WO2025076542A1 - Atovaquone as an ros inducer for use in the elimination of hiv-infected t-cells - Google Patents

Abstract

The disclosure relates to compositions and methods relating to treatment and prevention of retroviral infections, such as human immunodeficiency virus HIV.

Description

ATOVAQUONE AS AN ROS INDUCER FOR USE IN THE ELIMINATION OF HIV-INFECTED T-CELLS

CROSS reference TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. provisional patent applications No. 63/588,104, which was filed on October 5, 2023, which is hereby incorporated by reference in its entirety.

STATEMENT OF GOVERNMENT SUPPORT

[0002] This invention was made with government support under Contract No. 52500891 (RO1AI170245) and Contract No. 52900782 (UM1AI164565) awarded by the National Institutes of Health. The government has certain rights in the invention.

BACKGROUND

[3] Atovaquone (ATQ) is an FDA-approved naphthoquinone with broadspectrum antiprotozoal activity. It is commonly used for the prevention and treatment of Pneumocystis jirovecii pneumonia (PCP) and Plasmodium falciparum malaria. Recent reports have suggested that ATQ may also act on mammalian cells by increasing intracellular reactive oxygen species (ROS), but only having detrimental effects specifically on malignant cells (Coates et al., 2020; Das et al., 2018; Ke et al., 2018).

[4] Antiretroviral therapy (ART) has revolutionized human immunodeficiency virus (HIV) treatment in the past decades by controlling HIV replication, but it is unable to eliminate the HIV reservoir after establishment (Tseng et al., 2015). There is substantial academic and commercial interest in developing alternative therapeutics capable of either eliminating these HIV reservoirs ‘classical cure’ or enabling durable immune control of HIV replication off of ART (functional cure).

[5] Recent efforts at overcoming ‘viral latency’, commonly believed to be a main contributor to HIV persistence, by re-activating latently infected cells with latency reversal agents (LRAs) have proven ineffective at reducing the HIV reservoir. Furthermore, it has become increasingly evident that persistently infected cells under long-term ART are able to actively express HIV and appear to be recognized by the immune system, but are still unable to be cleared (Stevenson et al., 2022; Stevenson et al., 2021; Thomas et al., 2017). These and other observations have led to the hypothesis that a proportion of the reservoir persists not because of strict viral latency, but because of selection for HIV- infected cells that are resistant to killing - an idea which has a well-established parallel in cancer. We have thus far uncovered one such mechanism of resistance in over-expression of the pro-survival factor BCL-2. Based on this result, the BCL-2 antagonist Venetoclax is under investigation in clinical and non-human primate studies targeting an HIV cure.

[6] BCL-2 overexpression is just one mechanism used by HIV-infected cells to resist elimination. In investigating additional mechanisms, our lab has recently observed that a subset of HIV-infected CD4+ T-cells actively expressing HIV antigens is resistant to cytotoxic T-lymphocyte (CTL) elimination and are enriched for transcriptional signatures delineating metabolic quiescence and low oxidative burden. These signatures translate to CTL-resistant infected cells having lower levels of intracellular ROS compared to bystander, non-targeted infected cells. Due to ATQ’s excellent safety profile, with only mild reported side effects, and its ability to accumulate in tissues (Nixon et al., 2013), we proposed that the drug would be an excellent candidate to sensitize HIV-infected cells to CTL elimination in in vitro and in in vivo models. To this end, preliminary experiments in our lab seem to suggest that ATQ can sensitize (to a subtle but consistent effect) HIV-infected CD4+ T-cells to improved clearance by CTL in in vitro experiments conducted on cells from multiple donors.

SUMMARY OF THE INVENTION

[7] The present invention provides compositions and methods relating to treatment and prevention of retroviral infections, especially the human immunodeficiency virus HIV.

[8] The disclosure relates to a method of reducing HIV reservoirs comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone.

[9] The disclosure relates to a method of eradicating viral reservoirs comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone. [10] The disclosure relates to a method of controlling viral replication comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone.

[11] The disclosure relates to a method of treating an HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone. In embodiments, the method is a prophylactic treatment of an HIV infection. In embodiments, the methods is a therapeutic treatment of an HIV infection.

[12] The disclosure relates to a method of curing an HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone.

[13] The disclosure also relates to further administering an iron chelator to the patient.

[14] In embodiments, treatment with atovaquone is an adjunct to ART- treatment in order to reduce HIV reservoirs. In embodiments, treatment with atovaquone is an alternative to ART if treatments involving ATQ can lead to either eradication of viral reservoirs or to durable immune control of viral replication.

BRIEF DESCRIPTION OF THE FIGURES

[15] Figures 1A -1C show the effects of Atovaquone on sensitizing HIV infected cells to CTL elimination. Figure 1A shows the shifts in intracellular ROS accumulation that atovaquone accomplished in HIV infected cells. Figure IB shows that CTL drive greater elimination of HIV-infected cells (gated region) following pre-treatment with atovaquone (ATQ) versus negative control (DMSO). Figure 1C summary data of experiments with 5 different donors showing that pretreatment with atovaquone results in greater CTL-mediated elimination of HIV- infected cells.

[16] Figures 2A-2B show the effects of Atovaquone on sensitizing pep tide-pulsed cells to elimination by CTL. Figure 2A shows the ROS accumulation on general CD4+ T-cell subsets (naive vs memory). Figure 2B shows results with primary CD4 T-cells but without HIV infection. The peptide pulsed target cells also appear to be sensitized for elimination outside the context of infection, pointing to a cell-intrinsic effect of Atovaquone in enhancing susceptibility of target cells to CTL. This manifests as greater relative reductions in Target cells in the ATQ pre-treated (versus DMSO pre-treated) conditions that received CTL

[17] Figure 3 shows the additive effect of Atovaquone and DFO on sensitizing infected cells to CTL elimination.

[18] Figure 4 shows the additive effect of Atovaquone and DFO on allowing sustained higher levels of cytolytic effectors on CTLs.

[19] Figure 5 shows the additive effect of Atovaquone and DFO on sensitizing peptide-pulsed cells to CTL elimination.

DETAILED DESCRIPTION

Methods of Use

[20] The disclosure relates to a method of reducing HIV reservoirs comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone. The disclosure relates to a method of reducing HIV reservoirs comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone and an iron chelator.

[21] In embodiments, reduction of HIV reservoirs comprises a decrease in the number of cells containing dormant, replication-competent HIV. In embodiments, the decrease in the number of cells containing dormant, replication-competent HIV is of 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (and any number in between). In embodiments, the decrease in the number of cells containing dormant, replication-competent HIV is greater than 95%. In embodiments, the decrease in the number of cells containing dormant, replication- competent HIV is greater than 99%. In embodiments, the decrease in the number of cells containing dormant, replication-competent HIV is between 50 and 75%. In embodiments, the decrease in the number of cells containing dormant, replication-competent HIV is between 75 and 95%. In embodiments, the decrease in the number of cells containing dormant, replication-competent HIV is between 100%.

