% increase so long as the increase is statistically significant.

[0048] A "decrease" can refer to any change that results in a smaller amount of a symptom, disease, composition, condition, or activity. A substance is also understood to decrease the genetic output of a gene when the genetic output of the gene product with the substance is less relative to the output of the gene product without the substance. Also, for example, a decrease can be a change in the symptoms of a disorder such that the symptoms are less than previously observed. A decrease can be any individual, median, or average decrease in a condition, symptom, activity, composition in a statistically significant amount. Thus, the decrease can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% decrease so long as the decrease is statistically significant.

[0049] "Inhibit," "inhibiting," and "inhibition" mean to decrease an activity, response, condition, disease, or other biological parameter. This can include but is not limited to the complete ablation of the activity, response, condition, or disease. This may also include, for example, a 10% reduction in the activity, response, condition, or disease as compared to the native or control level. Thus, the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to native or control levels.

[0050] “Inhibitors” or “antagonist” of expression or of activity are used to refer to inhibitory molecules, respectively, identified using in vitro and in vivo assays for expression or activity of a described target protein, e.g., ligands, antagonists, and their homologs and mimetics. Inhibitors are agents that, e.g., inhibit expression or bind to, partially or totally block stimulation or activity, decrease, prevent, delay activation, inactivate, desensitize, or down regulate the activity of the described target protein, e.g., antagonists. Control samples (untreated with inhibitors) are assigned a relative activity value of 100%. Inhibition of a described target protein is achieved when the activity value relative to the control is about 80%, optionally 50% or 25, 10%, 5%, or 1% or less.

[0051] By “reduce” or other forms of the word, such as “reducing” or “reduction,” means lowering of an event or characteristic (e.g., viral load). It is understood that this is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to. For example, “reduces viral load” means reducing the amount of virus or virus particles in an infected person’s blood relative to a standard or a control.

[0052] By “prevent” or other forms of the word, such as “preventing” or “prevention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce. As used herein, something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed. The term “subject” refers to any individual who is the target of administration or treatment. The subject can be a vertebrate, for example, a mammal. In one aspect, the subject can be human, non-human primate, bovine, equine, porcine, canine, or feline. Thus, the subject can be a human or veterinary patient. The term “patient” refers to a subject under the treatment of a clinician, e.g., physician.

[0053] The term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.

[0054] The term “administer,” “administering”, or derivatives thereof refer to delivering a composition, substance, inhibitor, or medication to a subject or object by one or more the following routes: oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intrajoint, parenteral, intra-arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, by inhalation or via an implanted reservoir. The term “parenteral” includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques.

[0055] The term "antibody" is used in the broadest sense, and specifically covers monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, and multispecific antibodies (e.g., bispecific antibodies). Antibodies (Abs) are glycoproteins that exhibit binding specificity to a specific target. Native antibodies are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains. Each light chain has a variable domain at one end (VL) and a constant domain at its other end.

[0056] The term "antibody fragment" refers to a portion of a full-length antibody, generally the target binding or variable region. Examples of antibody fragments include Fab, Fab', F(ab')2 and Fv fragments. The phrase "functional fragment or analog" of an antibody is a compound having qualitative biological activity in common with a full-length antibody. For example, a functional fragment or analog of an anti-IgE antibody is one which can bind to an IgE immunoglobulin in such a manner so as to prevent or substantially reduce the ability of such molecule from having the ability to bind to the high affinity receptor, FceRI. As used herein, "functional fragment" with respect to antibodies, refers to Fv, F(ab) and F(ab')2 fragments. An "Fv" fragment is the minimum antibody fragment which contains a complete target recognition and binding site. This region consists of a dimer of one heavy and one light chain variable domain in a tight, non-covalent association (VH-VL dimer). It is in this configuration that the three CDRs of each variable domain interact to define a target binding site on the surface of the VH-VL dimer. Collectively, the six CDRs confer target binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for a target) has the ability to recognize and bind target, although at a lower affinity than the entire binding site. "Single-chain Fv" or "sFv" antibody fragments comprise the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain. Generally, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the sFv to form the desired structure for target binding.

[0057] The term “monoclonal antibody” as used herein refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies within the population are identical except for possible naturally occurring mutations that may be present in a small subset of the antibody molecules.

[0058] The term "variable" in the context of variable domain of antibodies, refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular target. However, the variability is not evenly distributed through the variable domains of antibodies. It is concentrated in three segments called complementarity determining regions (CDRs) also known as hypervariable regions both in the light chain and the heavy chain variable domains. The more highly conserved portions of variable domains are called the framework (FR). The variable domains of native heavy and light chains each comprise four FR regions, largely adopting a β-sheet configuration, connected by three CDRs, which form loops connecting, and in some cases forming part of, the,beta.-sheet structure. The CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, contribute to the formation of the target binding site of antibodies (see Kabat et al.) As used herein, numbering of immunoglobulin amino acid residues is done according to the immunoglobulin amino acid residue numbering system of Kabat et al., (Sequences of Proteins of Immunological Interest, National Institute of Health, Bethesda, Md.1987), unless otherwise indicated.

[0059] A “vaccine” refers to a biological preparation that provides active acquired immunity to a particular infectious diseases caused by a microorganism, such as, for example, a virus. Vaccines typically comprise an agent or several agents, also referred to as antigens, resembling the microorganism and is often made from weakened or killed forms of the microbe, its toxins, or its surface proteins / peptides. Vaccines are also made to comprise additional components, such as adjuvants, preservatives, and / or stabilizers to boost the immune response, improve safety, and improve vaccine storage.

[0060] The terms “treat,” “treating,” and grammatical variations thereof as used herein, include partially or completely delaying, alleviating, mitigating, or reducing the intensity of one or more attendant symptoms of a disorder or condition and / or alleviating, mitigating, or impeding one or more causes of a disorder or condition. Treatments according to the disclosure may be applied preventively, prophylactically, palliatively, or remedially. Treatments are administered to a subject during early onset (e.g., upon initial signs and symptoms of infection), or after an established development of infection.

[0061] “Serotype” as used herein refers to a distinct variation within a species of bacteria or virus or among immune cells of different individuals. These microorganisms, viruses, or cells are classified together based on their surface antigens, allowing the epidemiologic classification of organisms to the subspecies level.

[0062] As used herein, the term “infection” refers to the invasion of tissues by pathogens, their multiplication, and reaction of host tissues to the infectious agent and any toxins they release. Infections can be caused by a wide range of pathogen, most common are bacteria and viruses. A “vector” as used herein refers to any particle or composition used as a vehicle to artificially carry a foreign nucleic acid sequence into another cell, where it can be replicated and / or expressed. Examples of vectors include plasmids, viral vectors, cosmids, and artificial chromosomes.

[0063] As used herein a “viral vector” refers to a tool used in molecular biology to deliver genetic material (including DNA, RNA, and any other nucleic acid variations thereof) into a cell. This process is performed either inside a living organism or in cell culture. The viral genome is engineered to incorporate a desired gene or gene product, and following transduction, or transfer, of the virus into the host, said gene or gene product is expressed within the host.

[0064] An “adeno-associated virus” or an “AAV” as used herein refers to a small virus belonging to the genus Dependoparvovirus which are replicative defective, non-enveloped viruses with linear single-stranded DNA. These viruses are commonly used for creating viral vectors for gene therapy, wherein the viruses can infect dividing and quiescent cells and persist in an extrachromosomal state without integrating into the host genome. AAVs can be engineered to express desired genes or gene products such as mRNA, shRNA, or miRNAs to overexpress or silence a target gene. Adeno-associated virus 2 (AAV2) can also be used.

[0065] The primary method for AAV production involves transient transfection of HEK-293 cells using three plasmids that carry the therapeutic gene, AAV rep / cap genes, and helper adenoviral genes. The production process includes cultivation, particularly in bioreactors, and purification aimed at increasing the yield of full capsids and removing impurities.

[0066] Use of the virus does present some disadvantages. The cloning capacity of the vector is relatively limited and most therapeutic genes require the complete replacement of the virus's 4.8 kilobase genome. Large genes are, therefore, not suitable for use in a standard AAV vector. Options are currently being explored to overcome the limited coding capacity.

[0067] Because of AAVs specialized gene therapy advantages, researchers have created an altered version of AAV termed self-complementary adeno-associated virus (scAAV). Whereas AAV packages a single strand of DNA and must wait for its second strand to be synthesized, scAAV packages two shorter strands that are complementary to each other. By avoiding second-strand synthesis, scAAV can express more quickly, although as a caveat, scAAV can only encode half of the already limited capacity of AAV. Recent reports suggest that scAAV vectors are more immunogenic than single stranded adenovirus vectors, inducing a stronger activation of cytotoxic T lymphocytes.

[0068] Humoral immunity instigated by infection with the wild type is thought to be common. The associated neutralizing activity limits the usefulness of the most commonly used serotype AAV2 in certain applications.

[0069] By properly assessing the plasmid used to produce the desired proteins, one can enhance genome packaging efficiency, transgene expression levels, or stability. The assessment can consider, for example, inverted terminal repeat (ITR) size and integrity, homology between gene of interest (GOI) and rep / cap regions, regulatory element architecture, open reading frame (ORF) continuity, untranslated regions (UTR) structure, and overall cassette size relative to AAV packaging constraints. One example of this assessment is provided by Forge Biologies, as part of their preparation of FUEL™ gene of interest (GOI) and rep / cap plasmids. This assessment can, for example, eliminate any overlapping sequences while maintaining an AAV2 capsid.

