Combination therapy of TLR7 modifiers and HIV vaccines

Abstract

Providing a combination of a TLR7 modifier and an HIV vaccine. [Solution] This disclosure describes methods, compositions, and kits relating to the combined use of a TLR7 modulating compound and an HIV vaccine. This combined use can be used in methods for treating or preventing HIV infection in humans. In one embodiment, this disclosure provides a method for treating or preventing HIV infection in a person who has HIV infection or is at risk of developing HIV infection and who requires treatment or prevention of HIV infection.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 62 / 851,363, filed on 22 May 2019, which is incorporated herein by reference in its entirety for all purposes. Sequence List

[0002] This application includes an electronically submitted sequence listing in ASCII format, the entire listing of which is incorporated herein by reference. The ASCII copy, created on April 29, 2020, is named 1300PF_ST25.txt and has a size of 14,473 bytes. [Background technology]

[0003] The innate immune system provides the body's first line of defense against invading pathogens. In the innate immune response, invading pathogens are recognized by germline-encoded receptors, and their activation initiates a signaling cascade that leads to the induction of cytokine expression. Innate immune system receptors have broad specificity and recognize highly conserved molecular structures across different pathogens. One family of these receptors is known as Toll-like receptors (TLRs) due to their homology to the receptor first identified and named in Drosophila. TLRs are found in cells such as macrophages, dendritic cells, and epithelial cells.

[0004] Mammals have at least 10 different TLRs. Ligands and corresponding signaling cascades have been identified for some of these receptors. For example, TLR2 is activated by lipoproteins from bacteria (e.g., Escherichia coli), TLR3 is activated by double-stranded RNA, TLR4 is activated by lipopolysaccharides (i.e., LPS or endotoxin) from Gram-negative bacteria (e.g., Salmonella and Escherichia coli O157:H7), TLR5 is activated by flagellin from motile bacteria (e.g., Listeria), TLR7 recognizes and responds to imiquimod, and TLR9 is activated by unmethylated CpG sequences in pathogen DNA. Stimulation of each of these receptors leads to the activation of the transcription factor NF-κB, as well as the activation of other signaling molecules involved in regulating the expression of cytokine genes, including those encoding tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and certain chemokines. TLR7 agonists are immunostimulants that can induce endogenous interferon-α production in vivo.

[0005] There are many TLR-related diseases, disorders, and conditions for which therapies using TLR agonists are considered promising, including, but are not limited to, melanoma, non-small cell lung cancer, hepatocellular carcinoma, basal cell carcinoma, renal cell carcinoma, myeloma, allergic rhinitis, asthma, COPD, ulcerative colitis, hepatic fibrosis, and viral infections.

[0006] Examples of TLR7 modulating compounds include the TLR7 agonist compounds of U.S. Patent Nos. 8,367,670, 8,629,142, and 8,809,527, which have been demonstrated at the minimum effective concentration (MEC) of IFN-α. The activity of the TLR7 agonist GS-9620 is discussed in Lanford et al., Gastroenterology 2013, 144(7), 1508-17, and Roethle, P. et al., J. Med. Chem. 2013, 56(18), 7324-7333, and the TLR7 agonist activity of the compounds of U.S. Patent Nos. 8,367,670, 8,629,142, and 8,809,527, including those in Examples 4, 49, 89, 99, and 105, is discussed.

[0007] Worldwide, more than 36 million people are infected with the HIV virus. A number of drugs and combination therapies have been developed for the treatment of HIV infection in humans. Antiretroviral combination therapy (cART) and highly active antiretroviral therapy (HAART) can reduce the activation of the HIV virus and, in many cases, reduce HIV RNA / plasma mL to less than 50 copies, but there has generally been no treatment that can remove HIV-infected cells that are not actively replicating HIV, which are generally called the patient's latent HIV reservoir. Strategies for the "kick-and-kill" approach to treating HIV, in which cells in the latent reservoir "kick" HIV-infected cells and induce the transcription of latent replicable HIV proviruses, creating a state of transient viremia and making the activated cells sensitive to "death" from antiretroviral therapy, are being explored. The "kick" programs are testing various agents, including histone deacetylase inhibitors, disulfiram, PD-1 antibodies, and HIV vaccines, as described in Barton, K.M. et al. Clin. Pharmacol. Ther. 2013, 93(1), 46-56; Marsden, M.D. et al., Cell 2014, 158(5), 971-972; Battistini, A. et al., Viruses 2014, 6(4), 1715-1758; and Cillo, A.R. et al., Proc. Natl. Acad. Sci. 2014, 111(19), 7078-␣7083.

[0008] Increased access to highly active antiretroviral therapy (cART) has led to a dramatic reduction in the morbidity and mortality associated with human immunodeficiency virus (HIV) infection. However, despite new classes of antiretroviral drugs, currently available cART regimens cannot eradicate HIV from the body. As a result, viral rebound persists after cART discontinuation in participants who maintain undetectable viral loads. This reflects the fact that standard cART is unable to eliminate viral reservoirs formed by latently infected cells in which integrated proviruses have remained quiescent and stable since the initial stage of infection, and that the immune response is unable to effectively suppress viral rebound after treatment interruption. Even when cART results in viral load control (and thus prevents the development of AIDS and viral transmission), there are several problems. (a) Non-curative: cART is a lifelong treatment. If a person stops treatment, viral load generally rebounds to initial levels within 2 to 4 weeks, rendering the person infectious again. (b) Adherence issues: 30 - 50% of patients are unable to control viral load due to non-compliance with treatment regimens. This is highly related to psychological stress, and living with HIV without a prospect of cure affects the quality of life of patients, and even if not, patients feel inconvenienced by various degrees of treatment routines ("drug fatigue"). (c) Resistance: HIV may develop resistance to cART. (d) Side effects: Due to the long-term toxicity of cART, patients may develop cardiovascular disease, dyslipidemia, hypertension, diabetes, osteoporosis, or kidney disease. (e) High cost: Treating patients with cART costs approximately $20,000 per year, but the total cost to the healthcare system over a patient's lifetime is calculated to exceed $400,000. (f) Social stigma: The stigma surrounding HIV makes people unwilling to get tested or to disclose their HIV status, which also limits access to available HIV treatments. There is still a need for new drugs and therapies that can support the activation of latent HIV-infected cells in order to enhance antiretroviral therapy and the activity of the immune response. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] U.S. Patent No. 8,367,670 [Patent Document 2] U.S. Patent No. 8,629,142 [Patent Document 3] U.S. Patent No. 8,809,527 [Non-patent literature]

[0010] [Non-Patent Document 1] Lanford et al.,Gastroenterology2013,144(7),1508-17 [Non-Patent Document 2] Roethle,P.et al.,J.Med.Chem.2013,56(18),7324-7333 [Non-Patent Document 3] Barton,KMet al.Clin.Pharmacol.Ther.2013,93(1),46-56 [Non-Patent Document 4] Marsden,MDet al.,Cell2014,158(5),971-972,Battistini,A.et al.,Viruses2014,6(4),1715-1758 [Non-Patent Document 5] Cillo,ARet al.,Proc.Natl.Acad.Sci.2014,111(19), 7078-7083 [Overview of the project] [Means for solving the problem]

[0011] In one embodiment, the present disclosure provides a method for treating or preventing HIV infection in a person who has HIV infection or is at risk of developing HIV infection and who requires treatment or prevention of HIV infection, wherein the method comprises a therapeutically effective amount of a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, (i) A sequence having at least 90% sequence identity with sequence number 1, (ii) A sequence having at least 90% sequence identity with sequence number 2, (iii) A sequence having at least 90% sequence identity with sequence number 3, (iv) A sequence having at least 90% sequence identity with sequence number 4, (v) A sequence having at least 90% sequence identity with sequence number 5, (vi) A sequence having at least 90% sequence identity with sequence number 6, (vii) Sequences having at least 90% sequence identity with sequence number 7, (viii) Sequences having at least 90% sequence identity with sequence number 8, (ix) A sequence having at least 90% sequence identity with sequence number 9, (x) A sequence having at least 90% sequence identity with sequence number 10, (xi) A sequence having at least 90% sequence identity with sequence number 11, (xii) A sequence having at least 90% sequence identity with sequence number 12, (xiii) Sequences having at least 90% sequence identity with sequence number 13, (xiv) Sequences having at least 90% sequence identity with sequence number 14, (xv) A sequence having at least 90% sequence identity with sequence number 15, and (xvi) The administration of a first virus to a human being comprising nucleic acid encoding an immunogenic polypeptide having at least 90% sequence identity with sequence number 16, At least two of (i) to (xvi) are linked by single, double, or triple alanine amino acid linkers, which result in the formation of AAA sequences in the binding region between adjacent sequences, and each of the sequences (i) to (xvi) is 11 to 85 amino acids in length.