[22] In embodiments, reducing the HIV reservoir may be reductions in immune activation and inflammation - for example, hsCRP, IL-6, D-dimer, and cystatin C in plasma. In embodiments, reducing the HIV reservoir may be reductions in activation and/or exhaustion markers in T-cells (PD- 1 , CD69, CD25, Tim-3, Lag- 3, CD71). Changes in these measures can both be a useful surrogate of having reduced the HIV reservoir and a clinically beneficial outcome (Currier, J.S., et al. Circulation 118, e29-35 (2008); Dubrow, R., Silverberg, M.J., Park, L.S., Crothers, K. & Justice, A.C. Curr Opin Oncol 24, 506-516 (2012); Hsu, D.C., Sereti, I. & Ananworanich, J. AIDS Res Ther 10, 29 (2013); Hileman, C.O. & Funderburg, N.T. Curr HIV/ AIDS Rep 14, 93-100 (2017)).

[23] The disclosure relates to a method of eradicating viral reservoirs comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone. The disclosure relates to a method of eradicating viral reservoirs comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone and an iron chelator.

[24] In embodiments, the eradication of viral reservoirs comprises a partial or full elimination of the cells in the patient containing dormant, replication- competent HIV. In embodiments, the eradication of viral reservoirs comprises a partial elimination of the cells in the patient containing dormant, replication- competent HIV. In embodiments, the partial elimination of the cells in the patient containing dormant, replication-competent HIV is of 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (and any number in between). In embodiments, the partial elimination of the cells in the patient containing dormant, replication-competent HIV is greater than 95%. In embodiments, the partial elimination of the cells in the patient containing dormant, replication-competent HIV is greater than 99%. In embodiments, the partial elimination of the cells in the patient containing dormant, replication-competent HIV is greater than 99%. In embodiments, the partial elimination of the cells in the patient containing dormant, replication-competent HIV is between 50 and 75%. In embodiments, the partial elimination of the cells in the patient containing dormant, replication- competent HIV is between 75 and 95%. In embodiments, the eradication of viral reservoirs comprises a full (100%) elimination of the cells in the patient containing dormant, replication-competent HIV.

[25] In embodiments, the eradication of the viral reservoir size is measured by one of the following methods: quantitative viral outgrowth assay (QVOA), PCR-based assays, humanized mouse models, analytical treatment interruption, tissue biopsy, or single-cell assays.

[26] The disclosure relates to a method of controlling viral replication comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone. The disclosure relates to a method of controlling viral replication comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone and an iron chelator.

[27] In embodiments, controlling viral replication comprises a partial or full suppression of HIV reproduction in the patient. In embodiments, controlling viral replication comprises a partial suppression of HIV reproduction in the patient. In embodiments, the partial suppression of HIV reproduction in the patient is of 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% (and any number in between). In embodiments, the partial suppression of HIV reproduction in the patient is greater than 95%. In embodiments, the partial suppression of HIV reproduction in the patient is between 50 and 75%. In embodiments, the partial suppression of HIV reproduction in the patient is between 75 and 95%. In embodiments, controlling viral replication comprises a full (100%) suppression of HIV reproduction in the patient.

[28] In embodiments, the control of viral replication is measured by one of the following methods: viral load testing, CD4 T cell counts, drug resistance testing, adherence monitoring, or inflammatory marker detection.

[29] The disclosure relates to a method of treating an HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone. The disclosure relates to a method of treating an HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone and an iron chelator. In embodiments, the method is a prophylactic treatment of an HIV infection. In embodiments, the methods is a therapeutic treatment of an HIV infection.

[30] In embodiments, treating an HIV infection comprises one or more of partially or fully suppressing viral replication, preserving immune function, preventing disease progression, improving quality of life, or reducing transmission risk. In embodiments, treating an HIV infection comprises partially suppressing viral replication. In embodiments, treating an HIV infection comprises fully suppressing viral replication. In embodiments, treating an HIV infection comprises partially preserving immune function. In embodiments, treating an HIV infection comprises fully preserving immune function. In embodiments, treating an HIV infection comprises preventing disease progression. In embodiments, treating an HIV infection comprises, improving quality of life. In embodiments, treating an HIV infection comprises reducing transmission risk.

[31] In embodiments, a method of treating a human immunodeficiency virus (HIV) infection comprising administering a therapeutically effective amount of atovaquone, to a patient in need thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) additional therapeutic agents selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversing agents, compounds that target the HIV capsid, immune-based therapies, phosphatidylinositol 3 -kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p!7 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or any combinations thereof, is provided. In certain embodiments, the one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) additional therapeutic agents are selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, or any combinations thereof. In certain embodiments, the one or more additional therapeutic agent does not include a pharmacokinetic enhancer.

[32] In embodiments, the efficacy of HIV treatment is measured by one of the following methods: viral load, CD4 T cell counts, drug resistance testing, clinical outcomes, quality of life measures, or adherence rates.

[33] The disclosure relates to a method of curing an HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone.

[34] The disclosure also relates a method of treating AIDS or delaying the onset of AIDS symptoms in a patient comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone. The disclosure also relates a method of treating AIDS or delaying the onset of AIDS symptoms in a patient comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone and an iron chelator.

[35] In embodiments, atovaquone is administered in combination with an additional therapeutic agent. In embodiments, the additional therapeutic agent is an iron chelator.

[36] In embodiments, the iron chelator is desferrioxamine (DFO), deferiprone (DFP), def erasirox bleomycin, and tachpyridine. In embodiments, the iron chelator is deferiprone.

[37] In embodiments, treatment with atovaquone is an adjunct to ART treatment in order to reduce HIV reservoirs. In embodiment treatment with atovaquone is an alternative to ART if treatments involving ATQ can lead to either eradication of viral reservoirs or to durable immune control of viral replication.

[38] In embodiments, treatment with atovaquone and an iron chelator is an adjunct to ART-treatment in order to reduce HIV reservoirs. In embodiments, treatment with atovaquone and an iron chelator is an alternative to ART if treatments involving ATQ can lead to either eradication of viral reservoirs or to durable immune control of viral replication. [39] In embodiments, atovaquone is administered with one or more additional therapeutic agents. Co-administration of atovaquone with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of atovaquone and one or more additional therapeutic agents, such that therapeutically effective amounts of atovaquone and the one or more additional therapeutic agents are both present in the body of the patient. When administered sequentially, the combination may be administered together or in two or more administrations.

[40] In embodiments, atovaquone and an iron chelator is administered with one or more additional therapeutic agents. Co-administration of atovaquone with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of atovaquone and one or more additional therapeutic agents, such that therapeutically effective amounts of atovaquone and the one or more additional therapeutic agents are both present in the body of the patient. When administered sequentially, the combination may be administered together or in two or more administrations.

[41] Co-administration includes administration of unit dosages of the atovaquone before or after administration of unit dosages of one or more additional therapeutic agents. For example, atovaquone may be administered within seconds, minutes, or hours of the administration of the one or more additional therapeutic agents. In embodiments, a unit dose of atovaquone is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of atovaquone within seconds or minutes. In other embodiments, a unit dose of atovaquone is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In yet other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of atovaquone.