[0070] A “variant” or a “derivative” of a particular inhibitor may be defined as a chemical or molecular compound having at least 50% identity to a parent or original inhibitor. In some embodiments a variant inhibitor may show, for example, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% or greater identity relative to a reference parent or original inhibitor.

[0071] A “virus” is a microscopic infectious agent that replicates only inside the living cells of an organism. Viruses can infect all life forms, including mammalian and non-mammalian animals, plants, and other microorganisms. A complete virus, also known as a virion, consists of nucleic acid genetic material surrounded by a protective coat of protein called a capsid. Virus can have a lipid envelope derived from the infected host cell membrane. In general, there are five morphological virus types including helical, icosahedral, prolate, enveloped, and complex virus. A virus can either have a DNA or RNA genome, though a vast majority have RNA genomes. Irrespective of the type of nucleic acid genome, a viral genome can be either a single- stranded genome or a double-stranded genome.

[0072] An “epitope” or “antigenic determinant” refer to the part of an antigen, a molecular structure, or foreign particulate that can bind to a specific antibody or T-cell receptor. The presence of antigens or epitopes of antigens within a host can illicit an immune response. As used herein, microneedle (MN) patch technology for vaccine administration involves a relatively small (similar to a band-aid in size) microneedle patch, which can be a dissolvable microneedle patch, containing an array of micron-sized needles (usually 100-1000 μm in length) made from various materials (e.g., polymers, silicon, or metals). The patch is simply pressed onto the skin, often on the forearm or upper arm, and held in place for a few minutes. The tiny needles penetrate the outermost layer of the skin (stratum comeum) to deliver the vaccine to the epidermis and dermis, which are rich in antigen-presenting immune cells (Langerhans cells and dendritic cells). There are four main types of microneedle patches:

[0073] Dissolving MNs: These are made of biodegradable materials (like sugars or polymers) that dissolve in the skin, releasing the vaccine.

[0074] Coated MNs: Solid needles with a dry coating of the vaccine that quickly dissolves upon insertion.

[0075] Hollow MNs: Micro-versions of traditional needles that use pressure to deliver a liquid vaccine formulation.

[0076] Solid MNs: Used for skin pre-treatment, creating pores for a separate vaccine formulation to be applied.

[0077] Methods of treating and / or preventing infectious diseases

[0078] The present disclosure provides methods of treating and / or preventing infectious diseases, including, but not limited to Human immunodeficiency virus (HIV).

[0079] Human immunodeficiency virus (HIV) or human immunodeficiency virus- 1 (HIV-1) is the causative pathogen of acquired immunodeficiency syndrome (AIDS) and mainly infects CD4+ T cells leading to progressive damage of the immune system. Without defense and surveillance functions of the immune system, patients with an HIV infection are more susceptible to other pathogenic infections and gene mutations, resulting in opportunistic infections, cancers, and even death. Recent efforts have led to development of broadly neutralizing antibodies (bNAbs) as an approach to treat, prevent, and ideally eradicate HIV infections. However, administration of said bNAbs are complex due to short half-lives and launching an adverse immune response within the patients. Thus, there remains a need to improve administration by prolonging the effects of the bNAbs without eliciting harmful immune responses in patients. As used herein, a ’’broadly neutralizing antibody” or “bNAb” refers to a specific group of antibodies which neutralize multiple viral strains including, but not limited to HIV-1 viral strains, by targeting conserved epitopes of HIV, meaning that even if the virus mutates then the targeted epitopes still exist.

[0080] In one aspect, disclosed herein is method of treating or preventing a Human Immunodeficiency Virus (HIV), a Hepatitis B Virus (HBV), an influenza virus, or a respiratory syncytial virus (RSV) infection in a subject, the method comprising administering a therapeutic regimen comprising a 4-aminoquinoline antimalarial agent and a viral vector encoding a broadly neutralizing antibody (including, but not limited to a HIV broadly neutralizing antibody, a HBV broadly neutralizing antibody, an influenza broadly neutralizing antibody, or a RSV broadly neutralizing antibody).

[0081] In one aspect, disclosed herein is method of treating or preventing a Human Immunodeficiency Virus (HIV) in a subject, the method comprising administering a therapeutic regimen comprising a 4-aminoquinoline antimalarial agent and a viral vector encoding a HIV broadly neutralizing antibody.

[0082] In some embodiments, the 4-aminoquinoline antimalarial agent is hydroxychloroquine, but in other embodiments, the 4-aminoquinoline antimalarial agent is chloroquine (Aralen®), quinine / quinidine, mefloquine, primaquine, quinacrine (Atabrine®): or amodiaquine can also be used, and a viral vector encoding a broadly neutralizing antibody (including, but not limited to a HIV broadly neutralizing antibody, a HBV broadly neutralizing antibody, an influenza broadly neutralizing antibody, or a RSV broadly neutralizing antibody).

[0083] Additional 4-aminoquinoline derivatives are disclosed in Solomon, V. R., et al., “Examination of novel 4-aminoquinoline derivatives designed and synthesized by a hybrid pharmacophore approach to enhance their anticancer activities,” Sci Rep 9, 6315 (2019), the contents of which are hereby incorporated by reference. While hydroxychloroquine is the preferred compound, these additional compounds can also be used in place of hydroxychloroquine.

[0084] It should also be noted that administration of the 4-aminoquinoline antimalarial agent begins at week minus 1 (-1), week minus 2 (-2), week minus 3 (-3), or week minus 4 (-4) relative to the day of the viral vector administration, wherein the day of viral vector administration begins at week 0. Furthermore, the administration of the 4-aminoquinoline antimalarial agent can be continued for 8 weeks or more following administering the viral vector. In some embodiments, the 4-aminoquinoline antimalarial agent is administered 1, 2, 3, 4, or 5 days prior to administering the viral vector. In some embodiments, the 4-aminoquinoline antimalarial agent is further administered for at least 5 weeks following administering the viral vector. In some embodiments, the 4-aminoquinoline antimalarial agent is administered 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, or more following administering the viral vector. In a preferred embodiment, the 4-aminoquinoline antimalarial agent is administered 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks following administering the viral vector.

[0085] In some embodiments, the 4-aminoquinoline antimalarial agent is administered at least once per week. In some embodiments, the 4-aminoquinoline antimalarial agent is administered one, two, three, four, five, six, seven, or more per week. In some embodiments, the 4-aminoquinoline antimalarial agent is administered seven times per week. In some embodiments, the 4-aminoquinoline antimalarial agent is administered once per day.

[0086] In some embodiments, the 4-aminoquinoline antimalarial agent is administered by an intraperitoneal (i.p.) injection. In some embodiments, the 4-aminoquinoline antimalarial agent is administered intramuscularly. In some embodiments, the 4-aminoquinoline antimalarial agent is administered intravenously.

[0087] In some embodiments, the viral vector encodes a broadly neutralizing HIV antibody including, but not limited to 3BNC117, 10-1074, PGT145, 10E8, N6, 35022, 447-52D, 2G12, bl2, 2F5, 4E10, Z13, PG9, PG16, PGT141, PGT142, PGT143, PGT144, CHOI, CH02, CH03, CH04, PGDM1400, CAP256-VRC26.25, VRC38, PCT64, PGT121, PGT128, PGT135, PCDN-33A, PGDM12, PGDM21, VRC29.03, BF520.1, VRC41.01, BG18, DH270.1, DH270.6, VRC01, PGV04, 8ANC131, CH103, CH235, N6, IOMA, N49-P7, PGT151, PGT152, PGT153, PGT154, PGT155, PGT156, PGT157, PGT158, 8ANC195, 35022, N123- VRC34.01, ACS202, VRC-PG05, SF12, DH511, and variants thereof.

[0088] In some embodiments, the broadly neutralizing antibody of any preceding aspect further comprises a half-life extender, such as for example a Xencor half-life extender.

[0089] In some embodiments, the viral vector comprises an adeno-associated viral (AAV) vector. In some embodiments, the therapeutic regimen comprises administering one or more viral vectors encoding a 3BNC117 neutralizing antibody, a 10-1074 neutralizing antibody, or a PGT145 neutralizing antibody. In some embodiments, the therapeutic regimen comprises administering 3BNC117 and 10-1074 neutralizing antibodies. In some embodiments, the therapeutic regimen comprises administering 3BNC117 and PGT145 neutralizing antibodies. In some embodiments, the therapeutic regimen comprises administering 10-1074 and PGT145 neutralizing antibodies.

[0090] In some embodiments, the therapeutic regimen comprises administering 3BNC117, 101074, and PGT145 neutralizing antibodies.

[0091] In some embodiments, the one or more viral vectors are individually administered. In some embodiments, the viral vector is administered by an intramuscular (i.m.) injection, or a microneedle patch.

[0092] In some embodiments, the method expresses the neutralizing antibodies for more than 5 weeks. In some embodiments, the method expresses the neutralizing antibodies for about 10 weeks to about 400 weeks. In some embodiments, the method expresses the neutralizing antibodies for 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, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400 weeks or more. In some embodiments, the method expresses the neutralizing antibodies for the remainder of the subject’s life.