[0012] A method comprising administering the TLR7 modulating compounds and HIV vaccine described herein to a human is further provided. [Modes for carrying out the invention]

[0013] I. Overview This disclosure provides methods, compositions, and kits for the treatment or prevention of HIV infection in humans, including the combined use of a TLR7 modulating compound and an HIV vaccine. II. Definition

[0014] "The Compounds of the Disclosure" includes the compounds disclosed herein, for example, the Compounds of the Disclosure include the compound of formula (I) and its pharmaceutically acceptable salts.

[0015] The compounds known during medical use as "Tris" or tris(hydroxymethyl)aminomethane, or as tromethamine or THAM, are compounds having the formula (HOCH2)3CNH2.

[0016] "Modifying," "modulating," and "modulator" refer to the action of a drug that stimulates (activates or enhances) or antagonizes (inhibits or reduces) the function of a biological target. Agonists or enhancers include modulators that increase the activity of the TLR7 receptor. Each method, combination, kit, use, composition, and regimen described herein that utilizes or contains a TLR7 modulator or TLR7 modulator exists in separate embodiments in which the TLR7 modulator or TLR7 modulator is a TLR7 agonist. TLR7 agonism may be determined by the PBMC assay protocol of U.S. Patent Application Publication No. 8,367,670, the contents of which are incorporated herein by reference, and Bioorg.Med.Chem.Lett. 16,4559 (2006).

[0017] As used herein, "pharmaceutically acceptable" means a substance that, within the bounds of sound medical judgment, is free from excessive toxicity, irritation, or allergic reactions, is suitable for use in contact with human and lower animal tissues, has a reasonable benefit-to-risk ratio, and is effective for its intended purpose when used in a pharmaceutical composition.

[0018] As used herein, “pharmaceutically acceptable salt” means, within the bounds of sound medical judgment, a salt of the compound disclosed which is free from excessive toxicity, irritation, or allergic reactions, suitable for use in contact with human and lower animal tissues, commensurate with a reasonable benefit / risk ratio, generally water-soluble, oil-soluble, or dispersible, and effective for its intended use. The term includes, but is not limited to, pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. A list of suitable salts can be found, for example, in Berge, S.M. et al., J. Pharm. Sci., 1977, 66, 1-19.

[0019] In the context of proteins, functional equivalents or fragments of functional equivalents may have one or more conserved amino acid substitutions. The term "conserved amino acid substitution" refers to the substitution of an amino acid with another amino acid that has similar properties to the original amino acid. The conserved amino acid group is as follows: [Table 1]

[0020] Conservative substitutions may be introduced at any position in a given peptide or its fragment. However, it may also be desirable to introduce non-conservative substitutions, but not limited to, at any one or more positions. Non-conservative substitutions that result in the formation of a functionally equivalent fragment of the peptide are, for example, substantially different in polarity, charge, and / or steric bulk while maintaining the functionality of the derivative or mutant fragment.

[0021] The "sequence identity ratio" is determined by comparing two optimally aligned sequences across a comparison window, where portions of the polynucleotide or polypeptide sequence within the comparison window may have additions or deletions (i.e., gaps) compared to a reference sequence (without additions or deletions) for the optimal alignment of the two sequences. In some cases, the sequence identity ratio can be calculated by determining the number of positions in which identical nucleic acid bases or amino acid residues occur in both sequences, obtaining the number of matching positions, dividing the number of matching positions by the total number of positions in the comparison window, and multiplying the result by 100.

[0022] In the context of two or more nucleic acid or polypeptide sequences, “identical” or percentage “identical” means that two or more sequences or subsequences that, when compared across a comparison window or specified region measured by one of the following sequence comparison algorithms or by manual alignment and visual inspection, and aligned for maximum correspondence, are identical or have a specified percentage of the same amino acid residues or nucleotides (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identity across a specific region, e.g., the entire polypeptide sequence or individual domains of the polypeptide). Such sequences are then said to be “substantially identical.” This definition also refers to the complement of the test sequence.

[0023] A DNA sequence that "codes" a specific RNA is a DNA nucleic acid sequence that can be transcribed into RNA. A DNA polynucleotide may code for RNA that is translated into a protein (mRNA), or it may code for RNA that is not translated into a protein (e.g., tRNA, rRNA, or guide RNA, also referred herein as "non-coding" RNA or "ncRNA"). A protein-coding sequence or a sequence that codes for a specific protein or polypeptide is a nucleic acid sequence that, when transcribed into mRNA (in the case of DNA) and placed under the control of appropriate regulatory sequences, can be transcribed into a polypeptide in vitro or in vivo.

[0024] A “vector,” “expression vector,” or “construct” is a nucleic acid used to introduce a heterologous nucleic acid into a cell that has regulatory elements providing the expression of the heterologous nucleic acid within the cell. Examples of vectors include, but are not limited to, plasmids, minicircles, yeast, and viral genomes. In some embodiments, the vector is a plasmid, minicircle, yeast, or viral genome. In some embodiments, the vector is a viral vector.

[0025] As used herein, “treatment,” “to treat,” or “to treat” means an approach to obtain a beneficial or desired outcome. For the purposes of this disclosure, beneficial or desired outcomes include, but are not limited to, symptom relief and / or reduction in the severity of symptoms and / or prevention of exacerbation of symptoms associated with the disease or condition. In one embodiment, “treatment” or “to treat” includes one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition and / or reducing the severity of the disease or condition); b) delaying or cessating the onset of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the exacerbation or progression of the disease or condition); and c) alleviating the disease or condition, e.g., causing regression of clinical symptoms, improving the disease state, delaying the progression of the disease, improving the quality of life, and / or extending survival.

[0026] As used herein, “therapeutic dose” or “effective dose” means a sufficient amount of a drug, including, for example, a compound of formula (I) or an HIV vaccine, to induce a desired biological or medical response when administered to a patient to treat a disease. The effective dose varies depending on the drug, the disease and its severity, as well as the age, weight, etc., of the patient being treated. The effective dose may include a range of amounts. As understood in the art, the effective dose may be one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. The effective dose may be considered in the context of administering one or more therapeutic agents, where a desirable or beneficial outcome may be achieved, or if it is achieved, by combining one or more other agents, then a single agent is considered to be administered in an effective dose. The appropriate dose of any co-administered agent may be reduced due to the combined effects of the agents (e.g., additive or synergistic effects).

[0027] As used herein, “delay” means to postpone, interfere with, delay, prevent, stabilize, and / or postpone the onset of a disease or condition. This delay can be of varying lengths depending on the disease being treated and / or the medical history of the individual. As will be apparent to those skilled in the art, a sufficient or significant delay can encompass prevention in that the individual effectively does not develop the disease or condition.

[0028] As used herein, “prevention,” “preventing,” or “preventing” refers to a regimen that protects against the onset of a disease or disorder so that the clinical symptoms of the disease do not develop. Thus, “prevention” relates to the timing of treatment (e.g., administration of a therapeutic substance) before signs of the disease are detected in the patient (e.g., administration of a therapeutic substance to the patient while there is no detectable infectious pathogen (e.g., virus) in the patient). The patient may be an individual at risk of developing the disease or disorder, such as an individual with one or more risk factors known to be associated with the onset or development of the disease or disorder. Thus, in certain embodiments, the term “preventing HIV infection” refers to administering an anti-HIV therapeutic substance to a patient who does not have a detectable HIV infection. It is understood that patients receiving anti-HIV prophylactic therapy may be individuals at risk of contracting the HIV virus. It is also understood that prevention does not require a 100% success rate. In some cases, prevention may be understood as a reduction in the risk of infection, but not as a complete elimination of the occurrence of infection.