[42] In embodiments, atovaquone and one or more additional therapeutic agents are administered simultaneously. In embodiments, atovaquone is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration or in a solution for IV administration.

[43] In embodiments, the ART treatment can comprise administering to the patient one or more nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase strand transfer inhibitors, entry inhibitors, or post-attachment inhibitors.

[44] In embodiments, the ART treatment can comprise administering to the patient an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide of reverse transcriptase. Inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting the HIV capsid, immune-based therapy, phosphatidylinositol 3 -kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and/or “antibody-like” therapeutic proteins, HIV p!7 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, Protein disulfide isomerase inhibitor, complement C5a receptor antagonist, DNA methyltransferase inhibitor, HIV vif gene modulator, Vif dimerization antagonist, HIV-1 viral infectivity factor inhibitor, TAT protein inhibitor, HIV-1 Nef modulator, Hck tyrosine kinase Modulator, mixed family kinase-3 (MLK-3) inhibitor, HIV-1 splicing inhibitor, Rev protein inhibitor, integrin antagonist, nucleoprotein inhibitor, splicing factor modulator, COMM domain-containing protein 1 modulator, HIV ribonuclease H inhibitor, retrocycline modulator, CDK-9 inhibitor, dendritic ICAM-3 grabbing nonintegrin 1 inhibitor, HIV GAG protein inhibitor, HIV POL protein inhibitor, complement factor H modulator, ubiquitin ligase inhibitor, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulator, ATP- dependent RNA helicase DDX3X inhibitor, reverse transcriptase priming complex inhibitor, G6PD and NADH-oxidase inhibitor, pharmacokinetic enhancer, HIV gene therapy, HIV vaccine, and combinations thereof.

[45] In embodiments, the ART treatment comprises administering to the patient an HIV protease inhibitor compound, an HIV non-nucleoside inhibitor of reverse transcriptase, an HIV nucleoside of reverse transcriptase, inhibitors, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for treating HIV, and combinations thereof.

[46] In certain embodiments, the method comprises administering atovaquone, in combination with one, two, three, or four additional therapeutic agents. In embodiments, the patient has an HIV infection. In embodiments, the patient is at risk of contracting the HIV virus, such as a patient who has one or more risk factors known to be associated with contracting the HIV virus.

[47] In embodiments, the patient may have not previously received antiviral treatment (treatment naive). In embodiments, the patient may have previously received antiviral treatment (treatment experienced). In embodiments, the patient may have previously received antiviral treatment and developed resistance to the previously received antiviral treatment.

[48] In embodiments, the patient in need thereof is a human who has been infected with HIV. In embodiments, the patient in need thereof is a human who has been infected with HIV but who has not developed AIDS. In embodiments, the patient in need thereof is a patient at risk for developing AIDS. In embodiments, the patient in need thereof is a human who has been infected with HIV and who has developed AIDS.

[49] In embodiments, the patient is an adult patient. In embodiments, the patient is a pediatric patient.

[50] In embodiments, an adult patient is administered 750-2500mg atovaquone per day. In embodiments, an adult patient is administered 750-2000mg atovaquone per day. In embodiments, an adult patient is administered 750- 1500mg atovaquone per day. In embodiments, an adult patient is administered 1000-2500mg atovaquone per day. In embodiments, an adult patient is administered 1000-2000mg atovaquone per day. In embodiments, an adult patient is administered 1000-1500mg atovaquone per day. In embodiments, an adult patient is administered 1500mg atovaquone per day.

[51] In embodiments, a pediatric patient weighing greater than 5 kg patient is administered 325-1250mg atovaquone per day. In embodiments, a pediatric patient weighing greater than 5 kg is administered 325-1000mg atovaquone per day. In embodiments, a pediatric patient weighing greater than 5 kg patient is administered 325-750mg atovaquone per day. In embodiments, a pediatric patient weighing greater than 5 kg is administered 500-1250mg atovaquone per day. In embodiments, a pediatric patient weighing greater than 5 kg is administered 500- lOOOmg atovaquone per day. In embodiments, a pediatric patient weighing greater than 5 kg is administered 500-750mg atovaquone per day. In embodiments, an adult patient is administered 750mg atovaquone per day.

[52] In embodiments, atovaquone is administered once daily. In embodiments, atovaquone is administered twice daily.

[53] In embodiments, atovaquone is administered to a patient for 1-12 month.

In embodiments, atovaquone is administered to a patient for 1-6 month. In embodiments, atovaquone is administered to a patient for 3-6 month. In embodiments, atovaquone is administered to a patient for 1 month. In embodiments, atovaquone is administered to a patient for 2 months. In embodiments, atovaquone is administered to a patient for 3 months. In embodiments, atovaquone is administered to a patient for 4 months. In embodiments, atovaquone is administered to a patient for 5 months. In embodiments, atovaquone is administered to a patient for 6 months. In embodiments, atovaquone is administered to a patient for 7 months. In embodiments, atovaquone is administered to a patient for 8 months. In embodiments, atovaquone is administered to a patient for 9 months. In embodiments, atovaquone is administered to a patient for 10 months. In embodiments, atovaquone is administered to a patient for 11 months. In embodiments, atovaquone is administered to a patient for 12 months.

[54] Additional therapeutic agents are generally administered in a pharmaceutically effective amount. In some embodiments, for oral administration, each dosage unit contains from about 10 mg to about 1000 mg of a compound described herein, for example from about 50 mg to about 500 mg, for example about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg , or about 500 mg. In other embodiments, for parenteral administration, each dosage unit contains from 0.1 to 700 mg of a compound a compound described herein. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual subject, and the severity of the subject's symptoms.

[55] In certain embodiments, dosage levels may be from 0.1 mg to 100 mg per kilogram of body weight per day, for example from about 1 mg to about 50 mg per kilogram, for example from about 5 mg to about 30 mg per kilogram. Such dosage levels may, in certain instances, be useful in the treatment of the aboveindicated conditions. In other embodiments, dosage levels may be from about 10 mg to about 2000 mg per subject per day. The amount of active ingredient that may be combined with the vehicle to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms may contain from 1 mg to 1000 mg of an active ingredient.

[56] Additional therapeutic agents can be administered to a patient in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one day, at least about one week, at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, or at least about 12 months or longer. In one variation, the compound is administered on a daily or intermittent schedule. In one variation, the compound is administered on a monthly schedule. In one variation, the compound is administered every two months. In one variation, the compound is administered every three months. In one variation, the compound is administered every four months. In one variation, the compound is administered every five months. In one variation, the compound is administered every 6 months.

[57] The dosage or dosing frequency of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be adjusted over the course of the treatment, based on the judgment of the administering physician. The compound may be administered to a subject (e.g., a human) in an effective amount. In certain embodiments, the compound is administered once daily.