[0093] Viral vectors are molecular tools used to deliver genetic material into cells that can be performed inside a living organism (in vivo), or in cell culture (in vitro). In some embodiments, the viral vector includes, but is not limited to adeno-associated viral (AAV) vectors, adenoviral vectors, retroviral vectors, lentiviral vectors, and hybrid viral vectors.

[0094] Retroviral Vectors

[0095] A retrovirus is an animal virus belonging to the virus family of Retroviridae, including any types, subfamilies, genus, or tropisms. Retroviral vectors, in general, are described by Verma, I. M., Retroviral vectors for gene transfer.

[0096] A retrovirus is essentially a package which has packed into it nucleic acid cargo. The nucleic acid cargo carries with it a packaging signal, which ensures that the replicated daughter molecules will be efficiently packaged within the package coat. In addition to the package signal, there are a number of molecules which are needed in cis, for the replication, and packaging of the replicated virus. Typically, a retroviral genome contains the gag, pol, and env genes which are involved in the making of the protein coat. It is the gag, pol, and env genes which are typically replaced by the foreign DNA that it is to be transferred to the target cell. Retrovirus vectors typically contain a packaging signal for incorporation into the package coat, a sequence which signals the start of the gag transcription unit, elements necessary for reverse transcription, including a primer binding site to bind the tRNA primer of reverse transcription, terminal repeat sequences that guide the switch of RNA strands during DNA synthesis, a purine rich sequence 5' to the 3' LTR that serve as the priming site for the synthesis of the second strand of DNA synthesis, and specific sequences near the ends of the LTRs that enable the insertion of the DNA state of the retrovirus to insert into the host genome. The removal of the gag, pol, and env genes allows for about 8 kb of foreign sequence to be inserted into the viral genome, become reverse transcribed, and upon replication be packaged into a new retroviral particle. This amount of nucleic acid is sufficient for the delivery of a one to many genes depending on the size of each transcript. It is preferable to include either positive or negative selectable markers along with other genes in the insert. Since the replication machinery and packaging proteins in most retroviral vectors have been removed (gag, pol, and env), the vectors are typically generated by placing them into a packaging cell line. A packaging cell line is a cell line which has been transfected or transformed with a retrovirus that contains the replication and packaging machinery, but lacks any packaging signal. When the vector carrying the DNA of choice is transfected into these cell lines, the vector containing the gene of interest is replicated and packaged into new retroviral particles, by the machinery provided in cis by the helper cell. The genomes for the machinery are not packaged because they lack the necessary signals.

[0097] Adenoviral Vectors

[0098] The construction of replication-defective adenoviruses has been described (Berkner et al., J. Virology 61:1213-1220 (1987); Massie et al., Mol. Cell. Biol.6:2872-2883 (1986); Haj- Ahmad et al., J. Virology 57:267-274 (1986); Davidson et al., J. Virology 61:1226-1239 (1987); Zhang "Generation and identification of recombinant adenovirus by liposome- mediated transfection and PCR analysis" BioTechniques 15:868-872 (1993)). The benefit of the use of these viruses as vectors is that they are limited in the extent to which they can spread to other cell types, since they can replicate within an initial infected cell, but are unable to form new infectious viral particles. Recombinant adenoviruses have been shown to achieve high efficiency gene transfer after direct, in vivo delivery to airway epithelium, hepatocytes, vascular endothelium, CNS parenchyma and a number of other tissue sites (Morsy, J. Clin. Invest.92: 1580- 1586 (1993); Kirshenbaum, J. Clin. Invest.92:381-387 (1993); Roessler, J. Clin. Invest. 92:1085-1092 (1993); Moullier, Nature Genetics 4:154-159 (1993); La Salle, Science 259:988-990 (1993); Gomez-Foix, J. Biol. Chem.

[0099] 267:25129-25134 (1992); Rich, Human Gene Therapy 4:461-476 (1993); Zabner, Nature Genetics 6:75-83 (1994); Guzman, Circulation Research 73:1201-1207 (1993); Bout, Human Gene Therapy 5:3-10 (1994); Zabner, Cell 75:207-216 (1993); Caillaud, Eur. J. Neuroscience 5:1287-1291 (1993); and Ragot, J. Gen. Virology 74:501-507 (1993)). Recombinant adenoviruses achieve gene transduction by binding to specific cell surface receptors, after which the virus is internalized by receptor-mediated endocytosis, in the same manner as wild type or replication-defective adenovirus (Chardonnet and Dales, Virology 40:462-477 (1970); Brown and Burlingham, J. Virology 12:386-396 (1973); Svensson and Persson, J. Virology 55:442-449 (1985); Seth, et al., J. Virol. 51:650-655 (1984); Seth, et al., Mol. Cell. Biol. 4:1528-1533 (1984); Varga et al., J. Virology 65:6061-6070 (1991); Wickham et al., Cell 73:309-319 (1993)). A viral vector can be one based on an adenovirus which has had the El gene removed and these virons are generated in a cell line such as the human 293 cell line. In another preferred embodiment both the El and E3 genes are removed from the adenovirus genome.

[0100] Adeno-associated viral vectors

[0101] Another type of viral vector is based on an adeno-associated virus (AAV). This defective parvovirus is a preferred vector because it can infect many cell types and is nonpathogenic to humans. AAV type vectors can transport about 4 to 5 kb and wild type AAV is known to stably insert into chromosome 19. Vectors which contain this site specific integration property are preferred. An especially preferred embodiment of this type of vector is the P4.1 C vector produced by Avigen, San Francisco, CA, which can contain the herpes simplex virus thymidine kinase gene, HSV-tk, and / or a marker gene, such as the gene encoding the green fluorescent protein, GFP.

[0102] In another type of AAV virus, the AAV contains a pair of inverted terminal repeats (ITRs) which flank at least one cassette containing a promoter which directs cell-specific expression operably linked to a heterologous gene. Heterologous in this context refers to any nucleotide sequence or gene which is not native to the AAV or B19 parvovirus.

[0103] Typically the AAV and B19 coding regions have been deleted, resulting in a safe, noncytotoxic vector. The AAV ITRs, or modifications thereof, confer infectivity and site- specific integration, but not cytotoxicity, and the promoter directs cell-specific expression. United States Patent No. 6,261,834 is herein incorporated by reference for material related to the AAV vector.

[0104] Large payload viral vectors

[0105] Molecular genetic experiments with large human herpesviruses have provided a means whereby large heterologous DNA fragments can be cloned, propagated and established in cells permissive for infection with herpesviruses (Sun et al., Nature genetics 8: 33-41, 1994; Cotter and Robertson,. Curr Opin Mol Ther 5: 633-644, 1999). These large DNA viruses (herpes simplex virus (HSV) and Epstein-Barr virus (EBV), have the potential to deliver fragments of human heterologous DNA > 150 kb to specific cells. EBV recombinants can maintain large pieces of DNA in the infected B-cells as episomal DNA. Individual clones carried human genomic inserts up to 330 kb appeared genetically stable The maintenance of these episomes requires a specific EBV nuclear protein, EBNA1, constitutively expressed during infection with EBV. Additionally, these vectors can be used for transfection, where large amounts of protein can be generated transiently in vitro. Herpesvirus amplicon systems are also being used to package pieces of DNA > 220 kb and to infect cells that can stably maintain DNA as episomes.

[0106] Other useful systems include, for example, replicating and host-restricted non- replicating vaccinia virus vectors.

[0107] In some embodiments, the AAV vector comprises an AAV9 serotype. In some embodiments, the AAV vector comprises an AAV6 serotype. In some embodiments, the AAV vector comprises an AAV1, AAV2, AAV3, AAV4, AAV5, AAV7, or AAV8 serotype.

[0108] In some embodiments, the therapeutic regimen is administered in combination with an antiviral agent selected from a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, a fusion inhibitor, a CCR5 antagonist, an integrase strand transfer inhibitor, an attachment inhibitor, a post-attachment inhibitor, a capsid inhibitor, a CYP3A inhibitor, and combinations thereof. In some embodiments, the therapeutic regimen further comprises administering additional immunotherapeutic agents or compositions including, but not limited to CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, CAR-T cells, vaccines, and immunomodulatory agents (i.e.: interferons and / or interleukins).

[0109] In some embodiments, the method suppresses the immune response in the subject relative to an untreated subject with a viral infection. In some embodiments, the method suppresses the immune response in the subject by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more relative to an untreated subject with a viral infection.

[0110] In some embodiments, the method decreases viral loads in the subject relative to an untreated subject with a viral infection. In some embodiments, the method decreases viral loads in the subject by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or more relative to an untreated subject with a viral infection.

[0111] The therapeutic regimen may be administered in such amounts, time, and route deemed necessary in order to achieve the desired result. The exact amount of the therapeutic regimen will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular therapeutic regimen, its mode of administration, its mode of activity, and the like. The therapeutic regimen is preferably formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the therapeutic regimen will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the infection being treated and the severity of the infection; the activity of the therapeutic regimen employed; the specific therapeutic regimen employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific therapeutic regimen employed; the duration of the treatment; drugs used in combination or coincidental with the specific therapeutic regimen employed; and like factors well known in the medical arts.