[0029] As used herein, “person at risk” means a person who is at risk of developing the condition being treated. A person at risk may or may not have a detectable disease or condition, and may or may not exhibit a detectable disease prior to treatment by the method described herein. “At risk” means that a person has one or more risk factors, which are measurable parameters that correlate with the development of a disease or condition and are known in the art. A person having one or more of these risk factors is more likely to develop a disease or condition than a person not having these risk factors.

[0030] "Viral infection" describes a disease state in which a virus invades healthy cells, uses the cell's reproductive mechanisms to multiply or replicate, and ultimately leads to cell lysis and death, the release of viral particles, and infection of other cells by newly produced progeny viruses. Latent infection by certain viruses, such as HIV, is also a possible consequence of a viral infection.

[0031] As used herein, “ART” refers to antiretroviral therapy. Generally, the term refers to the combination of antiretroviral drugs used to treat human viral infections, including HIV infection. Combinations and regimens may include multiple, often three or more, drugs, such as nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, CCR5 agonists, and / or integrase inhibitors.

[0032] "Viral load" and "HIV viral load" refer to the level of HIV detectable in the blood of an HIV-infected person. This can be calculated by estimating the amount of virus in the bodily fluids involved. For example, it can be given as HIV RNA copies per milliliter of blood or plasma. "Undetectable" HIV viral load refers to a state where HIV RNA copies are not routinely detected by standard viral load tests, e.g., less than 50 copies of HIV RNA per milliliter of blood or plasma.

[0033] "Viremia" refers to the measurable presence of circulating virus or viral particles in a person infected with the virus. Transient viremia refers to a short-term, transient, or temporary increase in the measurable presence of circulating virus or viral particles in a person infected with the virus. An example of transient HIV viremia is a period during which the HIV-1 RNA level in the blood or plasma of an HIV-infected person, which has been maintained at a concentration of less than 50 copies / mL for a certain period, rises to a concentration greater than 50 copies / mL, such as 50-2,000 copies / mL, for a short period, transiently, or temporarily.

[0034] The terms “chronic set point,” “set point in chronic HIV infection,” “viral load set point,” and “viral set point in chronic HIV infection” refer to the steady-state HIV viral load established in the blood of an HIV-infected person. The chronic set point may refer to the post-infection steady-state HIV viral load value after the introduction of antiretroviral therapy or treatment, including the administration of ARTs, TLR7 modulators, and / or HIV vaccines as described herein, or after the discontinuation of antiretroviral therapy or treatment. The chronic set point may be determined in a single HIV-infected person or as the median chronic set point in a cohort of HIV-infected people. When comparing two chronic set points, the first chronic set point may be a percentage of the second chronic set point, or the second chronic set point may be multiple first chronic set points. For example, the first chronic set point of 100 copies of HIV-1 RNA per mL is 10% of the second chronic set point of 1000 copies of HIV-1 RNA per mL, or it can be described as a second chronic set point that is 10 times higher than the first chronic set point.

[0035] "Viral rebound" refers to the finding that the undetectable HIV viral load in virologically suppressed HIV-infected individuals after treatment with ART often returns to a detectable HIV viral load after discontinuation of ART. Viral rebound can occur within a few days or weeks, e.g., within four weeks, after discontinuation of ART. "Delayed viral rebound" refers to the period between the observation of expected viral rebound after discontinuation of ART, e.g., four weeks, and the actual viral rebound observed after discontinuation of another treatment, e.g., 12 weeks, compared to ART, TLR7 modifier, and HIV vaccine as described herein. In the above hypothetical example, the delayed viral rebound is eight weeks after treatment with ART, TLR7 modifier, and HIV vaccine. The delayed viral rebound can be determined in a single HIV-infected individual or as the median delayed viral rebound in a cohort of HIV-infected individuals. III.Compound

[0036] This disclosure describes TLR7 modulating compounds that can be used in the methods, compositions, and / or kits of this disclosure. In some embodiments, the TLR7 modulating compound is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof.

[0037] The pharmaceutically acceptable salts of the TLR7 modulating compounds described herein include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, and phosphoric acid, which retain the biological efficacy and properties of the free base and are not biologically or otherwise undesirable, as well as acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphate, hemisulfonic acid, and hexanoic acid. Examples of organic acids that make up salts include, but are not limited to, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid, pectinic acid, phenylacetic acid, 3-phenylpropionic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, and undecanoic acid.

[0038] The solid-state forms of the compounds of this disclosure are also included. The crystalline forms of the TLR7-modulated compounds of formula (I) are described in U.S. Patents 9,738,646 and 10,202,384, which are incorporated herein by reference in their entirety. Exemplary crystalline forms of the compounds of formula (I) can be characterized by X-ray powder diffraction (XRPD) patterns having peaks at 5.8, 11.4, 11.6, 17.7, 20.1, 20.9, 22.3, 23.9, 26.0 and 26.8 degrees 2θ (±0.2 degrees 2θ), where the XRPD is CuK α1 Created using radiation, differential scanning calorimetry (DSC) plots show endothermic activity at approximately 133°C, 170°C, and 273°C. Another exemplary crystalline form of the compound of formula (I) can be characterized by an XRPD pattern with peaks at 4.6, 9.2, 15.8, 17.8, 18.3, 19.2, 19.9, 22.4, 25.5, and 29.1 degrees 2θ (±0.2 degrees 2θ), where the XRPD shows CuK α1Created using radiation, the DSC endothermic temperatures are approximately 98°C and 253°C. IV. Vaccines

[0039] This specification describes HIV vaccines that specifically target regions on the Gag, Pol, Vif, and Nef proteins of the HIV virus. Such HIV vaccines may induce an immune response to one or more HIV proteins and may protect a person not infected with HIV from becoming infected with the virus, or may have a therapeutic effect on a person who is infected with HIV or who will later become infected with HIV. The vaccine generally comprises a package such as a delivery mechanism, e.g., a viral vector, and an immunogenic composition or nucleic acid encoding the immunogenic composition, designed to produce a desired immune response. In some embodiments, the immunogenic composition comprises an immunogenic polypeptide, which is an antigen that, when introduced in vivo, can induce an adaptive immune response, i.e., a humoral or cell-mediated immune response.

[0040] Any viral vector capable of introducing a desired package into the body to promote an adaptive response can be used in the methods, compositions, and / or kits described herein. In some embodiments, the viral vector includes a live vector vaccine, an inactivated vaccine, or a modified envelope vaccine. In some embodiments, the viral vector includes adenoviridae, poxviridae, herpesviridae, adeno-associated viruses, cytomegalovirus, carynpox, rubella poliovirus, Venezuelan encephalitis virus, lentivirus, or Sendai virus vectors. In some embodiments, the viral vector includes a viral vector from the adenoviridae or poxviridae families. In some embodiments, the viral vector includes a poxvirus viral vector, such as a modified vaccinia virus ankara (MVA) vector. A representative MVA vector is described in Barouch, H. D et al. Cell 2013, 155(3), 531-539 (which is incorporated herein by reference in its entirety). In some embodiments, the viral vector includes adenovirus vectors such as chimpanzee adenovirus, for example, replication-deficient chimpanzee adenovirus. Exemplary chimpanzee adenovirus vectors are described, for example, in U.S. Patent No. 9,714,435 (which is incorporated herein by reference in its entirety).

[0041] International Publication No. 2013 / 110818 and U.S. Patent No. 9,988,425 (each of which is incorporated herein by reference in its entirety) describe immunogens for HIV vaccination. Sixteen regions in the Gag, Pol, Vif, and Nef proteins of the HIV-1 virus are relatively conserved and have been targeted in HIV patients with reduced viral loads, specifically HIV-1 RNA of less than 5,000 copies per mL. (Hancock, G. et al. PLOS Pathogens 2015, 11(2), e1004658; Mothe, B. et al. J. Translational Med. 2015, 13, 60). These regions of the HIV protein formed the basis for immunogens for therapeutic HIV vaccination. The following table summarizes the regions of HIV-1 targeted by immunogens. [Table 2] The HIV numbering is as described in Korber, BT et al. (1998) Numbering positions in HIV relative to HXB2CG. In: Korber, CK, Foley, B., Hahn, B., McCutchan, F., Mellors, J. and Sodroski, J (eds). Human Retroviruses and AIDS 1998. Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, pp. III-102-111.