[58] In embodiment treatment with atovaquone is an adjunct to ART-treatment in order to reduce HIV reservoirs. In embodiment treatment with atovaquone is an alternative to ART if treatments involving ATQ can lead to either eradication of viral reservoirs or to durable immune control of viral replication.

HIV Combination Drugs

[59] Examples of combination drugs include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCO VY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine ;tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®; lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dolutegravir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine and lamivudine; Vacc-4x and romidepsin; and APH-0812.

Other HIV Drugs

[60] Examples of other drugs for treating HIV include acemannan, alisporivir, BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, Hlviral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR- CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, ABX- 464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV- 90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576.

HIV Protease Inhibitors

[61] Examples of HIV protease inhibitors include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, and TMC- 310911.

HIV Reverse Transcriptase Inhibitors

[62] Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, AIC-292, KM-023, and VM-1500.

[63] In some embodiments, examples of HIV non-nucleoside or non- nucleotide inhibitors of reverse transcriptase include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, AIC-292, KM-023, PC-1005, and VM-1500.

[64] Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX® and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148, and KP-1461.

HIV Integrase Inhibitors

[65] Examples of HIV integrase inhibitors include elvitegravir, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5- dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, cabotegravir (long-acting injectable), diketo quinolin-4- 1 derivatives, integrase-LEDGF inhibitor, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC- 699173, NSC-699174, stilbenedisulfonic acid, T-169 and cabotegravir.

[66] Examples of HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) include CX-05045, CX-05168, and CX-14442.

HIV Entry Inhibitors

[67] Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gpl20 inhibitors, and CXCR4 inhibitors.

[68] Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, adaptavir (RAP-101), nifeviroc (TD-0232), anti- GP120/CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD- 0680, and vMIP (Haimipu).

[69] Examples of gp41 inhibitors include albuvirtide, enfuvirtide, BMS- 986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer and sifuvirtide.

[70] Examples of CD4 attachment inhibitors include ibalizumab and CAD A analogs

[71] Examples of gp 120 inhibitors include Radha-108 (receptol) 3B3-PE38, BanLec, bentonite -based nanomedicine, fostemsavir tromethamine, IQP-0831, and BMS-663068

[72] Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

HIV Maturation Inhibitors

[73] Examples of HIV maturation inhibitors include BMS-955176 and GSK- 2838232.

Latency Reversing Agents

[74] Examples of latency reversing agents include histone deacetylase (HD AC) inhibitors, proteasome inhibitors such as velcade, protein kinase C (PKC) activators, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), IL-15, JQ1, disulfram, amphotericin B, and ubiquitin inhibitors such as largazole analogs, and GSK-343.

Examples of HD AC inhibitors include romidepsin, vorinostat, and panobinostat. Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG- lactones.

Capsid Inhibitors

[75] Examples of capsid inhibitors include capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, AVI-621, AVI-101, AVI- 201, AVI-301, and AVI-CAN1-15 series.

[76] In some embodiments, examples of capsid inhibitors include:

[77] In some embodiments, the capsid inhibitor is selected from:

or a pharmaceutically acceptable salt thereof.

[78] In some embodiments, the capsid inhibitor is:

[79] In some embodiments, the capsid inhibitor is:

’ or a pharmaceutically acceptable salt thereof.

Immune-based Therapies

[80] Examples of immune-based therapies include toll-like receptors modulators such as tlrl, tlr2, tlr3, tlr4, tlr5, tlrb, tlr7, tlr8, tlr9, tlrlO, tlrll, tlrl2, and tlr 13 ; programmed cell death protein 1 (Pd-1) modulators; programmed deathligand 1 (Pd-Ll) modulators; IL-15 agonists; DermaVir; interleukin-7; plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alfa; interferon alfa-2b; interferon alfa-n3; pegylated interferon alfa; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; rintatolimod, polymer polyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1; MOR-22;

BMS-936559; CYT-107, interleukin- 15/Fc fusion protein, normferon, peginterferon alfa-2a, peginterferon alfa-2b, recombinant interleukin- 15, RPI- MN, GS-9620, and IR- 103.

[81] In some embodiments, examples of immune-based therapies include tolllike receptors modulators such as tlrl, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlrlO, tlrll, tlrl2, and tlrl3; programmed cell death protein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd-Ll) modulators; IL-15 agonists; DermaVir; interleukin-7; plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alfa; interferon alfa-2b; interferon alfa-n3; pegylated interferon alfa; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; rintatolimod, polymer polyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin- 15/Fc fusion protein, normferon, peginterferon alfa-2a, peginterferon alfa-2b, recombinant interleukin- 15, RPI- MN, GS-9620, STING modulators, RIG-I modulators, NOD2 modulators, andlR- 103.

Phosphatidylinositol 3-kinase (PI3K) Inhibitors

[82] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC- 907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB- 040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765, and ZSTK-474. alpha-4/b eta-7 antagonists

[83] Examples of Integrin alpha-4/beta-7 antagonists include PTG-100, TRK- 170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

HIV Antibodies, Bispecific Antibodies, and "Antibody-like" Therapeutic Proteins

[84] Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bnABs (broadly neutralizing HIV-1 antibodies), BMS-936559, TMB-360, and those targeting HIV gpl20 or gp41, antibody- Recruiting Molecules targeting HIV, anti-CD63 monoclonal antibodies , anti-GB virus C antibodies, anti-GP120/CD4, CCR5 bispecific antibodies, anti-nef single domain antibodies, anti-Rev antibody, camelid derived anti-CD 18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gpl40 targeted antibodies, gp41 -based HIV therapeutic antibodies, human recombinant mAbs (PGT-121), ibalizumab, Immuglo, MB-66

[85] Examples of those targeting HIV in such a manner include bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117, PGT145, PGT121, MDX010 (ipilimumab), VRC01, A32, 7B2, 10E8, VRC-07-523, VRC- HIVMAB080-00-AB, MGD-014 and VRC07.

[86] In embodiments, examples of those targeting HIV in such a manner include bavituximab, UB-421, C2F5, 2G12, C4E10, C2F5+C2G12+C4E10, 8ANC195, 3BNC117, 3BNC60, 10-1074, PGT145, PGT121, PGT-151, PGT- 133, MDX010 (ipilimumab), DH511, N6, VRC01 PGDM1400, A32, 7B2, 10E8, 10E8v4, CAP256-VRC26.25, DRVIA7, VRC-07-523, VRC-HIVMAB080-00- AB, VRC-HIVMAB060-00-AB, MGD-014 and VRC07.

Example of HIV bispecific antibodies include MGD014.

Pharmacokinetic Enhancers

[87] Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

Additional Therapeutic Agents

[88] Examples of additional therapeutic agents include the compounds disclosed in WO 2004/096286 (Gilead Sciences), WO 2006/015261 (Gilead

Sciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (Gilead

Sciences), WO 2012/003498 (Gilead Sciences), WO 2012/145728 (Gilead

Sciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (Gilead

Sciences), WO 2014/100323 (Gilead Sciences), US

2013/0165489 (University of Pennsylvania), US 2014/0221378 (Japan

Tobacco), US 2014/0221380 (Japan Tobacco), WO 2009/062285 (Boehringer

Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO

2013/006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US

20100143301 (Gilead Sciences) and WO 2013/091096 (Boehringer Ingelheim).