[0112] The therapeutic regimen may be administered by any route. In some embodiments, the therapeutic regimen is administered via a variety of routes, including intravenous, intraperitoneal, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, mucosal, nasal, oral, buccal, enteral, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the therapeutic regimen (e.g., its stability in the environment of the body), the condition of the subject (e.g., whether the subject is able to tolerate administration by injection), etc. In some embodiments, the therapeutic regimen of any preceding aspect can be administered by in vivo electroporation. As used herein, “in vivo electroporation” refers to a physical method of gene transfer, wherein a series of electric or mechanical pulses are delivered through a subject’s intact tissue or cell for a short duration of time to enhance the transfer of macromolecules, including but not limited to DNA, RNA, and proteins.

[0113] In some embodiments, the 4-aminoquinoline antimalarial agent thereof of any preceding aspect administered by ways known in the art to maintain long-acting release or sustained release. In some embodiments, the 4-aminoquinoline antimalarial agent of any preceding aspect administered as components of a prodrug. As used herein, a “prodrug” refers to a compound with little or no pharmacological activity upon administration, but is metabolized inside the body and is converted into a pharmacologically active drug compound.

[0114] The exact amount of the therapeutic regimen required to achieve a therapeutically effective amount will vary from subject to subject, depending on species, age, weight, and general condition of a subject, severity of the side effects, identity of the particular compound(s), mode of administration, and the like. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0115] Methods of preventing and / or reducing an anti-drug antibody response

[0116] Anti-drug antibody (ADA) responses refers to immune responses caused by an antibody binding to the epitope of another antibody including, but not limited to an antibody drug. Such processes cause adverse events in a subject, including inflammation and cytokine storms (also referred to when too many cytokines Eire released into the bloodstream to quickly), however the most common problem caused is loss of drug efficacy, drug neutralization, and / or drug elimination. Current practices test for ADA after a drug is delivered to the subject, however there are limited techniques that actively prevent, reduce, and / or decrease ADA.

[0117] In one aspect, disclosed herein is a method of preventing and / or reducing an anti-drug antibody (ADA) response in a subject with a disease, wherein the 4-aminoquinoline antimalarial agent is administered to the subject prior to administration of at least one viral vector-delivered antibody or antibody-like molecule.

[0118] In some embodiments, the 4-aminoquinoline antimalarial agent, such as hydroxychloroquine, is administered to prevent or reduce an ADA response.

[0119] In some embodiments, the 4-aminoquinoline antimalarial agent is used to prevent ADA in the passive administration of broadly neutralizing antibodies. Thus, in the event broadly neutralizing antibodies are administered periodically, the 4-aminoquinoline antimalarial agent can also be administered periodically, though before and after administration of the antibodies, to avoid production of anti-antibody antibodies.

[0120] In some embodiments, the at least one viral vector-delivered antibody or antibody-like molecule comprises one antibody, or two or more antibody combinations. In some embodiments, the at least one viral vector-delivered antibody or antibody-like molecule comprises a monoclonal antibody (mAb). In some embodiments, the at least one viral vector- delivered antibody or antibody-like molecule comprises an adeno-associated viral (AAV) vector. In some embodiments, the AAV vector comprises an AAV9 serotype. In some embodiments, the at least one viral vector-delivered antibody or antibody-like molecule comprises an adenoviral vector, a retroviral vector, a lentiviral vector, or a hybrid viral vector. In some embodiments, the disease comprises an infectious disease. In some embodiments, the infectious disease includes, but is not limited to Human immunodeficiency virus (HIV). In some embodiments, the kit is used to treat and / or prevent HIV, common cold, influenza (including, but not limited to human, bovine, avian, porcine, and simian strains of influenza), measles, acquired immune deficiency syndrome / human immunodeficiency virus (AIDS / HIV), anthrax, botulism, cholera, Campylobacter infections, chickenpox, chlamydia infections, cryptosporidosis, dengue fever, diphtheria, hemorrhagic fevers, Escherichia coli (E. coli) infections, ehrlichiosis, gonorrhea, hand-foot-mouth disease, hepatitis A, hepatitis B, hepatitis C, legionellosis, leprosy, leptospirosis, listeriosis, malaria, meningitis, meningococcal disease, mumps, pertussis, polio, pneumococcal disease, paralytic shellfish poisoning, rabies, rocky mountain spotted fever, rubella, salmonella, shigellosis, small pox, syphilis, tetanus, trichinosis (trichinellosis), tuberculosis (TB), typhoid fever, typhus, west Nile virus, yellow fever, yersiniosis, and zika. In some embodiments, the disease comprises a proliferative disease and / or cancer.

[0121] In some embodiments, the method prevents and / or reduces an ADA caused by one or more diseases of any preceding aspect. In some embodiments, the method inhibits and / or prevents an ADA from biological treatments (including, but not limited to anti-human IgE antibodies) used from gastrointestinal complications and / or allergies.

[0122] In some embodiments, the ADA response comprises an immune response wherein the subject generates an antibody targeting the at least one viral vector-delivered antibody or antibodylike molecule.

[0123] Pharmaceutical Kits

[0124] The present disclosure also provides a kit for the treatment and / or prevention of disease or disorder including, but not limited to infectious diseases and proliferative diseases including cancer.

[0125] In one aspect, disclosed herein is a pharmaceutical kit comprising a 4-aminoquinoline antimalarial agent, such as hydroxychloroquine, and one or more viral vectors encoding a broadly neutralizing antibody.

[0126] In some embodiments, the broadly neutralizing antibody includes, but is not limited to 3BNC117, 10-1074, and PGT145. In some embodiments, the broadly neutralizing antibody of any preceding aspect further comprises a half-life extender, such as for example a Xencor half- life extender).

[0127] In some embodiments, the 4-aminoquinoline antimalarial agent is in a pharmaceutically acceptable carrier selected from an excipient, a diluent, a salt, a buffer, a stabilizer, a preservative, a lipid, an emulsion, and a nanoparticle. In some embodiments, the viral vector is in a pharmaceutically acceptable carrier selected from an excipient, a diluent, a salt, a buffer, a stabilizer, a preservative, a lipid, an emulsion, and a nanoparticle.

[0128] In some embodiments, the viral vector comprises an adeno-associated viral (AAV) vector. In some embodiments, the AAV vector comprises an AAV9 serotype.

[0129] In some embodiments, the kit is combined with an antiviral agent selected from a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, a fusion inhibitor, a CCR5 antagonist, an integrase strand transfer inhibitor, an attachment inhibitor, a post-attachment inhibitor, a capsid inhibitor, a CYP3A inhibitor, and combinations thereof.

[0130] In some embodiments, said kit treats or prevents a viral infection in a subject. In some embodiments, the kit treats or prevents infection from a virus, a bacterium, or other pathogenic microorganisms. In some embodiments, said kit reduces viral loads in the subject with the viral infection. In some embodiments, the kit reduces viral loads by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 100%, or more in the subject with the viral infection. In some embodiments, said kit reduces viral loads in a subject with Acquired Immunodeficiency Syndrome (AIDS). In some embodiments, the kit reduces viral loads by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 100%, or more in the subject with AIDS.

[0131] In some embodiments, the subject is a human.

[0132] A number of embodiments of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. By way of non-limiting illustration, examples of certain embodiments of the present disclosure are given below.

[0133] Example 1: Anti-3BNC117 Antibody levels Anti 3BNC117 ELISA was used to measure antibody responses in macaque serum against the AAV-delivered 3BNC117. Figure 1A is a chart showing the results of 4 historic control macaques that received AAV9-3BNC117 intramuscularly on day 0 without hydroxychloroquine, in terms of optical density (O. D.) over time (days). In contrast, Figure IB is a chart showing the results of treatment of 3 macaques that received hydroxychloroquine orally 1 week before AAV inoculation and once a week for two weeks after AAV inoculation, in terms of O. D. over time (weeks).

[0134] The results show that, at least with respect to r21023, anti-antibody antibodies were substantially suppressed for around 18 weeks when the animals were treated with hydroxychloroquine both before, and after, administration of the AAV-delivered 3BNC117.

[0135] Example 2: Anti-10-1074 Antibody levels

[0136] Anti- 10- 1074 ELISA was used to measure antibody responses in macaque serum against the AAV-delivered 10-10741. 3 treatment macaques received hydroxychloroquine orally 1 week before AAV inoculation and once a week for two weeks post AAV inoculation. AAV9-10-1074 was delivered intramuscularly. The results are shown in Figure 2, in terms of O. D. over time (weeks). At least with respect to r21023, Anti-10-1074 antibody levels were essentially zero for a period of five weeks.

[0137] Example 3: 3BN C 117 Expression Levels

[0138] 3BNC117 levels in macaque serum was measured by ELISA, in both control macaques receiving no hydroxychloroquine, and in macaques that received hydroxychloroquine.

[0139] Four historic control macaques that received AAV9-3BNC117 intramuscularly on day 0, and the results are shown in Figure 3 A, in terms of ug / ml 3BNC117 / day. While an increase in antibody was observed from around day 5 to day 10, the concentration decreased to essentially zero by day 15. As shown in Figures 3B-D, three treatment macaques received hydroxychloroquine orally 1 week before AAV inoculation and once a week for two weeks after AAV inoculation. AAV9-3BNC117 was delivered intramuscularly.