[0042] In some embodiments, the HIV vaccine comprises a virus containing an immunogenic polypeptide, or a nucleic acid encoding an immunogenic polypeptide, where the immunogenic polypeptide is (i) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 1, (ii) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 2, (iii) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 3, (iv) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 4, (v) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 5, (vi) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 6, (vii) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 7, (viii) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 8, (ix) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 9, (x) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 10, (xi) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 11, (xii) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 12, (xiii) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 13, (xiv) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 14, (xv) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 15, (xvi) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 16, At least two of (i) to (xvi) are linked by single, double, or triple alanine amino acid linkers, the linkers resulting in the formation of AAA sequences in the binding region between adjacent sequences, and each of sequences (i) to (xvi) is 11 to 85 amino acids in length, e.g., 11 to 82, 11 to 80, or 11 to 78. In some embodiments, the immunogenic polypeptide includes a sequence having an amino acid sequence with 1, 2, or 3 or fewer substitutions in any one of SEQ ID NOs. 1 to 16.

[0043] In some embodiments, the immunogenic polypeptide comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 17. In some embodiments, the immunogenic polypeptide comprises the amino acid sequence of SEQ ID NO: 17.

[0044] Immunogenic polypeptides can be encoded by any suitable nucleic acid sequence. In some embodiments, the nucleic acid encoding the immunogenic polypeptide comprises a nucleic acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 18. In some embodiments, the nucleic acid encoding the immunogenic polypeptide comprises the nucleic acid sequence of SEQ ID NO: 18.

[0045] In some embodiments, the HIV vaccine comprises a modified vaccinia virus Ankara (MVA) containing a nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17. In some embodiments, the HIV vaccine comprises a replication-deficient chimpanzee adenovirus containing a nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17. V. Composition

[0046] In some embodiments, the disclosure provides pharmaceutical compositions comprising a TLR7 modulating compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0047] In some embodiments, the pharmaceutical composition comprises an HIV vaccine described herein and pharmaceutically acceptable excipients.

[0048] In some embodiments, the pharmaceutical composition includes one or more additional therapeutic agents, as fully described below.

[0049] Pharmaceutical compositions comprising the compounds of this disclosure or pharmaceutically acceptable salts thereof can be prepared with one or more pharmaceutically acceptable excipients, which may be selected according to common practice. Tablets may contain excipients, including lubricants, fillers, and binders. In certain embodiments, compositions comprising TLR7 modulated compounds are provided in solid dosage forms, including solid oral dosage forms.

[0050] The compositions described herein, suitable for oral administration, may be presented as separate units (unit dosage forms), each containing a predetermined amount of the active ingredient, including but not limited to capsules, sachets, or tablets. In one embodiment, the pharmaceutical composition is a tablet.

[0051] The pharmaceutical compositions disclosed herein comprise one or more therapeutic agents disclosed herein, for example, the compounds of this disclosure or an HIV vaccine, together with pharmaceutically acceptable excipients and optionally other therapeutic agents. The pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. Pharmaceutically acceptable excipients may be any adjuvants, carriers, excipients, lubricants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are approved by the U.S. Food and Drug Administration as acceptable for use in humans.

[0052] Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more excipients, including sweeteners, flavoring agents, coloring agents, and preservatives, in order to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch, or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained effect over a long period of time. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with wax.

[0053] The amount of the active ingredient, which may be combined with an inactive ingredient to produce a dosage form, may vary depending on the patient being treated and the specific mode of administration. For example, in some embodiments, a dosage form of the compound of formula (I) for oral administration to humans may contain about 1 to 10 mg of the active substance, e.g., about 2, 3, 4, 5, 6, 7, or about 8 mg of the active substance, formulated with a suitable and convenient amount of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutically acceptable excipients constitute about 5 to about 95% (by weight) of the total composition.

[0054] In certain embodiments, compositions comprising the compounds of the Disclosure or pharmaceutically acceptable salts thereof in one variant form do not contain any agents that affect the rate at which the active ingredient is metabolized. Therefore, in one embodiment, it is understood that compositions comprising the compounds of the Disclosure do not contain any agents that affect (e.g., delay, inhibit, or block) the metabolism of the compounds of the Disclosure or any other active ingredient administered separately, sequentially, or simultaneously with the compounds of the Disclosure. In one embodiment, it is also understood that none of the methods, kits, articles, etc., detailed herein contain any agents that affect (e.g., delay, inhibit, or block) the metabolism of the compounds of the Disclosure or any other active ingredient administered separately, sequentially, or simultaneously with the compounds of the Disclosure.

[0055] Aqueous compositions, such as those used to prepare HIV vaccine formulations, may be prepared in sterile form and may generally be isotonic if intended for delivery by means other than oral administration. All compositions are based on Rowe et al, Handbook of Pharmaceutical Excipients, 6. th Excipients may be included, such as those described in edition, American Pharmacists Association, 2009. Examples of excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, and carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, and stearic acid.

[0056] The amount of virus in an HIV vaccine preparation can be measured by any means known in the art. The amount may be determined, for example, by bulk measurement of the number of viral particles (vp) in a large aqueous composition by flow cytometry. Alternatively, the amount may be determined by the activity of the virus in the composition, for example, by a plaque assay. A plaque-based assay can be used to determine the viral concentration in relation to the infectious dose. A viral plaque assay determines the number of plaque-forming units (pfu) in a viral sample, which can be used as a measure of viral load. See, for example, Kaufmann, S.H. Kabelitz, D. (2002). Methods in Microbiology Vol.32: Immunology of Infection. Academic Press. ISBN 0-12-521532-0.

[0057] The compositions include those suitable for various routes of administration, including oral and intramuscular administration. The compositions may be presented in unit dosage forms and may be prepared by any method known in the field of pharmacy. Such methods include the step of associating an active ingredient (e.g., the compounds of this disclosure or their pharmaceutically acceptable salts) with one or more pharmaceutically acceptable excipients. The compositions may also be prepared by homogeneously and closely associating the active ingredient with a liquid excipient or a finely divided solid excipient or both, and then, if necessary, shaping the product. The techniques and formulations are generally described in Remington: The Science and Practice. of Pharmacy, 21 st See Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0058] In some embodiments, the composition comprises about 2 to about 6 mg, such as about 2, 3, 4, 5, or about 6 mg, such as 2 mg or 4 mg of a compound of formula (I), lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

[0059] In some embodiments, the composition comprises a nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 in about 0.5 mL of formulation buffer of a replication-deficient chimpanzee adenovirus at about 1×10 10 to about 1×10 11 , such as about 1×10 10 , 2×10 10 , 3×10 10 , 4×10 10 , 5×10 10 , 6×10 10 , 7×10 10 , 8×10 10 , 9×10 10 or about 1×10 11 viral particles (vp). In some embodiments, the formulation buffer comprises about 10 mM of L-histidine. In some embodiments, the formulation buffer comprises about 35 mM of NaCl. In some embodiments, the formulation buffer comprises about 7.5% (w / v) of sucrose. In some embodiments, the formulation buffer comprises about 1 mM of MgCl2. In some embodiments, the formulation buffer comprises about 0.1 mM of disodium EDTA. In some embodiments, the formulation buffer comprises about 0.1% (w / v) of polysorbate-80. In some embodiments, the formulation buffer comprises about 0.5% (v / v) of ethanol. In some embodiments, the formulation buffer has a pH of about 6.6. In some embodiments, the composition comprises a nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 in 0.5 mL of formulation buffer of a replication-deficient chimpanzee adenovirus at 5×10 10The formulation buffer contains virus particles (vp), and comprises 10 mM L-histidine, 35 mM NaCl, 7.5% (w / v) sucrose, 1 mM MgCl2, 0.1 mM disodium EDTA, 0.1% (w / v) polysorbate-80, 0.5% (v / v) ethanol, and a pH of 6.6.

[0060] In some embodiments, the composition contains approximately 0.5 × 10⁶ modified vaccinia virus Ankara (MVA) in approximately 0.5 mL of Tris buffer, comprising a nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17. 8 ~Approx. 5×10 8 For example, approximately 1 × 10 8 , 2×10 8 , 3 x 10 8 , 4×10 8 , or approximately 5 x 10 8 It contains 10 plaque-forming units (pfus). In some embodiments, the composition contains 2 × 10⁶ modified vaccinia virus Ankara (MVA) in 0.5 mL Tris buffer, comprising a nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17. 8 It contains individual plaque-forming units (PFUs). VI. Method

[0061] As those skilled in the art will understand, when treating viral infections such as HIV, such treatments may be characterized in various ways and measured by various endpoints. The scope of this disclosure is intended to encompass all such characteristics.