HIV Vaccines

[89] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, rgpl20 (AIDS VAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp!20) (RV144), monomeric gp!20 HIV-1 subtype C vaccine, Remune, ITV-1, Centre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly- ICLC adjuvanted vaccines, Tatlmmune, GTU-multiHIV (FIT-06), gpl40[delta]V2.TVl+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC-M4, HIV AX, HIV AX-2, NYVAC-HIV- PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAVl-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, AD VAX, MYM- V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOSl.HIV-Env, Ad26.Mod.HIV vaccine, AGS- 004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particle vaccines such as pseudovirion vaccine, CombiVICHvac, LFn-p24 B/C fusion vaccine, GTU-based DNA vaccine, HIV gag/pol/nef/env DNA vaccine, anti-TAT HIV vaccine, conjugate polypeptides vaccine, dendritic-cell vaccines, gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), I i-key/MHC class II epitope hybrid peptide vaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVA vaccine, Pennvax-GP, pp71 -deficient HCMV vector HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgpl60 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine , UBI HIV gp!20, Vacc-4x + romidepsin, variant gp!20 polypeptide vaccine, rAd5 gag-pol env A/B/C vaccine.

[90] In embodiments, examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4- derived peptide vaccines, vaccine combinations, rgpl20 (AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp!20) (RV144), monomeric gpl20 HIV-1 subtype C vaccine, Remune, ITV-1, Centre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly- ICLC adjuvanted vaccines, Tatlmmune, GTU-multiHIV (FIT-06), gpl40[delta]V2.TVl+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC-M4, HIV AX, HIV AX-2, NYVAC-HIV- PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAVl-PG9DP, G0VX-B 11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADV AX, MYM- V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOSl.HIV-Env, Ad26.Mod.HIV vaccine, AGS- 004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particle vaccines such as pseudovirion vaccine, CombiVICHvac, LFn-p24 B/C fusion vaccine, GTU-based DNA vaccine, HIV gag/pol/nef/env DNA vaccine, anti-TAT HIV vaccine, conjugate polypeptides vaccine, dendritic-cell vaccines, gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), I i-key/MHC class II epitope hybrid peptide vaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVA vaccine, Pennvax-GP, pp71 -deficient HCMV vector HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgpl60 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gpl20, Vacc-4x + romidepsin, variant gp!20 polypeptide vaccine, rAd5 gag-pol env A/B/C vaccine, DNA.HTI and MVA.HTI. HIV Combination Therapy

[91] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents selected from ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF +FTC); DESCO VY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GEN VO YA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[92] It will be appreciated by one of skill in the art that the additional therapeutic agents listed above may be included in more than one of the classes listed above. The particular classes are not intended to limit the functionality of those compounds listed in those classes.

Methods of Administration

[93] In vivo application of the disclosed compounds, and compositions containing them, can be accomplished by any suitable method and technique presently or prospectively known to those skilled in the art. For example, the disclosed compounds can be formulated in a physiologically- or pharmaceutically-acceptable form and administered by any suitable route known in the art including, for example, oral and parenteral routes of administration. As used herein, the term parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, intrasternal, and intrathecal administration, such as by injection. Administration of the disclosed compounds or compositions can be a single administration, or at continuous or distinct intervals as can be readily determined by a person skilled in the art.

[94] In embodiments, the route of administration of atovaquone is oral, sublingual, buccal, topical, transdermal, ocular, otic, nasal, inhalation, oropharyngeal, rectal, vaginal, intravenous, intramuscular, subcutaneous, intradermal, intra-arterial, intrathecal, epidural, intraosseous, intravitreal, intracerebral, intravesical, intra-articular, intralesional, subconjunctival, intracavernous, or intratumoral.

[95] In embodiments, the route of administration of atovaquone is oral, sublingual, buccal, intravenous, intramuscular, subcutaneous, intradermal, intraarterial, intrathecal, or epidural.

[96] The compounds disclosed herein can be formulated according to known methods for preparing pharmaceutically acceptable compositions. Formulations are described in detail in a number of sources which are well known and readily available to those skilled in the art. For example, Remington’s Pharmaceutical Science by E.W. Martin (1995) describes formulations that can be used in connection with the disclosed methods. In general, the compounds disclosed herein can be formulated such that an effective amount of the compound is combined with a suitable carrier in order to facilitate effective administration of the compound. The compositions used can also be in a variety of forms. These include, for example, solid, semi-solid, and liquid dosage forms, such as tablets, pills, powders, liquid solutions or suspension, suppositories, injectable and infusible solutions, and sprays. The form depends on the intended mode of administration and therapeutic application. The compositions also include conventional pharmaceutically-acceptable carriers and diluents which are known to those skilled in the art. Examples of carriers or diluents for use with the compounds include ethanol, dimethyl sulfoxide, glycerol, alumina, starch, saline, and equivalent carriers and diluents.

[97] Formulations suitable for administration include, for example, aqueous sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions, which can include suspending agents and thickening agents. The formulations can be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze dried (lyophilized) condition requiring only the condition of the sterile liquid carrier, for example, water for injections, prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powder, granules, tablets, etc. It should be understood that in addition to the ingredients particularly mentioned above, the compositions can include other agents conventional in the art having regard to the type of formulation in question.

[98] Compounds and compositions disclosed herein, including pharmaceutically acceptable salts or prodrugs thereof, can be administered intravenously, intramuscularly, or intraperitoneally by infusion or injection. Solutions of the active agent or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations can contain a preservative to prevent the growth of microorganisms.

[99] The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient, which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. The ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. Optionally, the prevention of the action of microorganisms can be brought about by various other antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, isotonic agents are included, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the inclusion of agents that delay absorption, for example, aluminum monostearate and gelatin.

[100] Sterile injectable solutions are prepared by incorporating a compound and/or agent in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation include vacuum drying and the freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

[101] Useful dosages of the compounds and agents and pharmaceutical compositions can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art.

[102] The dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the symptoms or disorder are affected. The dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, sex and extent of the disease in the patient and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician in the event of any counterindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days.

[103] Also disclosed are pharmaceutical compositions that comprise a compound in combination with a pharmaceutically acceptable carrier. Pharmaceutical compositions adapted for oral, topical or parenteral administration, comprising an amount of a compound are provided. The dose administered to a patient, particularly a human, should be sufficient to achieve a therapeutic response in the patient over a reasonable time frame, without lethal toxicity, and causing no more than an acceptable level of side effects or morbidity. One skilled in the art will recognize that dosage will depend upon a variety of factors including the condition (health) of the subject, the body weight of the subject, kind of concurrent treatment, if any, frequency of treatment, therapeutic ratio, as well as the severity and stage of the pathological condition.