[0140] Example 4: 10-1074 Expression Levels

[0141] 10-1074 levels in macaque serum were measured by ELISA. Figures 4A-C show the results where 3 treatment macaques received hydroxychloroquine orally 1 week before AAV inoculation and once a week for two weeks after AAV inoculation. AAV9-10-1074 was delivered intramuscularly. R21019 10-1074 levels (jrg / ml) over time (weeks) are shown in Figure 4A. The results show maximum levels by week five, which levels reduced over time. The results for R21057 10-1074 are shown in Figure 4B, which also showed maximum levels by week five, but the levels also reduced over time. The results for R21023 10-1074 are shown in Figure 4C, which also showed maximum levels by week five, but while the levels also reduced over time, they remained clinically significant, at around a third of the maximum levels, for up to 18 weeks.

[0142] Example 5: Combination of PD-L1 and pbn-mAbs, and

[0143] Despite discovery of the virus more than 40 years ago, there is no vaccine to prevent HIV infection, the cause of AIDS. There have been numerous vaccine efficacy trials that have ended in failure. There are no vaccines on the horizon. The difficulty lies in the properties of the virus itself. It is extremely variable, difficult to neutralize, and once it gets its foot in the door, it is there for life. However, there is an alternate approach: long-term delivery of anti-HIV monoclonal antibodies with potent neutralizing activity against a broad range of isolates (pbn-mAbs) using AAV vector. For years the obstacle to this approach has been unwanted antibody responses to the delivered antibodies that negate their continuing presence. However, as discussed elsewhere herein, transient uptake of the FDA-approved hydroxychloroquine allows continuous long-term delivery for years, probably for life.

[0144] Development of anti-retroviral therapies (ART) for those already infected has been a huge success. Nonetheless, ART is not without its problems. Continuous uptake is required, month after month, year after year. Consequently, compliance is a problem. A gap in compliance can lead to viral rebound and resistance of virus to the antiviral drugs. The silent viral reservoir remains largely unperturbed. The chronic lymphoid activation caused by HIV persists. And, there are comorbidities associated with long-term ART uptake. Lifelong pbn-mAb delivery could eliminate all of these deficiencies. While transient administration of 4-aminoquinoline antimalarial agents can allow long-term delivery in uninfected mice and uninfected monkeys as described above, it may be more difficult for the 4-aminoquinoline antimalarial agents to achieve the antigen-specific tolerance in infected monkeys as compared to uninfected monkeys. This is likely due to the chronic lymphoid activation resulting from AIDS virus infection even in the presence of ART.

[0145] This roadblock can be addressed with the following two approaches.

[0146] Approach 1 - Longer Duration of ART and the 4-Aminoquinoline Antimalarial Agents SHIV-infected monkeys receive daily ART for five months. They are put on a 4-aminoquinoline antimalarial agent, such as hydroxychloroquine (or rapamycin, or a variant thereof, in another embodiment), beginning around 5 weeks after the initiation of ART. AAV vectors providing three pbn-mAbs (3BNC117, 10-1074, and PGT145) are administered around 8 weeks after the initiation of the 4-aminoquinoline (or rapamycin or a variant thereof). They will remain on the 4-aminoquinoline for around 8 months. Ideally, 4-aminoquinoline levels, viral loads, levels of delivered mAbs, and concentration of anti-drug antibodies are monitored throughout.

[0147] Approach 2 - 4-Aminoquinolines plus PD-L1

[0148] PD-L1 is an important regulator of immune responses to foreign antigens. Expression of PD-L1 on the surface of a cell minimizes or stops immune responses to potential immunogens from that cell. For example, cancer cells frequently select for expression of PD-L1 on their surface to avoid immune recognition and elimination.

[0149] A combination of 4-aminoquinolines (and / or rapamycin or analogs thereof) with PD-L1 expression can increase the tolerization potential for AAV -delivered mAbs. Unfortunately, the size encapsidation potential for AAV vectors is just enough for the DNA needed to encode heavy and light chains of antibodies. The length of the coding sequences for a combination of PD-L1 and the mAb expression vectors for the three pbn-mAbs would be too large to encapsidate into standard AAV vectors. However, certain modified AAV capsid proteins allow encapsidation of longer segments of vector DNA, and using these modified AAV capsid proteins, one can provide an AAV vector capable of expressing 3BNC117 together with PD-L1 in a single vector.

[0150] An expression cassette using a beta-actin promoter driving PD-L1 expression, placed downstream of 3BNC117 coding sequences in the existing 3BNC117 AAV vector DNA, is used to produce an AAV to synthesize both 3BNC117 and PD-L1 in cultured cells from this single vector. Similar vectors are optionally provided for 10-1074+PD-L1 and PGT145+PD-L1.

[0151] The PD-L1 and one, two or three of these mABs can be evaluated using SHIV-infected macaques using a 4-aminoquinoline antimalarial agent and / or rapamycin or analogs thereof, as described in PCT / US2024 / 039323, the contents of which are hereby incorporated by reference in its entirety.

[0152] The following sequence information relates to PD-L1, and the sequences of the 3BNC117, 10-1074 and PGT145 are provided elsewhere herein. Programmed death-ligand 1 (PD-L1) is also known as cluster of differentiation 274 (CD274). The amino acid sequence (SEQ ID. NO: 42) and gene sequence (SEQ ID NO: 43) are disclosed, for example, in Murray, et al. “Tumour-intrinsic PDL1 signals regulate the Chk2 DNA damage response in cancer cells and mediate resistance to Chkl inhibitors,” Mol. Cancer 23 (1), 242 (2024), the contents of which are hereby incorporated by reference.

[0153] In those embodiments that include rapamycin or analogs thereof, rapamycin (Sirolimus), tacrolimus (Prograf), prednisone, everolimus, or mycophenolate mofetil can be administered, alone or in combination with the 4-aminoquinoline antimalarial agents, to prevent or reduce an ADA response. In some embodiments, Temsirolimus, Everolimus, Umirolimus, Zotarolimus, Torin-1, Torin-2, Vistusertib, and other mTOR inhibitors can administered, alone or in combination with the 4-aminoquinoline antimalarial agents, to prevent or reduce an ADA response.

[0154] The combination of a 4-aminoquinoline and / or rapamycin or analogs thereof, with these modified vectors, can enhance antigen-specific tolerance and long-term delivery. It will be apparent to those skilled in the art that various modifications and variations can be made in the present disclosure without departing from the scope or spirit of the invention. Other embodiments of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the methods disclosed herein.

[0155] It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims. SEQUENCES

[0156] 1. SEQ ID NO: 1 - C-rhesus 3BNC117 IgG-LS kappa Heavy chain MKHLWFY LLN AAP WVLSQVOLLOSGAAVTKPGASVRVSCEASGYNIRDYFIHWWROAP GQGLQWVGWINPKTGQPNNPRQFQGR VSLTRHASWDFDTFSFYMDLKALRSDDTA VYFCAR

[0157] gTJSDIWD DFJFGS'GTigITPS'S'ASTKGPSVFPLAPSSRSTSESTAALGCLVKDYFEPVTVS WNSGSLTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYVCNVNHKPSN TKVDKRVEIKTCGGGSKPPTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSQEDPDVKFNWYVNGAEVHHAQTKPRETQYNSTYRVVSVLTVTHQDWLNGKE YTCKVSNKALPAPIQKTISKDKGQPREPQVYTLPPSREELTKNQVSLTCLVKGFYPSDI VVEWESSGQPENTYKTTPPVLDSDGSYFLYSKLTVDKSRWQQGNVFSCSVLHEALH SHYTQKSLSLSPGK*

[0158] Underline indicates a Signal Peptide, Italicize indicates a variable domain, and Bold indicates a LS mutation

[0159] 2. SEQ ID NO: 2 - C-rhesus 3BNC117 IgG-LS kappa Light chain MKR WFFLLLNAAPR^NLSDIOMTOSPSSLSASVGDTVTITCOANGYLNWYQORRGKAPKL LIYDGSKLERGVPSRFSGRRWGQEYNLTINNLQPEDUTYFCQVYEFWPGTRLDLKRANAAP SVFIFPPSEDQVKSGTVSVVCLLNNFYPREASVKWKVDGVLKTGNSQESVTE QDSKDNTYSLSSTLTLSSTDYQSHNVYACEVTHQGLSSPVTKSFNRGEC*

[0160] Underline indicates a Signal Peptide and Italicize indicates a variable domain

[0161] 3. SEQ ID NO: 3 - C-rhesus 10-1074 IgG-LS lambda Heavy chain MKRLWFFLLLNAAPRWNLSQVOLOESGPGLVKPSETLSVTCSVSGDSA NNYYWTWIROSP GKGLEWIGYISDRESATYNPSLNSRVVISRDTSKNQLSLKLNSVTPADTAVYYCATARRGQRIYG

[0162] G£ HT5 DIWG!^G7TP HS'5ASTKGPSVFPLAPSSRSTSESTAALGCLVKDYFPEP VTVSWNSGSLTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYVCNVNHKPSNTKVD KRVEIKTCGGGSKPPTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSQEDPDVKFNWYVNGAEVHHAQTKPRETQYNSTYRWSVLTVTHQDWL NGKEYTCKVSNKALPAPIQKTISKDKGQPREPQVYTLPPSREELTKNQVSLTCLVKGF YPSDIVVEWESSGQPENTYKTTPPVLDSDGSYFLYSKLTVDKSRWQQGNVFSCSVLH EALHSHYTQKSLSLSPGK*