[0062] In some embodiments, in a person who has HIV infection or is at risk of developing HIV infection and requires treatment or prevention of HIV infection, a method for treating or preventing HIV infection includes administering to the person a TLR7 modulating compound of the Disclosure (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an HIV vaccine described herein. In some embodiments, the method is effective in inducing an immune response to one or more clades of HIV. In some embodiments, the method can be used to induce an immune response to multiple epitopes of viral infection in a person. The induction of an immune response to a viral infection can be evaluated using any technique known to those skilled in the art to determine whether an immune response has occurred. Suitable methods for detecting an immune response of the Disclosure include, among other things, detecting a decrease in viral load or antigen in the patient's serum, detecting interferon (IFN)-γ secreted antigen-specific T cells, and detecting elevated levels of one or more liver enzymes such as alanine transferase (ALT) and aspartate transferase (AST). In one embodiment, detection of IFN-γ secretory antigen-specific T cells is achieved using an ELISPOT assay or FACS analysis. Another embodiment includes reducing the viral load associated with HIV infection, including a reduction measured by a PCR test.

[0063] TLR7 modulating compounds can induce transient viremia from latent HIV reservoirs. See, for example, U.S. Patent Publication 20160008374 (which is incorporated herein by reference in its entirety). Latent HIV reservoirs and latent HIV infection refer to a state in which quiescent CD4+ T lymphocytes or other cells are infected with HIV but do not actively produce HIV. Inactive HIV-infected cells are commonly referred to as latent infected cells. Antiretroviral therapy (ART) can reduce the level of HIV in the blood to undetectable levels, but latent HIV reservoirs persist. When latent infected cells are reactivated, they begin to produce HIV (HIV replication).

[0064] Methods for treating or preventing HIV infection, including the “kick-and-kill” combination of the TLR7 modulating compounds of this disclosure and the HIV vaccines described herein, can target and eliminate active HIV virus and activate latent HIV virus to target and eliminate HIV virus from latent reservoirs. Methods for determining the level of HIV in latent reservoirs are known in the art and include, for example, direct measurement of HIV DNA levels in CD4+ T cells and indirect measurement of viral rebound time after discontinuation of anti-HIV therapy. Improved control of HIV viremia by the treatment or prevention methods described herein can be reflected in a delayed viral rebound compared to the viral rebound observed with standard HIV therapy.

[0065] In some embodiments, a method for treating or preventing HIV infection in humans, comprising administering a TLR7 modifier of the Disclosure and an HIV vaccine described herein to a human, further comprises maintaining a low viral load (e.g., less than about 200, 100, 50, or about 20 copies of HIV-1 RNA per mL of blood or plasma) for a certain period, for example, about 1 week to about 9 months, after discontinuation of anti-HIV treatment including ART, TLR7 modifier, and HIV vaccine. In some embodiments, the period is longer after administration of TLR7 modifier and HIV vaccine compared to administration of TLR7 modifier or HIV vaccine alone. In some embodiments, the period is 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, or longer.

[0066] In some embodiments, in a person who has HIV infection or is at risk of developing HIV infection and requires treatment or prevention of HIV infection, a method of treating or preventing HIV infection comprises administering to the person a TLR7 modifier of formula (I) or a pharmaceutically acceptable salt thereof, and an HIV vaccine. In some embodiments, the TLR7 modifier is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the HIV vaccine comprises a virus comprising an immunogenic polypeptide having the amino acid sequences of SEQ ID NOs: 1-16, for example, a nucleic acid encoding an immunogenic polypeptide having the sequence of SEQ ID NO: 17.

[0067] In some embodiments, the person requiring it who has HIV infection is a virologically suppressed person, i.e., a person infected with the virus who is maintained at or below the desired viremia level for the specified person or antiviral treatment or regimen. An example of HIV virological suppression in an HIV-infected person may be maintenance in a person with a measurable HIV viral load of less than 200 copies of HIV-1 RNA per mL of blood or plasma. Other examples of virological suppression are maintenance in a person with viral loads of less than 100 copies / mL, less than 50 copies / mL, less than 40 copies / mL, less than 30 copies / mL, and less than 20 copies / mL.

[0068] In some embodiments, a method for treating or preventing HIV infection includes achieving virological suppression in humans. In some embodiments, a method for treating or preventing HIV infection includes maintaining virological suppression in humans.

[0069] In some embodiments, virological suppression can be achieved by other anti-HIV therapies such as antiretroviral therapy (ART). In some embodiments, antiretroviral therapy includes HIV reverse transcriptase inhibitors (e.g., nucleoside or non-nucleoside reverse transcriptase inhibitors), HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, or combinations thereof. Examples of antiretroviral agents include the HIV integrase catalytic site inhibitors raltegravir (ISENTRESS®, Merck), bictegravir (Gilead), elvitegravir (Gilead), solutegravir (GSK, ViiV), cabotegravir (GSK1265744, GSK744, GSK, ViiV), and dolutegravir; the HIV nucleoside reverse transcriptase inhibitors abacavir (ZIAGEN®, GSK), didanosine (VIDEX®, BMS), tenofovir disoproxil fumarate (VIREAD®, Gilead), tenofovir alafenamide (TAF), emtricitabine (EMTRIVA®, Gilead), and lamivudine (EPI VIR (registered trademark, GSK / Shire), stabuzin (ZERIT (registered trademark, BMS), zidovudine (RETROVIR (registered trademark, GSK), abacavir, erbucitabine, tenofovir exalidex (CMX-157, Chimerix), and festinavir (Oncolys); HIV non-nucleoside reverse transcriptase inhibitors nevirapine (VIRAMUNE (registered trademark, BI), efavirenz (SUSTIVA (registered trademark, BMS), etravirine (INTELENCE (registered trademark, J&J), rilpivirine (TMC278, R278474, J&J), fosdevine (GSK, ViiV), doravirine (MK-1439, Merck), and relsivirine (Pfizer / ViiV);HIV protease inhibitors: atazanavir (REYATAZ®, BMS), darunavir (PREZISTA®, J&J), indinavir (CRIXIVAN®, Merck), lopinavir (KALETRA®, Abbvie), nelfinavir (VIRACEPT®, Pfizer), saquinavir (INVIRASE®, Hoffmann-LaRoche), tipranavir (A Examples include PTIVUS® (BI), ritonavir (NORVIR®, Abbvie), and fosamprenavir (LEXIVA®, GSK / Vertex); HIV entry inhibitors such as maraviroc (SELZENTRY®, Pfizer), enfuvirtide (FUZEON®, Trimeris), and fostemsavir (BMS-663068, BMS); and the HIV maturation inhibitor bevirimat (Myriad Genetics).

[0070] In some embodiments, antiretroviral therapy includes raltegravir, elvitegravir, solutegravir, cabotegravir, dolutegravir, abacavir, didanosine, tenofovir disoproxil fumarate, tenofovir alafenamide, emtricitabine, lamivudine, stabudine, zidovudine, abacavir, erubcitabine, tenofovir exalidex, festinavir, nevirapine, and efaviren. The drug comprises one or more drugs selected from the group consisting of etravirine, rilpivirine, fosdevine, doravirine, relcivirine, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir, ritonavir, fosamprenavir, maraviroc, enfuvirtide, fostemsavir, bevirimat, cobicistat, and bictegravir; or pharmaceutically acceptable salts thereof. In some embodiments, the antiretroviral therapy comprises one or more agents selected from the group consisting of raltegravir, solutegravir, cabotegravir, dolutegravir, abacavir, didanosine, tenofovir disoproxil fumarate, tenofovir alafenamide, emtricitabine, lamivudine, stabudine, zidovudine, abacavir, erbucitabine, tenofovir exalidex, festinavir, rilpivirine, fosdevine, doravirine, relcivirine, maraviroc, enfuvirtide, fostemsavir, bevirimat, and bictegravir; or pharmaceutically acceptable salts thereof. In some embodiments, the antiretroviral therapy comprises three or more agents, for example, two nucleoside reverse transcriptase inhibitors and a non-nucleoside reverse transcriptase inhibitor or integrase inhibitor.