[104] Also disclosed are kits that comprise a compound disclosed herein in one or more containers. The disclosed kits can optionally include pharmaceutically acceptable carriers and/or diluents. In embodiments, a kit includes one or more other components, adjuncts, or adjuvants as described herein. In embodiments, a kit includes one or more anti-cancer agents, such as those agents described herein. In embodiments, a kit includes instructions or packaging materials that describe how to administer a compound or composition of the kit. Containers of the kit can be of any suitable material, e.g., glass, plastic, metal, etc., and of any suitable size, shape, or configuration. In embodiments, a compound and/or agent disclosed herein is provided in the kit as a solid, such as a tablet, pill, or powder form. In embodiments, a compound and/or agent disclosed herein is provided in the kit as a liquid or solution. In embodiments, the kit comprises an ampoule or syringe containing a compound and/or agent disclosed herein in liquid or solution form.

[105] A number of embodiments of the invention 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.

[106] While the concepts of the present disclosure are illustrated and described in detail in the figures and descriptions herein, results in the figures and their description are to be considered as examples and not restrictive in character; it being understood that only the illustrative embodiments are shown and described and that all changes and modifications that come within the spirit of the disclosure are desired to be protected.

[107] Unless defined otherwise, the scientific and technology nomenclatures have the same meaning as commonly understood by a person in the ordinary skill in the art pertaining to this disclosure.

[108] The entire contents of each and every patent publication, non-patent publication, and reference text cited herein are hereby incorporated by reference, except that in the event of any inconsistent disclosure or definition from the present specification, the disclosure or definition herein shall be deemed to prevail.

Certain Definitions

[109] Unless defined otherwise, the scientific and technology nomenclatures have the same meaning as commonly understood by a person in the ordinary skill in the art pertaining to this disclosure.

[HO] As used in the description and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a composition” includes mixtures of two or more such compositions, reference to “an agent” includes mixtures of two or more such agents, reference to “the component” includes mixtures of two or more such components, and the like.

[111] The term “about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values such as “about 49, about 50, about 55, ...”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 52.5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein. Similarly, the term “about” when preceding a series of numerical values or a range of values (e.g., “about 10, 20, 30” or “about 10-30”) refers, respectively to all values in the series, or the endpoints of the range.

[112] 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.

[113] The term “therapeutically effective” or “effective amount” refer to the amount of the composition used is of sufficient quantity to ameliorate one or more causes or symptoms of a disease or disorder. Such amelioration only requires a reduction or alteration, not necessarily elimination.

[114] Hence, an “effective amount” or “therapeutically effective amount” refer to an amount of a compound, formulation, material, or composition, as described herein effective to achieve a particular biological result or provides a therapeutic or prophylactic benefit. Such results may include, but are not limited to, decreasing the number of cells in the patient containing dormant, replication- competent HIV ; eliminating cells in the patient that contain dormant, replication- competent HIV; suppressing HIV reproduction in the patient; suppressing viral replication, preserving immune function, preventing disease progression, improving the patient’s quality of life, or reducing transmission risk; or eliminating HIV from the patient’s body.

[115] The term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.

[116] The term “carrier” means a compound, composition, substance, or structure that, when in combination with a compound or composition, aids or facilitates preparation, storage, administration, delivery, effectiveness, selectivity, or any other feature of the compound or composition for its intended use or purpose. For example, a carrier can be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject.

[117] As used herein, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose.

[118] The terms, “improve,” “increase,” “reduce,” “decrease,” and the like, as used herein, indicate values that are relative to a control. In embodiments, a suitable control is a baseline measurement, such as a measurement in the same individual prior to initiation of the treatment described herein, or a measurement in a control individual (or multiple control individuals) in the absence of the treatment described herein. A “control individual” is an individual afflicted with the same disease, who is about the same age and/or gender as the individual being treated (to ensure that the stages of the disease in the treated individual and the control individual(s) are comparable).

[119] The individual (also referred to as “patient” or "subject") being treated is an individual (fetus, infant, child, adolescent, or adult human) having a disease or having the potential to develop a disease.

[120] In embodiments, the individual is an individual who has been recently diagnosed with the disease. Typically, early treatment (treatment commencing as soon as possible after diagnosis) is important to minimize the effects of the disease and to maximize the benefits of treatment.

[121] The terms “inhibit”, “inhibiting” or “inhibition” refer to a decrease in an activity, expression, function or other biological parameter and can include, but does not require complete ablation of the activity, expression, function or other biological parameter. Inhibition can include, for example, at least about a 10% reduction in the activity, response, condition, or disease as compared to a control. In embodiments, expression, activity or function of a gene or protein is decreased by a statistically significant amount.

[122] As used herein, the term "dosage unit" refers to a form in which a pharmaceutical agent is provided.

[123] A number of embodiments have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Other embodiments are within the scope of the following claims. [124] All publications, patents and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications, patents and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

EXAMPLES

Example 1:

[125] While latency is a principal contributor to immune evasion by the HIV reservoir, there is evidence of ongoing recognition of some infected cells by HIV- specific cytotoxic T-lymphocytes (CTL) under ART. The selection of CTL- resistant infected cells may thus contribute to HIV persistence, and BCL-2 overexpression has been identified as one underlying mechanism. To identify additional mechanisms of resistance, an in vitro model was developed that compares infected cells that survive CTL pressure to non-targeted infected bystander cells in the same environment. Here, we highlight gene and surface protein expression profiles delineating a ‘CTL-resistant’ phenotype in infectedcell survivors.

Method:

[126] Central memory CD4+ T-cells from HLA-B57⁺ donors were infected with HIVJRSCF (WT) or an HIVJRSCF. rwioesc variant containing an escape mutation in the Gag-TWIO epitope (TWIOesc). Killing assays were performed by labeling infected T-cells with CTFR (WT) or CFSE/CTV (TWIOesc) dyes, then culturing these together with a TW10 epitope-specific CTL clone. Surviving WT-infected and bystander TWIOesc-infected cells were sorted based on HIV-envelope expression and profiled by RNA-seq, CITE-seq and flow cytometry. Killing assays were also performed with pre-treatment of infected cells with the FDA- approved anti-malarial drug Atovaquone (ATQ).

Results:

[127] Up to 90% of WT infected cells were eliminated by CTL. Survivors were resistant to a second round of CTL exposure and exhibited distinctive transcriptional and protein expression profiles, relative to bystanders. GSEA analysis of RNAseq data revealed that WT survivors were negatively enriched for Hallmark Glycolysis (n=4, P < 2.96e-05) and Reactome Glucose Metabolism (P < 0.038) pathways, in addition to pathways related to by-products of active metabolism such as Hallmark Hypoxia (P < le-05) and Reactome FOXO mediated transcription of oxidative stress (P < 0.006). Flow cytometry on WT survivors demonstrated an enrichment of cells expressing lower levels of cellular reactive oxygen species (ROS) (P = 0.058), and also downregulation of transferrin receptor (CD71). Pre-treatment of infected cells with ATQ, to induce intracellular ROS accumulation, modestly enhanced susceptibilities of infected cells to CTL- mediated elimination.