[0163] Underline indicates a Signal Peptide, Italicize indicates a variable domain, and Bold indicates a LS mutation

[0164] 4. SEQ ID NO: 4 - C-rhesus 10-1074 IgG-LS lambda Light chain

[0165] MKHLWFFLELNAAPR^VLSSYVRPLSVALGETARISCGROALGSRAVOWYOHRPGOAPILLI YNNQDRPSGIPERFSGTPDINFGTRATLTISGVEAGDEADYYCHMWDSRSGFSWSFGGATRLT ELGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVEVAWKADGSAVN AGVETTKPSKQSNNKYAASSYLSLTSDQWKSHKSYSCQVTHEGSTVEKTVAPAECS*

[0166] Underline indicates a Signal Peptide and Italicize indicates a variable domain

[0167] 5. SEQ ID NO: 5 - C-rhesus PGT145 IgG-LS-STII kappa Heavy chain MY^EWFYEELNAAPE^NESOVOLVOSGAEVKKPGSSVKVSCKASGNSFSNHDVHWVRQAT GQGLEWMGWMSHEGDKTGLAQKFQGRVTITRDSGASTVYMELRGLTADDTAIYYCLTGSKH RLRDYFLYNEYGPNYEEWGDYLATLDVWGHGTAVTVSSAS ¥G? SNEVE^PSSES> Y3ESYNA LGCLVKDYFPEPVTVSWNSGSLTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYVCN VNHKPSNTKVDKRVEIKTCGGGSKPPTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSQEDPDVKFNWYVNGAEVHHAQTKPRETQYNSTYRVVSVLTVTHQDWLN GKEYTCKVSNKALPAPIQKTISKDKGQPREPQVYTLPPSREELTKNQVSLTCLVKGFYPS DIVVEWESSGQPENTYKTTPPVLDSDGSYFLYSKLTVDKSRWQQGNVFSCSVLHEALHS HYTOKSLSLSPSAWSHPQFEKGK*

[0168] Underline indicates a Signal Peptide, Italicize indicates a variable domain, Bold indicates a LS mutation, and Bold and Underlined indicates a Strep-tag II.

[0169] 6. SEQ ID NO: 6 - C-rhesus PGT145 IgG-LS-STII kappa Light chain MKiL'W Y ENAAPE^NE EVVITOSPLFLPVTPGEAASLSCKCSHSLOHSTGANYLAW YLQRPGQTPRLLIHLATHRASGVPDRFSGSGSGTDFTLKISRVESDDVGTYYCMQGLHSPWTF GgGT^KEI RAVAAPSVFIFPPSEDQVKSGTVSVVCLLNNFYPREASVKWKVDGV LKTGNSQESVTEQDSKDNTYSLSSTLTLSSTDYQSHNVYACEVTHQGLSSPVTKSFN RGEC*

[0170] Underline indicates a Signal Peptide and Italicize indicates a variable domain

[0171] 7. SEQ ID NO: 7 — C-human Heavy chain IgG (No LS) (Follows variable domain) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK*

[0172] 8. SEQ ID NO: 8 - C-human Light chain kappa (Follows variable domain) RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*

[0173] 9. SEQ ID NO: 9 - C-human Light chain lambda (Follows variable domain) GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTT PSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGSTVEKTVAPTECS*

[0174] 10. SEQ ID NO: 10 - Signal peptide MKHLWFFLLLVAAPRWVLS

[0175] 11. SEQ ID NO: 11 - C-rhesus 3BNC117 IgG-LS kappa heavy chain variable domain QVQLLQSGAAVTKPGASVRVSCEASGYNIRDYFIHWWRQAPGQGLQWVGWINPKT GQPNNPRQFQGRVSLTRHASWDFDTFSFYMDLKALRSDDTAVYFCARQRSDYWDF DVWGSGTQVTVSS 12. SEQ ID NO: 12 - C-rhesus 3BNC117 IgG-LS kappa light chain variable domain DIQMTQSPSSLSASVGDTVTITCQANGYLNWYQQRRGKAPKLLIYDGSKLERGVPSR FSGRRWGQEYNLTINNLQPEDIATYFCQVYEFVVPGTRLDLK

[0176] 13. SEQ ID NO: 13 - C-rhesus 10-1074 IgG-LS lambda heavy chain variable domain QVQLQESGPGLVKPSETLSVTCSVSGDSMNNYYWTWIRQSPGKGLEWIGYISDRESA TYNPSLNSRVVISRDTSKNQLSLKLNSVTPADTAVYYCATARRGQRIYGVVSFGEFF YYYSMDVWGKGTTVTVSS

[0177] 14. SEQ ID NO: 14 — C-rhesus 10-1074 IgG-LS lambda light chain variable domain SYVRPLSVALGETARISCGRQALGSRAVQWYQHRPGQAPILLIYNNQDRPSGIPERFS GTPDINFGTRATLTISGVEAGDEADYYCHMWDSRSGFSWSFGGATRLTVL

[0178] 15. SEQ ID NO: 15 - C-rhesus PGT145 IgG-LS kappa heavy chain variable domain QVQLVQSGAEVKKPGSSVKVSCKASGNSFSNHDVHWVRQATGQGLEWMGWMSHE GDKTGLAQKFQGRVTITRDSGASTVYMELRGLTADDTAIYYCLTGSKHRLRDYFLY NEYGPNYEEWGDYLATLDVWGHGTAVTVSS

[0179] 16. SEQ ID NO: 16 - C-rhesus PGT145 IgG-LS kappa light chain variable domain EVVITQSPLFLPVTPGEAASLSCKCSHSLQHSTGANYLAWYLQRPGQTPRLLIHLATH RASGVPDRFSGSGSGTDFTLKISRVESDDVGTYYCMQGLHSPWTFGQGTKVEIK

[0180] 17. SEQ ID NO: 17 - Strep-tag II SAWSHPQFEKGK

[0181] 18. SEQ ID NO: 18 - C-rhesus heavy chain constant domain ASTKGPSVFPLAPSSRSTSESTAALGCLVKDYFPEPVTVSWNSGSLTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYVCNVNHKPSNTKVDKRVEIKTCGGGSKPPTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPDVKFNWYVNGAEVHH AQTKPRETQYNSTYRVVSVLTVTHQDWLNGKEYTCKVSNKALPAPIQKTISKDKGQ PREPQVYTLPPSREELTKNQVSLTCLVKGFYPSDIWEWESSGQPENTYKTTPPVLDS DGSYFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 19. SEQ ID NO: 19 - C-rhesus heavy chain constant domain with M428L and N434S mutations ASTKGPSVFPLAPSSRSTSESTAALGCLVKDYFPEPVTVSWNSGSLTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYVCNVNHKPSNTKVDKRVEIKTCGGGSKPPTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPDVKFNWYVNGAEVHH AQTKPRETQYNSTYRVVSVLTVTHQDWLNGKEYTCKVSNKALPAPIQKTISKDKGQ PREPQVYTLPPSREELTKNQVSLTCLVKGFYPSDIWEWESSGQPENTYKTTPPVLDS DGSYFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

[0182] Bold indicates an LS mutation.

[0183] 20. SEQ ID NO: 20 - C-rhesus heavy chain constant domain with Strep-tagll ASTKGPSVFPLAPSSRSTSESTAALGCLVKDYFPEPVTVSWNSGSLTSGVHTFPAV LQ SSGLYSLSSVVTVPSSSLGTQTYVCNVNHKPSNTKVDKRVEIKTCGGGSKPPTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPDVKFNWYVNGAEVHH AQTKPRETQYNSTYRVVSVLTVTHQDWLNGKEYTCKVSNKALPAPIQKTISKDKGQ PREPQVYTLPPSREELTKNQVSLTCLVKGFYPSDIWEWESSGQPENTYKTTPPVLDS DGSYFLYSKLTVDKSRWOQGNVFSCSVMHEALHNHYTOKSLSLSPSAWSHPQFEKGK

[0184] Bold and Underlined indicates a Strep-tag II.

[0185] 21. SEQ ID NO: 21 - C-rhesus heavy chain constant domain with M428L and N434S mutations and Strep-tag II ASTKGPSVFPLAPSSRSTSESTAALGCLVKDYFPEPVTVSWNSGSLTSGVHTFPAV LQ SSGLYSLSSVVTVPSSSLGTQTYVCNVNHKPSNTKVDKRVEIKTCGGGSKPPTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPDVKFNWYVNGAEVHH AQTKPRETQYNSTYRVVSVLTVTHQDWLNGKEYTCKVSNKALPAPIQKTISKDKGQ PREPQVYTLPPSREELTKNQVSLTCLVKGFYPSDIWEWESSGQPENTYKTTPPVLDS DGSYFLYSKLTVDKSRWOQGNVFSCSVLHEALHSHYTOKSLSLSPSAWSHPQFEKGK Bold indicates an LS mutation, and Bold and Underlined indicates a Strep-tag II.