[0071] In some embodiments, a method for treating or preventing HIV infection includes the administration of a TLR7 modifier of formula (I) and an HIV vaccine after administration of ART. In some embodiments, a method for treating or preventing HIV infection includes the administration of the TLR7 modifier and HIV vaccine of the present disclosure in parallel with ART. In some embodiments, the therapeutic agent of ART is the same before and during administration of the TLR7 modifier and HIV vaccine. In some embodiments, the therapeutic agent of ART differs before and during administration of the TLR7 modifier and HIV vaccine.

[0072] HIV vaccination protocols have been developed in non-human primates involving two different viruses, e.g., an adenovirus priming immunization vector and a modified vaccinia virus Ankara (MVA) boosted vector. See, for example, Barouch, H.H. et al. Cell 2013, 155(3), 531-539. This heterologous priming-boosting vaccination approach may provide a more effective HIV vaccine than one using a single viral vector. Thus, in some embodiments, the HIV vaccine comprises a first virus and a second virus. In some embodiments, the first virus comprises a viral vector of the Adenoviridae or Poxviridae family, e.g., an adenovirus viral vector, e.g., a chimpanzee adenovirus such as replication-deficient chimpanzee adenovirus. In some embodiments, the second virus comprises a viral vector of the Poxviridae family, e.g., modified vaccinia virus Ankara (MVA).

[0073] In some embodiments, in a person who has HIV infection or is at risk of developing HIV infection and requires treatment or prevention of HIV infection, the method of treating or preventing HIV infection is a therapeutically effective amount of a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, The method involves administering to a human being an immunogenic polypeptide, or a first virus containing a nucleic acid encoding an immunogenic polypeptide, wherein the immunogenic polypeptide is (i) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 1, (ii) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 2, (iii) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 3, (iv) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 4, (v) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 5, (vi) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 6, (vii) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 7, (viii) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 8, (ix) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 9, (x) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 10, (xi) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 11, (xii) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 12, (xiii) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 13, (xiv) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 14, (xv) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 15, (xvi) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 16, At least two of (i) to (xvi) are linked by single, double, or triple alanine amino acid linkers, the linkers resulting in the formation of AAA sequences in the binding region between adjacent sequences, and each of sequences (i) to (xvi) is 11 to 85 amino acids in length, e.g., 11 to 82, 11 to 80, or 11 to 78. In some embodiments, the immunogenic polypeptide includes a sequence having an amino acid sequence with 1, 2, or 3 or fewer substitutions in any one of SEQ ID NOs. 1 to 16.

[0074] In some embodiments, the method comprises an immunogenic polypeptide having an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 17. In some embodiments, the immunogenic polypeptide comprises the amino acid sequence of SEQ ID NO: 17.

[0075] In some embodiments, the method includes a nucleic acid encoding an immunogenic polypeptide comprising a nucleic acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 18. In some embodiments, the nucleic acid encoding the immunogenic polypeptide comprises the nucleic acid sequence of SEQ ID NO: 18.

[0076] In some embodiments, in a person who has HIV infection or is at risk of developing HIV infection and requires treatment or prevention of HIV infection, the method of treating or preventing HIV infection is a therapeutically effective amount of a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, (i) A sequence having at least 90% sequence identity with sequence number 1, (ii) A sequence having at least 90% sequence identity with sequence number 2, (iii) A sequence having at least 90% sequence identity with sequence number 3, (iv) A sequence having at least 90% sequence identity with sequence number 4, (v) A sequence having at least 90% sequence identity with sequence number 5, (vi) A sequence having at least 90% sequence identity with sequence number 6, (vii) Sequences having at least 90% sequence identity with sequence number 7, (viii) Sequences having at least 90% sequence identity with sequence number 8, (ix) A sequence having at least 90% sequence identity with sequence number 9, (x) A sequence having at least 90% sequence identity with sequence number 10, (xi) A sequence having at least 90% sequence identity with sequence number 11, (xii) A sequence having at least 90% sequence identity with sequence number 12, (xiii) Sequences having at least 90% sequence identity with sequence number 13, (xiv) Sequences having at least 90% sequence identity with sequence number 14, (xv) A sequence having at least 90% sequence identity with sequence number 15, and (xvi) The administration of a first virus to a human being comprising nucleic acid encoding an immunogenic polypeptide having at least 90% sequence identity with sequence number 16, At least two of (i) to (xvi) are linked by single, double, or triple alanine amino acid linkers, which result in the formation of AAA sequences in the binding region between adjacent sequences. Each of the sequences (i) to (xvi) consists of 11 to 85 amino acids in length.

[0077] In some embodiments of the method, the immunogenic polypeptide is (i) A sequence having at least 95% sequence identity with sequence number 1, (ii) A sequence having at least 95% sequence identity with sequence number 2, (iii) A sequence having at least 95% sequence identity with sequence number 3, (iv) A sequence having at least 95% sequence identity with sequence number 4, (v) A sequence having at least 95% sequence identity with sequence number 5, (vi) A sequence having at least 95% sequence identity with sequence number 6, (vii) A sequence having at least 95% sequence identity with sequence number 7, (viii) A sequence having at least 95% sequence identity with sequence number 8, (ix) A sequence having at least 95% sequence identity with sequence number 9, (x) A sequence having at least 95% sequence identity with sequence number 10, (xi) A sequence having at least 95% sequence identity with sequence number 11, (xii) A sequence having at least 95% sequence identity with sequence number 12, (xiii) A sequence having at least 95% sequence identity with sequence number 13, (xiv) A sequence having at least 95% sequence identity with sequence number 14, (xv) A sequence having at least 95% sequence identity with sequence number 15, (xvi) Includes a sequence having at least 95% sequence identity with sequence number 16.

[0078] In some embodiments of the method, the immunogenic polypeptide comprises the sequences of SEQ ID NOs. 1 to 16, where at least two of SEQ ID NOs. 1 to 16 are linked by single, double, or triple alanine amino acid linkers, which result in the formation of AAA sequences in the binding region between adjacent sequences.

[0079] In some embodiments of the method, the immunogenic polypeptide has the amino acid sequence of SEQ ID NO: 17.

[0080] In some embodiments of the method, the nucleic acid has the nucleic acid sequence of SEQ ID NO: 18.

[0081] In some embodiments of the method, the first virus comprises a viral vector of the Adenoviridae or Poxviridae family. In some embodiments, the first virus comprises an adenovirus viral vector. In some embodiments, the first virus comprises a chimpanzee adenovirus viral vector. In some embodiments, the first virus comprises a replication-deficient chimpanzee adenovirus viral vector. In some embodiments, approximately 5 × 10 10 A number of virus particles of the first virus are administered. In some embodiments, the first virus is administered once every 12 weeks. In some embodiments, the first virus is administered twice.

[0082] In some embodiments, the method further comprises administering a second virus containing nucleic acid encoding an immunogenic polypeptide. In some embodiments, the second virus comprises a modified vaccinia virus ankara (MVA) vector. In some embodiments, approximately 2 × 10⁻⁶ 8A plaque-forming unit of the second virus is administered. In some embodiments, the second virus is administered once every 12 weeks. In some embodiments, the second virus is administered twice.

[0083] In some embodiments of the method, the first virus and the second virus are administered intramuscularly.

[0084] In some embodiments of the method, the first virus is administered in weeks 0 and 12, and the second virus is administered in weeks 24 and 36.

[0085] In some embodiments of the method, approximately 6 mg to approximately 8 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered every two weeks after the third dose of the virus. In some embodiments, the compound of formula (I) is administered at weeks 26, 28, 30, 32, 34, 38, 40, 42, 44 and 46.

[0086] In some embodiments of the method, a human is virologically suppressed. In some embodiments, a virologically suppressed human has a viral load of approximately 200, 100, less than 50, or approximately 20 copies of HIV-1 RNA per mL of plasma or blood. In some embodiments, virological suppression results from the administration of antiretroviral therapy. In some embodiments, the antiretroviral therapy is raltegravir, elvitegravir, solutegravir, cabotegravir, dolutegravir, abacavir, didanosine, tenofovir disoproxil fumarate, tenofovir alafenamide, emtricitabine, lamivudine, stavudine, zidovudine, abacavir, erbucitabine, tenofovir exalidex, festinavir, nevirapine, or efaviren The drug comprises one or more drugs selected from the group consisting of etravirine, rilpivirine, fosdevine, doravirine, relcivirine, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir, ritonavir, fosamprenavir, maraviroc, enfuvirtide, fostemsavir, bevirimat, cobicistat, and bictegravir; or pharmaceutically acceptable salts thereof.