[128] ROS production, as a result of granzyme-mediated damage to the mitochondria, contributes to CTL-mediated killing. Our results suggest that lower levels of baseline ROS in HIV-infected cells with particular metabolic features renders these cells less susceptible to killing by CTL. Treatment with the FDA- approved and well-tolerated ROS inducer ATQ modestly increased CTL- mediated elimination of infected cells in vitro. Targeting metabolic and oxidative balance may be a strategy to enhance elimination of persistent HIV-infected CD4+ T-cells.

Example 2

[129] CD4+ T-cells from an HIV+ donor were superinfected in vitro with the clinical HIV-JRCSF strain and subjected to a 16 hour killing assay with an HLA- matched HIV-specific cytotoxic T-lymphocyte (CTL) clone (targeting the Gag- TW 10 epitope) isolated from an HIV+ donor, infected CD4 cells were pretreated with vehicle (left), 10 uM deferoxamine (DFO) (middle) or a combination of DFO and 60 uM atovaquone ((right) for 72 hours before the drugs were washed away and cells were incubated without (top) and with CTLs (bottom). Surviving CTL- resistant infected cells were quantified as CD4-lo, Gag-p24+ cells by flow cytometry.

[130] CTLs after a killing assay, were isolated by magnetic sorting and restimulated with PMA/Ionomycin and protein transport inhibitors to capture cytokine and cytolytic effector molecules production intracellularly by flow cytometry. CTLs from vehicle condition with no infected targets added (top), or from killing assays (bottom) after pretreatment of infected CD4+ T cell targets with vehicle (left), DFO (middle) and DFO and ATQ combo (right) were quantified for surface CD 107a expression (degranulation marker) and perforin production/accumulation.

[131] CD4+ T-cells from an uninfected donor were pulsed with either an HIV Gag-TWIO peptide (targets) or the same peptide but with an escape mutation blocking recognition byTW 10-specific CTLs (bystanders), stained with different cell trace dyes (targets- cell trace far red, CTFR; Bystanders- cell trace violet, CTV) and cocultured in a 16 hour killing assay without (top) and with (bottom) an HLA matched TW 10-specific CTL clone after pre-treatment with vehicle, Atovaquone (Atov), DFO or a combination of the two. Surviving CD4+ T-cells were quantified by flow cytometry

Results are show in Figures 3-5.

REFERENCES

Coates, J.T.T., Rodriguez-Berriguete, G., Puliyadi, R., Ashton, T., Prevo, R., Wing, A., Granata, G., Pirovano, G., McKenna, G.W., and Higgins, G.S. (2020). The anti-malarial drug atovaquone potentiates platinum-mediated cancer cell death by increasing oxidative stress. Cell Death Discov 6, 110.

Das, S., Dielschneider, R., Chanas-LaRue, A., Johnston, J.B., and Gibson, S.B. (2018). Antimalarial drugs trigger lysosome-mediated cell death in chronic lymphocytic leukemia (CLL) cells. Leuk Res 70, 79-86.

Ke, F„ Yu, J., Chen, W., Si, X., Li, X., Yang, F„ Liao, Y„ and Zuo, Z. (2018). The anti-malarial atovaquone selectively increases chemosensitivity in retinoblastoma via mitochondria] dysfunction-dependent oxidative damage and Akt/AMPK/mTOR inhibition. Biochem Biophys Res Commun 504, 374-379. McCann, C.D., van Dorp, C.H., Danesh, A., Ward, A.R., Dilling, T.R., Mota, T.M., Zale, E., Stevenson, E.M., Patel, S., Brumme, C.J., et al. (2021). A participant-derived xenograft model of HIV enables long-term evaluation of autologous immunotherapies. J Exp Med 218. Nixon, G.L., Moss, D.M., Shone, A.E., Lalloo, D.G., Fisher, N., O'Neill, P.M., Ward, S.A., and Biagini, G.A. (2013). Antimalarial pharmacology and therapeutics of atovaquone. J Antimicrob Chemother 68, 977-985.

Stevenson, E.M., Terry, S., Copertino, D., Leyre, L., Danesh, A., Weiler, J., Ward, A.R., Khadka, P„ McNeil, E„ Bernard, K„ el al. (2022). SARS CoV-2 mRNA vaccination exposes latent HIV to Nef-specific CD8(+) T-cells. Nat Common 13, 4888.

Stevenson, E.M., Ward, A.R., Truong, R., Thomas, A.S., Huang, S.H., Dilling, T.R., Terry, S., Bui, J.K., Mota, T.M., Danesh, A., et al. (2021). HIV-specific T cell responses reflect substantive in vivo interactions with antigen despite longterm therapy. JCI Insight 6.

Thomas, A.S., Jones, K.L., Gandhi, R.T., McMahon, D.K., Cyktor, J.C., Chan, D., Huang, S.H., Truong, R., Bosque, A., Macedo, A.B., et al. (2017). T-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy. PLoS Pathog 13, e 1006629.

Tseng, A., Seet, J., and Phillips, E.J. (2015). The evolution of three decades of antiretroviral therapy: challenges, triumphs and the promise of the future. Br J Clin Pharmacol 79, 182-194.

Claims

CLAIMS We claim:

1. A method of reducing HIV reservoirs comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone.

2. The method of claim 1, wherein the reduction of HIV reservoirs comprises a decrease in the number of cells containing dormant, replication-competent HIV.

3. The method of claim 1 or 2, wherein the therapeutically effective amount of atovaquone comprises a dosing regimen of atovaquone sufficient to partially or fully decrease the number of cells in the patient containing dormant, replication- competent HIV.

4. The method of any one of claims 1 to 3, wherein the route of administration of atovaquone is oral, sublingual, buccal, intravenous, intramuscular, subcutaneous, intradermal, intra-arterial, intrathecal, or epidural.

5. The method of any one of claims 1 to 4, wherein atovaquone is administered in combination with an additional therapeutic agent.

6. The method of claim 5, wherein the additional therapeutic agent is an iron chelator.

7. The method of any one of claims 1 to 6, further comprising ART-treatment.

8. The method of any one of claims 1 to 7, wherein an adult patient is administered 1500 mg atovaquone per day, continuously for 1 to 3 months.

9. The method of any one of claims 1 to 8, wherein a pediatric patient weighing greater than 5 kg is administered 750 mg atovaquone per day, continuously for 1 to 3 months.

10. The method of any one of claims 1 to 9, wherein atovaquone is administered twice daily.

11. The method of any one of claims 1 to 10, wherein the reduction of HIV reservoir size is measured by one of the following methods: quantitative viral outgrowth assay (QVOA),

PCR-based assays, flow cytometry, single-cell assays, biomarker detection, PET imaging, or viral sequencing.

12. A method of eradicating viral reservoirs comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone.

13. The method of claim 12, wherein the eradication of viral reservoirs comprises a partial or full elimination cells in the patient containing dormant, replication-competent HIV.