[0186] 22. SEQ ID NO: 22 - C-rhesus kappa light chain constant domain RAVAAPSVFIFPPSEDQVKSGTVSVVCLLNNFYPREASVKWKVDGVLKTGNSQESVT EQDSKDNTYSLSSTLTLSSTDYQSHNVYACEVTHQGLSSPVTKSFNRGEC

[0187] 23. SEQ ID NO: 23 - C-rhesus lambda light chain constant domain GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVEVAWKADGSAVNAGVETTK PSKQSNNKYAASSYLSLTSDQWKSHKSYSCQVTHEGSTVEKTVAPAECS

[0188] 24. SEQ ID NO: 24 - C-rhesus 3BNC117 IgG-LS kappa heavy chain variable domain CDR1 GYNIRDYF

[0189] 25. SEQ ID NO: 25 - C-rhesus 3BNC117 IgG-LS kappa heavy chain variable domain CDR2 INPKTGQP

[0190] 26. SEQ ID NO: 26 - C-rhesus 3BNC117 IgG-LS kappa heavy chain variable domain CDR3 ARQRSDYWDFDV

[0191] 27. SEQ ID NO: 27 - C-rhesus 3BNC117 IgG-LS kappa light chain variable domain CDR1 NGY

[0192] 28. SEQ ID NO: 28 - C-rhesus 3BNC117 IgG-LS kappa light chain variable domain CDR2 DGS

[0193] 29. SEQ ID NO: 29 - C-rhesus 3BNC117 IgG-LS kappa light chain variable domain CDR3 QVYEF

[0194] 30. SEQ ID NO: 30 - C-rhesus 10-1074 IgG-LS lambda heavy chain variable domain CDR1

[0195] GDSMNNYY 31. SEQ ID NO: 31 - C-rhesus 10-1074 IgG-LS lambda heavy chain variable domain CDR2

[0196] ISDRESA

[0197] 32. SEQ ID NO: 32 - C-rhesus 10-1074 IgG-LS lambda heavy chain variable domain CDR3

[0198] ATARRGQRIYGVVSFGEFFYYYSMDV

[0199] 33. SEQ ID NO: 33 - C-rhesus 10-1074 IgG-LS lambda light chain variable domain CDR1 ALGSRA

[0200] 34. SEQ ID NO: 34 - C-rhesus 10-1074 IgG-LS lambda light chain variable domain CDR2 NNQ

[0201] 35. SEQ ID NO: 35 - C-rhesus 10-1074 IgG-LS lambda light chain variable domain CDR3 HMWDSRSGFSWS

[0202] 36. SEQ ID NO: 36 - C-rhesus PGT145 IgG-LS kappa heavy chain variable domain CDR1 GNSFSNHD

[0203] 37. SEQ ID NO: 37 - C-rhesus PGT145 IgG-LS kappa heavy chain variable domain CDR2 MSHEGDKT

[0204] 38. SEQ ID NO: 38 - C-rhesus PGT145 IgG-LS kappa heavy chain variable domain CDR3 LTGSKHRLRDYFLYNEYGPNYEE

[0205] 39. SEQ ID NO: 39 - C-rhesus PGT145 IgG-LS kappa light chain variable domain CDR1 HSLQHSTGANY 40. SEQ ID NO: 40 - C-rhesus PGT145 IgG-LS kappa light chain variable domain CDR2 LAT

[0206] 41. SEQ ID NO: 41 - C-rhesus PGT145 IgG-LS kappa light chain variable domain CDR3 MQGLHSPWT

[0207] 42. SEQ ID NO: 42 - Amino acid sequence of Homo sapiens PD-L1 MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWE MEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMI SYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVL SGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNE RTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSDTHLEET

[0208] 43. SEQ ID NO: 43 - mRNA sequence for Homo sapiens CD274 molecule (CD274), transcript variant 1:

[0209] AGTTCTGCGC AGCTTCCCGA GGCTCCGCAC CAGCCGCGCT TCTGTCCGCC TGCAGGGCAT

[0210] TCCAGAAAGA TGAGGATATT TGCTGTCTTT ATATTCATGA CCTACTGGCA TTTGCTGAAC

[0211] GCATTTACTG TCACGGTTCC CAAGGACCTA TATGTGGTAG AGTATGGTAG CAATATGACA

[0212] ATTGAATGCA AATTCCCAGT AGAAAAACAA TTAGACCTGG CTGCACTAAT TGTCTATTGG

[0213] GAAATGGAGG ATAAGAACAT TATTCAATTT GTGCATGGAG AGGAAGACCT GAAGGTTCAG

[0214] CATAGTAGCT ACAGACAGAG GGCCCGGCTG TTGAAGGACC AGCTCTCCCT GGGAAATGCT

[0215] GCACTTCAGA TCACAGATGT GAAATTGCAG GATGCAGGGG TGTACCGCTG CATGATCAGC

[0216] TATGGTGGTG CCGACTACAA GCGAATTACT GTGAAAGTCA ATGCCCCATA CAACAAAATC

[0217] AACCAAAGAA TTTTGGTTGT GGATCCAGTC ACCTCTGAAC ATGAACTGAC ATGTCAGGCT

[0218] GAGGGCTACC CCAAGGCCGA AGTCATCTGG ACAAGCAGTG ACCATCAAGT CCTGAGTGGT AAGACCACCA CCACCAATTC CAAGAGAGAG GAGAAGCTTT TCAATGTGAC CAGCACACTG AGAATCAACA CAACAACTAA TGAGATTTTC TACTGCACTT TTAGGAGATT AGATCCTGAG GAAAACCATA CAGCTGAATT GGTCATCCCA GAACTACCTC TGGCACATCC TCCAAATGAA AGGACTCACT TGGTAATTCT GGGAGCCATC TTATTATGCC TTGGTGTAGC ACTGACATTC ATCTTCCGTT TAAGAAAAGG GAGAATGATG GATGTGAAAA AATGTGGCAT CCAAGATACA AACTCAAAGA AGCAAAGTGA TACACATTTG GAGGAGACGT AATCCAGCAT TGGAACTTCT GATCTTCAAG CAGGGATTCT CAACCTGTGG TTTAGGGGTT CATCGGGGCT GAGCGTGACA AGAGGAAGGA ATGGGCCCGT GGGATGCAGG CAATGTGGGA CTTAAAAGGC CCAAGCACTG AAAATGGAAC CTGGCGAAAG CAGAGGAGGA GAATGAAGAA AGATGGAGTC AAACAGGGAG CCTGGAGGGA GACCTTGATA CTTTCAAATG CCTGAGGGGC TCATCGACGC CTGTGACAGG GAGAAAGGAT ACTTCTGAAC AAGGAGCCTC CAAGCAAATC ATCCATTGCT CATCCTAGGA AGACGGGTTG AGAATCCCTA ATTTGAGGGT CAGTTCCTGC AGAAGTGCCC TTTGCCTCCA CTCAATGCCT CAATTTGTTT TCTGCATGAC TGAGAGTCTC AGTGTTGGAA CGGGACAGTA TTTATGTATG AGTTTTTCCT ATTTATTTTG AGTCTGTGAG GTCTTCTTGT CATGTGAGTG TGGTTGTGAA TGATTTCTTT TGAAGATATA TTGTAGTAGA TGTTACAATT TTGTCGCCAA ACTAAACTTG CTGCTTAATG ATTTGCTCAC ATCTAGTAAA ACATGGAGTA TTTGTAAGGT GCTTGGTCTC CTCTATAACT ACAAGTATAC ATTGGAAGCA TAAAGATCAA ACCGTTGGTT GCATAGGATG TCACCTTTAT TTAACCCATT AATACTCTGG TTGACCTAAT CTTATTCTCA GACCTCAAGT GTCTGTGCAG TATCTGTTCC ATTTAAATAT CAGCTTTACA ATTATGTGGT AGCCTACACA CATAATCTCA TTTCATCGCT GTAACCACCC TGTTGTGATA ACCACTATTA TTTTACCCAT CGTACAGCTG AGGAAGCAAA CAGATTAAGT AACTTGCCCA AACCAGTAAA TAGCAGACCT CAGACTGCCA CCCACTGTCC TTTTATAATA CAATTTACAG CTATATTTTA CTTTAAGCAA TTCTTTTATT CAAAAACCAT TTATTAAGTG CCCTTGCAAT ATCAATCGCT GTGCCAGGCA TTGAATCTAC AGATGTGAGC AAGACAAAGT ACCTGTCCTC AAGGAGCTCA TAGTATAATG AGGAGATTAA CAAGAAAATG TATTATTACA ATTTAGTCCA GTGTCATAGC ATAAGGATGA TGCGAGGGGA AAACCCGAGC AGTGTTGCCA AGAGGAGGAA ATAGGCCAAT GTGGTCTGGG ACGGTTGGAT ATACTTAAAC ATCTTAATAA TCAGAGTAAT TTTCATTTAC AAAGAGAGGT CGGTACTTAA AATAACCCTG AAAAATAACA CTGGAATTCC TTTTCTAGCA TTATATTTAT TCCTGATTTG CCTTTGCCAT ATAATCTAAT GCTTGTTTAT ATAGTGTCTG GTATTGTTTA ACAGTTCTGT CTTTTCTATT TAAATGCCAC TAAATTTTAA ATTCATACCT TTCCATGATT CAAAATTCAA AAGATCCCAT GGGAGATGGT TGGAAAATCT CCACTTCATC CTCCAAGCCA TTCAAGTTTC CTTTCCAGAA GCAACTGCTA CTGCCTTTCA TTCATATGTT CTTCTAAAGA TAGTCTACAT TTGGAAATGT ATGTTAAAAG CACGTATTTT TAAAATTTTT TTCCTAAATA GTAACACATT GTATGTCTGC TGTGTACTTT GCTATTTTTA TTTATTTTAG TGTTTCTTAT ATAGCAGATG GAATGAATTT GAAGTTCCCA GGGCTGAGGA TCCATGCCTT CTTTGTTTCT AAGTTATCTT TCCCATAGCT TTTCATTATC TTTCATATGA TCCAGTATAT GTTAAATATG TCCTACATAT ACATTTAGAC AACCACCATT TGTTAAGTAT TTGCTCTAGG ACAGAGTTTG GATTTGTTTA TGTTTGCTCA AAAGGAGACC CATGGGCTCT CCAGGGTGCA CTGAGTCAAT CTAGTCCTAA AAAGCAATCT TATTATTAAC TCTGTATGAC AGAATCATGT CTGGAACTTT TGTTTTCTGC TTTCTGTCAA GTATAAACTT CACTTTGATG CTGTACTTGC AAAATCACAT TTTCTTTCTG GAAATTCCGG CAGTGTACCT TGACTGCTAG CTACCCTGTG CCAGAAAAGC CTCATTCGTT GTGCTTGAAC CCTTGAATGC CACCAGCTGT CATCACTACA CAGCCCTCCT AAGAGGCTTC CTGGAGGTTT CGAGATTCAG ATGCCCTGGG AGATCCCAGA GTTTCCTTTC CCTCTTGGCC ATATTCTGGT GTCAATGACA AGGAGTACCT TGGCTTTGCC ACATGTCAAG GCTGAAGAAA CAGTGTCTCC AACAGAGCTC CTTGTGTTAT CTGTTTGTAC ATGTGCATTT GTACAGTAAT TGGTGTGACA GTGTTCTTTG TGTGAATTAC AGGCAAGAAT TGTGGCTGAG CAAGGCACAT AGTCTACTCA GTCTATTCCT AAGTCCTAAC TCCTCCTTGT GGTGTTGGAT TTGTAAGGCA CTTTATCCCT TTTGTCTCAT GTTTCATCGT AAATGGCATA GGCAGAGATG ATACCTAATT CTGCATTTGA TTGTCACTTT TTGTACCTGC ATTAATTTAA TAAAATATTC TTATTTATTT TGTTACTTGG TACACCAGCA TGTCCATTTT CTTGTTTATT TTGTGTTTAA TAAAATGTTC AGTTTAACAT COCA