[0087] In some embodiments, in a person who has HIV infection or is at risk of developing HIV infection and requires treatment or prevention of HIV infection, a method for treating or preventing HIV infection involves a compound of formula (I) and: [ka] 5 × 10⁶ copies of replication-deficient chimpanzee adenovirus containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 10 The first virus contains individual virus particles, 2 × 10⁶ modified vaccinia virus Ankara (MVA) containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 8 The procedure involves administering a second virus containing plaque-forming units to a human, The first virus is administered in weeks 0 and 12, the second virus in weeks 24 and 36, 4 mg of compound (I) is administered in weeks 26 and 28, and 6 mg of compound (I) is administered in weeks 30, 32, 34, 38, 40, 42, 44 and 46.

[0088] In some embodiments, a method for treating or preventing HIV infection in a person who has HIV infection or is at risk of developing HIV infection and requires treatment or prevention of HIV infection involves a compound of formula (I) and: [ka] 5 × 10⁶ copies of replication-deficient chimpanzee adenovirus containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 10 The first virus contains individual virus particles, 2 × 10⁶ modified vaccinia virus Ankara (MVA) containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 8 The procedure involves administering a second virus containing plaque-forming units to a human, The first virus was administered in weeks 0 and 12, the second virus in weeks 24 and 36, 4 mg of compound (I) in weeks 26, 28 and 30, and 6 mg of compound (I) in weeks 32, 34, 38, 40, 42, 44 and 46.

[0089] In some embodiments, in a person who has HIV infection or is at risk of developing HIV infection and requires treatment or prevention of HIV infection, a method for treating or preventing HIV infection involves a compound of formula (I) and: [ka] 5 × 10⁶ copies of replication-deficient chimpanzee adenovirus containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 10 The first virus contains individual virus particles, 2 × 10⁶ modified vaccinia virus Ankara (MVA) containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 8 The procedure involves administering a second virus containing plaque-forming units to a human, The first virus was administered in weeks 0 and 12, the second virus in weeks 24 and 36, 4 mg of compound (I) in weeks 26, 28, 30 and 32, and 6 mg of compound (I) in weeks 34, 38, 40, 42, 44 and 46.

[0090] In some embodiments, in a person who has HIV infection or is at risk of developing HIV infection and requires treatment or prevention of HIV infection, a method for treating or preventing HIV infection involves a compound of formula (I) and: [ka] 5 × 10⁶ copies of replication-deficient chimpanzee adenovirus containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 10 The first virus contains individual virus particles, 2 × 10⁶ modified vaccinia virus Ankara (MVA) containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 8 The procedure involves administering a second virus containing plaque-forming units to a human, The first virus is administered in weeks 0 and 12, the second virus in weeks 24 and 36, and 6 mg of the compound of formula (I) is administered in weeks 26, 28, 30, 32, 34, 38, 40, 42, 44 and 46.

[0091] In some embodiments, in a person who has HIV infection or is at risk of developing HIV infection and requires treatment or prevention of HIV infection, a method for treating or preventing HIV infection involves a compound of formula (I) and: [ka] 5 × 10⁶ copies of replication-deficient chimpanzee adenovirus containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 10 The first virus contains individual virus particles, 2 × 10⁶ modified vaccinia virus Ankara (MVA) containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 8 The procedure involves administering a second virus containing plaque-forming units to a human, The first virus is administered in weeks 0 and 12, the second virus in weeks 24 and 36, 6 mg of compound (I) is administered in weeks 26 and 28, and 8 mg of compound (I) is administered in weeks 30, 32, 34, 38, 40, 42, 44 and 46.

[0092] In some embodiments, in a person suffering from HIV infection and requiring treatment or prevention of HIV infection, a method of treating HIV infection involves a compound of formula (I) and: [ka] 5 × 10⁶ copies of replication-deficient chimpanzee adenovirus containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 10 The first virus contains individual virus particles, 2 × 10⁶ modified vaccinia virus Ankara (MVA) containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 8 The procedure involves administering a second virus containing plaque-forming units to a human, The first virus is administered in weeks 0 and 12, the second virus in weeks 24 and 36, 6 mg of compound (I) is administered in weeks 26 and 28, and 8 mg of compound (I) is administered in weeks 30, 32, 34, 38, 40, 42, 44 and 46.

[0093] A method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof and the HIV vaccine described herein to a human is expected to generate a cellular and humoral response to HIV in humans. In some embodiments, the vaccine generates an effective cytotoxic T cell response. Cytotoxic T cell or cytotoxic T lymphocyte (CTL) assays can be used to monitor the cellular immune response after viral sequence-mediated subgenomic immunization using viral sequences against allogeneic and heterologous HIV strains. Burke, S. et al. See al., J. Inf. Dis. 1994; 170: 1110-1119 and Tigges, M. et al., J. Immunol, 1996; 156: 3901-3910. Conventional assays used to detect T cell responses include, for example, proliferation assays, lymphokine secretion assays, direct cytotoxicity assays, and limiting dilution assays. For example, antigen-presenting cells incubated with peptides can be assayed for their ability to induce a CTL response in a responding cell population. Antigen-presenting cells can be cells such as peripheral blood mononuclear cells (PBMCs) or dendritic cells (DCs). Alternatively, mutant non-human mammalian cell lines lacking the ability to load MHC class I molecules with internally processed peptides and transfected with appropriate human MHC class I genes can be used to test the ability of the target peptide to induce an in vitro primary CTL response. PBMCs can be used as a responding cell source for CTL precursors. Appropriate antigen-presenting cells are incubated with peptides, and then protein-loaded antigen-presenting cells are incubated with a population of responders under optimized culture conditions. Positive CTL activation can be determined by assaying the culture for the presence of CTLs that kill radiolabeled target cells, both those expressing specific peptide pulsed targets and those expressing an endogenously processed form of the antigen from which the peptide sequence originates. For example, target cells are... 51It can be radiolabeled with Cr, and cytotoxic activity can be calculated from the radioactivity released from target cells. Another suitable method allows for the direct quantification of antigen-specific T cells by staining with fluorescein-labeled HLA tetramer complexes. See Altman J, et al., Proc. Natl. Acad. Sci. USA 1993;90:10330-10334 and Altman J, et al., Science 1996;274:94-96. Other relatively recent technological developments include intracellular lymphokine staining and interferon release assays or ELISPOT assays. In some embodiments, a method for generating effective CTLs in a human requiring the generation of effective CTLs comprises administering a therapeutically effective amount of a compound of the present disclosure to a human, wherein the virus encoding the immunogenic polypeptide comprises the sequence of SEQ ID NOs: 1-16, and the CTLs are directed towards one or more of the following regions of the HIV virus: p17 17-94, p24 30-43, p24 61-71, p24 91-150, p24 164-177, p24 217-231, p2p7p1p6 63-89, protease 45-99, reverse transcriptase 34-50, reverse transcriptase 210-264, reverse transcriptase 309-342, integrase 210-243, integrase 266-282, Vif 25-50, Vif 166-184 and Nef 56-68, and the amino acid numbering is HIV-1 Follow HXB2.

[0094] Furthermore, methods for enhancing the efficacy of HIV vaccines are also provided, the methods comprising administering to a person in need a pharmaceutically effective amount of a TLR7 modifier of formula (I) or a pharmaceutically acceptable salt thereof, and the HIV vaccine described herein.

[0095] Clinical improvement is expected in treated HIV-infected individuals compared to control HIV-infected individuals treated with standard care. Clinical improvement may include one or more of the following: lower peak viral load, lower chronic set point, or increased delay in viral rebound.