14. The method of claims 12 or 13, wherein the therapeutically effective amount of atovaquone comprises a dosing regimen of atovaquone sufficient to partially or fully eliminate cells in the patient that contain dormant, replication-competent HIV.

15. The method of any one of claims 12 to 14, wherein the route of administration of atovaquone is oral, sublingual, buccal, intravenous, intramuscular, subcutaneous, intradermal, intra-arterial, intrathecal, or epidural.

16. The method of any one of claims 12 to 15, wherein atovaquone is administered in combination with another therapeutic agent.

17. The method of any one of claims 12 to 16, further comprising ART- treatment.

18. The method of any one of claims 12 to 17, wherein the additional therapeutic agent is an iron chelator.

19. The method of any one of claims 12 to 18, wherein an adult patient is administered 1500 mg atovaquone per day, continuously for 1 to 3 months.

20. The method of any one of claims 12 to 19, wherein a pediatric patient weighing greater than 5 kg is administered 750 mg atovaquone per day, continuously for 1 to 3 months.

21. The method of any one of claims 12 to 20, wherein atovaquone is administered twice daily.

22. The method of any one of claims 12 to 21, wherein the eradication of the viral reservoir size is measured by one of the following methods: quantitative viral outgrowth assay (QVOA), PCR-based assays, humanized mouse models, analytical treatment interruption, tissue biopsy, or single-cell assays.

23. A method of controlling viral replication comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone.

24. The method of claim 23, wherein controlling viral replication comprises a partial or full suppression of HIV reproduction in the patient.

25. The method of claims 23 or 24, wherein the therapeutically effective amount of atovaquone comprises a dosing regimen of atovaquone sufficient to partially or fully suppress HIV reproduction in the patient.

26. The method of any one of claims 23 to 25, wherein the route of administration of atovaquone is oral, sublingual, buccal, intravenous, intramuscular, subcutaneous, intradermal, intra-arterial, intrathecal, or epidural.

27. The method of any one of claims 23 to 26, wherein atovaquone is administered in combination with another therapeutic agent.

28. The method of any one of claims 23 to 27, wherein the additional therapeutic agent is an iron chelator.

29. The method of any one of claims 23 to 27, further comprising ART- treatment.

30. The method of any one of claims 23 to 29, wherein an adult patient is administered 1500 mg atovaquone per day, continuously for three days.

31. The method of any one of claims 23 to 30, wherein a pediatric patient weighing greater than 5 kg is administered 750 mg atovaquone per day, continuously for three days.

32. The method of any one of claims 23 to 31, wherein atovaquone is administered twice daily.

33. The method of any one of claims 23 to 32, wherein control of viral replication is measured by one of the following methods: viral load testing, CD4 T cell counts, drug resistance testing, adherence monitoring, or inflammatory marker detection.

34. A method of treating an HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone.

35. The method of claim 34, wherein treating the HIV infection comprises one or more of partially or fully suppressing viral replication, preserving immune function, preventing disease progression, improving quality of life, or reducing transmission risk.

36. The method of claim 34 or 35, wherein the therapeutically effective amount of atovaquone comprises a dosing regimen of atovaquone sufficient to partially or fully suppress viral replication, preserve immune function, prevent disease progression, improve the patient’s quality of life, or reduce transmission risk.

37. The method of any one of claims 34 to 36, wherein the route of administration of atovaquone is oral, sublingual, buccal, intravenous, intramuscular, subcutaneous, intradermal, intra-arterial, intrathecal, or epidural.

38. The method of any one of claims 34 to 37, wherein atovaquone is administered in combination with another therapeutic agent.

39. The method of any one of claims 34 to 38, wherein the additional therapeutic agent is an iron chelator.

40. The method of any one of claims 34 to 39, further comprising ART- treatment.

41. The method of any one of claims 34 to 40, wherein an adult patient is administered 1500 mg atovaquone per day, continuously for three days.

42. The method of any one of claims 34 to 41, wherein a pediatric patient weighing greater than 5 kg is administered 750 mg atovaquone per day, continuously for three days.

43. The method of any one of claims 34 to 42, wherein atovaquone is administered twice daily.

44. The method of any one of claims 34 to 43, wherein the efficacy of HIV treatment is measured by one of the following methods: viral load, CD4 T cell counts, drug resistance testing, clinical outcomes, quality of life measures, or adherence rates.

45. A method of curing an HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone.

46. The method of claim 45, wherein curing the HIV infection comprises partial or full elimination of HIV from the patient’ s body.

47. The method of claims 45 or 46, wherein the therapeutically effective amount of atovaquone comprises a dosing regimen of atovaquone sufficient to eliminate HIV from the patient’s body.

48. The method of any one of claims 45 to 47, wherein the route of administration of atovaquone is oral, sublingual, buccal, intravenous, intramuscular, subcutaneous, intradermal, intra-arterial, intrathecal, or epidural.

49. The method of any one of claims 45 to 48, wherein atovaquone is administered in combination with another therapeutic agent.

50. The method of any one of claims 45 to 49, wherein the additional therapeutic agent is an iron chelator.

51. The method of any one of claims 45 to 49, further comprising ART- treatment.

52. The method of any one of claims 45 to 51, wherein an adult patient is administered 1500 mg atovaquone per day, continuously for 1-3 months.

53. The method of any one of claims 45 to 52, wherein a pediatric patient weighing greater than 5 kg is administered 750 mg atovaquone per day, continuously for 1-3 months.

54. The method of any one of claims 45 to 53, wherein atovaquone is administered twice daily.

55. The method of any one of claims 45 to 54, wherein curing the patient of an HIV infection is measured by one of the following methods: analytical treatment interruption, viral testing, PCR-based assays, quantitative viral outgrowth assay (QVOA), tissue biopsy, immunological assessment, or long-term follow up.

56. A method of treating AIDS or delaying the onset of AIDS symptoms in a patient comprising administering to a patient in need thereof a therapeutically effective amount of atovaquone.

57. The method of any one of claims 56, wherein the route of administration of atovaquone is oral, sublingual, buccal, intravenous, intramuscular, subcutaneous, intradermal, intra-arterial, intrathecal, or epidural.

58. The method of claims 56 or 57, wherein atovaquone is administered in combination with another therapeutic agent.

59. The method of any one of claims 56 to 59, wherein the additional therapeutic agent is an iron chelator.

60. The method of any one of claims 56 to 59, further comprising ART- treatment.

61. The method of any one of claims 56 to 60, wherein an adult patient is administered 1500 mg atovaquone per day, continuously for 1-3 months.

62. The method of any one of claims 56 to 60, wherein a pediatric patient weighing greater than 5 kg is administered 750 mg atovaquone per day, continuously for 1-3 months.

63. The method of any one of claims 56 to 62, wherein atovaquone is administered twice daily.

64. The method of any one of claims 56 to 63, wherein treating AIDS or delaying the onset of AIDS symptoms in a patient is measured by one of the following methods: analytical treatment interruption, viral testing, PCR-based assays, quantitative viral outgrowth assay (QVOA), tissue biopsy, immunological assessment, or long-term follow up.