Claims

ClaimsWhat is claimed is:

1. A method of treating or preventing a Human Immunodeficiency Virus (HIV), a Hepatitis B Virus (HBV), an influenza virus, or a respiratory syncytial virus (RSV) infection in a subject, the method comprising administering a therapeutic regimen comprising:a) a 4-aminoquinoline, andb) a viral vector encoding a broadly neutralizing antibody specific for Human Immunodeficiency Virus (HIV), a Hepatitis B Virus (HBV), an influenza virus, or a respiratory syncytial virus (RSV).

2. The method of Claim 1, wherein the broadly neutralizing antibody comprises 3BNC 117, 10-1074, or PGT145.

3. The method of Claim 1 or 2, wherein the viral vector comprises an adeno-associated viral (AAV) vector.

4. The method of any one of Claims 1-3, wherein the 4-aminoquinoline is administered 1, 2, 3, 4, or 5 days prior to administering the viral vector.

5. The method of any one of Claims 1-3, wherein hydroxychloroquine, or the variant thereof, is administered for one or two weeks prior to administering the viral vector.

6. The method of any one of Claims 1-4, wherein hydroxychloroquine, or the variant thereof, is further administered for two weeks or more following administering the viral vector.

7. The method of any one of Claims 1-4, wherein hydroxychloroquine, or the variant thereof, is further administered for eight weeks or more following administering the viral vector.

8. The method of any one of Claims 1-5, wherein the 4-aminoquinoline is administered one, two, three, four, five, six, or seven times per week.

9. The method of any one of Claims 1-5, wherein hydroxychloroquine, or the variant thereof, is administered once per week.

10. The method of any one of Claims 1-6, wherein the 4-aminoquinoline is administered by an intraperitoneal (i.p.) injection, intraveneously or subcutaneously.

11. The method of any one of Claims 1-6, wherein the 4-aminoquinoline is administered orally.

12. The method of any one of Claims 1-7, wherein the therapeutic regimen comprises administering one or more viral vectors encoding a 3BNC117 neutralizing antibody, a 10-1074 neutralizing antibody, or a PGT145 neutralizing antibody.

13. The method of Claim 12, wherein the one or more viral vectors are individually administered.

14. The method of any one of Claims 1-3, wherein the viral vector is administered by an intramuscular (i.m.) injection.

15. The method of any one of Claims 1-14, wherein the method expresses the neutralizing antibodies for more than 5 weeks.

16. The method of any one of Claims 1-14, wherein the method expresses the neutralizing antibodies for more than 15 weeks.

17. The method of any one of Claims 1-15, wherein the method expresses the neutralizing antibodies for more than 7 years.

18. The method of any one of Claims 1-17, wherein the method expresses the neutralizing antibodies during a remainder of the subject’s life.

19. The method of any one of Claims 3-18, wherein the AAV vector comprises an AAV9 serotype.

20. The method of any one of Claims 1-14, wherein the therapeutic regimen is administered in combination with an antiviral agent selected from a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, a fusion inhibitor, a CCR5 antagonist, an integrase strand transfer inhibitor, an attachment inhibitor, a post-attachment inhibitor, a capsid inhibitor, a CYP3 A inhibitor, and combinations thereof.

21. The method of any one of Claims 1-20, wherein the method decreases a viral load in the subject relative to an untreated subject with a viral infection.

22. A method of preventing or reducing an anti-drug antibody (ADA) response in a subject with a disease, wherein a 4-aminoquinoline is administered to the subject prior to administration of at least one viral vector-delivered antibody or antibody-like molecule.

23. The method of Claim 22, wherein the at least one viral vector-delivered antibody or antibody-like molecule comprises two or more antibody combinations.

24. The method of Claim 22 or 23, wherein the at least one viral vector-delivered antibody or antibody-like molecule comprises a monoclonal antibody (mAb).

25. The method of any one of Claims 22-24, wherein the at least one viral vector-delivered antibody or antibody-like molecule comprises an adeno-associated viral (AAV) vector.

26. The method of Claim 25, wherein the AAV vector comprises an AAV9 serotype.

27. The method of any one of Claims 22-26, wherein the disease comprises an infectious disease.

28. The method of claim 27, wherein the infectious disease comprises acquired immune deficiency syndrome / human immunodeficiency virus (AIDS / HIV), malaria, hepatitis A, hepatitis B, hepatitis C, influenza, or variants thereof.

29. The method of any one of Claims 22-28, wherein the ADA response comprises an immune response wherein the subject generates an antibody targeting the at least one viral vector-delivered antibody or antibody-like molecule.

30. The method of any one of Claims 1-29, wherein the subject is a human.

31. A pharmaceutical kit comprising a 4-aminoquinoline and one or more viral vectors encoding a broadly neutralizing antibody selected from 3BNC117, 10-1074, or PGT145.

32. The pharmaceutical kit of Claim 31, wherein the 4-aminoquinoline is in a pharmaceutically acceptable carrier selected from an excipient, a diluent, a salt, a buffer, a stabilizer, a preservative, a lipid, an emulsion, and a nanoparticle.

33. The pharmaceutical kit of Claim 31 or 32, wherein the viral vector is in a pharmaceutically acceptable carrier selected from an excipient, a diluent, a salt, a buffer, a stabilizer, a preservative, a lipid, an emulsion, and a nanoparticle.

34. The pharmaceutical kit of any one of Claims 31-33, wherein the viral vector comprises an adeno-associated viral (AAV) vector.

35. The pharmaceutical kit of Claim 34, wherein the AAV vector comprises an AAV9 serotype.

36. The pharmaceutical kit of any one of Claims 31-35, wherein said kit is combined with an antiviral agent selected from a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, a fusion inhibitor, a CCR5 antagonist, an integrase strand transfer inhibitor, an attachment inhibitor, a post-attachment inhibitor, a capsid inhibitor, a CYP3 A inhibitor, and combinations thereof.

37. The pharmaceutical kit of any one of Claims 31-36, wherein said kit treats or prevents an infection in a subject.

38. The pharmaceutical kit of any one of Claims 31-37, wherein said kit reduces viral loads in the subject with the infection.

39. The pharmaceutical kit of any one of Claims 31-38, wherein said kit reduces viral loads in a subject with Acquired Immunodeficiency Syndrome (AIDS).

40. The pharmaceutical kit of any one of Claims 31-39, wherein the subject is a human.

41. The method of any of Claims 1-30, wherein the vector encodes PD-L1 in addition to a 3BNC117 neutralizing antibody, a 10-1074 neutralizing antibody, or a PGT145 neutralizing antibody.

42. The pharmaceutical kit of Claims 34, wherein the viral vector comprises an adeno-associated viral (AAV) vector.

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