[0096] In some embodiments, the methods described herein are effective in treating HIV infection, as determined, for example, by a lower peak viral load compared to standard therapy, such as ART alone. As is commonly understood in the art, the comparison of a first peak viral load in a first HIV-infected person with a second peak viral load in a second HIV-infected person is measured over the same period. In some embodiments, the measurement is performed after discontinuation of all antiviral therapy. In some embodiments, the viral load is maintained at an undetectable level in the first HIV-infected person after treatment with ART, a TLR7 modulating compound, and an HIV vaccine.

[0097] In some embodiments, the first peak viral load in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine is lower than the second peak viral load in a second HIV-infected person after treatment with ART alone. In some embodiments, the second peak viral load in a second HIV-infected person after treatment with ART alone is higher than the first peak viral load in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine, for example, by about 1.2 to about 10,000 times, about 2 to about 10,000 times, about 5 to about 10,000 times, and about 10 to about 10,000 times. In some embodiments, the second peak viral load in a second HIV-infected person after treatment with ART alone is about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 10, about 20, about 50, about 100, about 200, about 500, about 1000, about 200, about 500, about 1000, about 2000, about 500, about 1000, about 2000, about 5000, or about 10000 times higher than the first peak viral load in a first HIV-infected person after treatment with ART, TLR7 modifier, and HIV vaccine.

[0098] In some embodiments, the first peak viral load in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine is lower than the second peak viral load in a second HIV-infected person after treatment with ART and a TLR7 modifier. In some embodiments, the second peak viral load in a second HIV-infected person after treatment with ART and a TLR7 modifier is higher than the first peak viral load in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine, for example, by about 1.2 to about 10,000 times, about 2 to about 10,000 times, about 5 to about 10,000 times, and about 10 to about 10,000 times. In some embodiments, the second peak viral load in a second HIV-infected person after treatment with ART and a TLR7 modifier is about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 10, about 20, about 50, about 100, about 200, about 500, about 1000, about 200, about 500, about 1000, about 2000, about 5000, about 1000, about 2000, about 5000, or about 10000 times higher than the first peak viral load in a first HIV-infected person after treatment with ART and a TLR7 modifier. In some embodiments, the second peak viral load in a second HIV-infected person after treatment with ART and a TLR7 modifier is about 20 times higher than the first peak viral load in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine.

[0099] In some embodiments, the first peak viral load in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine is lower than the second peak viral load in a second HIV-infected person after treatment with ART and an HIV vaccine. In some embodiments, the second peak viral load in a second HIV-infected person after treatment with ART and an HIV vaccine is higher than the first peak viral load in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine, for example, by about 1.2 to about 10,000 times, about 2 to about 10,000 times, about 5 to about 10,000 times, and about 10 to about 10,000 times. In some embodiments, the second peak viral load in a second HIV-infected person after treatment with ART and HIV vaccine is about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 10, about 20, about 50, about 100, about 200, about 500, about 1000, about 200, about 500, about 1000, about 2000, about 500, about 1000, about 2000, about 5000, or about 10000 times higher than the first peak viral load in a first HIV-infected person after treatment with ART, TLR7 modifier and HIV vaccine.

[0100] In some embodiments, the methods described herein are effective in treating HIV infection as determined by a lower chronic set point compared to, for example, standard therapy, such as ART. As is commonly understood in the art, the comparison of a first chronic set point in a first HIV-infected person with a second chronic set point in a second HIV-infected person is measured at the same time. In some embodiments, the measurement is performed after discontinuation of all antiviral therapy.

[0101] In some embodiments, the first chronic set point in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine is lower than the second chronic set point in a second HIV-infected person after treatment with ART alone. In some embodiments, the second chronic set point in a second HIV-infected person after treatment with ART alone is higher than the first chronic set point in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine, for example, by about 1.2 to about 10,000 times, about 2 to about 10,000 times, about 5 to about 10,000 times, and about 10 to about 10,000 times. In some embodiments, the second chronic set point in a second HIV-infected person after treatment with ART alone is about 1.2, 1.5, 2, 3, 4, 5, 10, 20, 50, 100, 200, 500, 1000, 200, 500, 1000, 2000, 5000, 1000, 2000, 5000, or 10000 times higher than the first chronic set point in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine.

[0102] In some embodiments, the first chronic set point in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine is lower than the second chronic set point in a second HIV-infected person after treatment with ART and a TLR7 modifier. In some embodiments, the second chronic set point in a second HIV-infected person after treatment with ART and a TLR7 modifier is higher than the first chronic set point in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine, for example, by about 1.2 to about 10,000 times, about 2 to about 10,000 times, about 5 to about 10,000 times, and about 10 to about 10,000 times. In some embodiments, the second chronic set point in a second HIV-infected person after treatment with ART and a TLR7 modifier is about 1.2, 1.5, 2, 3, 4, 5, 10, 20, 50, 100, 200, 500, 1000, 200, 500, 1000, 2000, 5000, 1000, 2000, 5000, or 10000 times higher than the first chronic set point in a first HIV-infected person after treatment with ART and a TLR7 modifier. In some embodiments, the second chronic set point in a second HIV-infected person after treatment with ART and a TLR7 modifier is about twice as high as the first chronic set point in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine.

[0103] In some embodiments, the first chronic set point in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine is lower than the second chronic set point in a second HIV-infected person after treatment with ART and an HIV vaccine. In some embodiments, the second chronic set point in a second HIV-infected person after treatment with ART and an HIV vaccine is higher than the first chronic set point in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine, for example, by about 1.2 to about 10,000 times, about 2 to about 10,000 times, about 5 to about 10,000 times, and about 10 to about 10,000 times. In some embodiments, the second chronic set point in a second HIV-infected person after treatment with ART and HIV vaccine is about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 10, about 20, about 50, about 100, about 200, about 500, about 1000, about 200, about 500, about 1000, about 2000, about 5000, about 1000, about 2000, about 5000, or about 10000 times higher than the first chronic set point in a first HIV-infected person after treatment with ART and HIV vaccine.

[0104] The method can increase the delay of viral rebound compared to standard therapy after discontinuation of all antiviral therapy. In some embodiments, viral load does not rebound in HIV-infected individuals after treatment with ART, TLR7 modulating compounds, and HIV vaccines. In the absence of rebound, previously HIV-infected individuals maintain an undetectable viral load for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 1.5 years, 2 years, 3 years, 5 years, or at least 10 years or more after discontinuing antiviral therapy.

[0105] In some embodiments, the first delay in viral rebound in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine is longer than the second delay in viral rebound in a second HIV-infected person after treatment with ART alone. In some embodiments, the first delay in viral rebound in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine is longer than the second delay in viral rebound in a second HIV-infected person after treatment with ART alone, ranging from about 1 day to about 10 years, for example, about 1 week to about 1 year, about 2 weeks to about 1 year, about 3 weeks to about 1 year, about 1 month to about 1 year, about 2 months to about 1 year, about 3 months to about 1 year, about 3 months to about 2 years, etc. In some embodiments, the first delay in viral rebound in a first HIV-infected person after treatment with ART, a TLR7 modulating compound, and an HIV vaccine is longer than the second delay in viral rebound in a second HIV-infected person after treatment with ART alone, by 1 day, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 1.5 years, 2 years, 3 years, 5 years, 10 years or more. In some embodiments, the first delay in viral rebound in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine is about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 1.5 years, 2 years, 3 years or longer, compared to the second delay in viral rebound in a second HIV-infected person after treatment with ART alone. In some embodiments, the first delay in viral rebound in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine is about 3 months longer, compared to the second delay in viral rebound in a second HIV-infected person after treatment with ART alone.

[0106] In some embodiments, the first delay in viral rebound in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine is longer than the second delay in viral rebound in a second HIV-infected person after treatment with ART and a TLR7 modifier. In some embodiments, the first delay in viral rebound in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine is longer than the second delay in viral rebound in a second HIV-infected person after treatment with ART and a TLR7 modifier, for example, about 1 day to about 10 years, about 1 week to about 1 year, about 2 weeks to about 1 year, about 3 weeks to about 1 year, about 1 month to about 1 year, about 2 months to about 1 year, about 3 months to about 1 year, about 3 months to about 2 years, etc. In some embodiments, the first delay in viral rebound in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine is longer by 1 day, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 1.5 years, 2 years, 3 years or more, compared to the second delay in viral rebound in a second HIV-infected person after treatment with ART and a TLR7 modifier. In some embodiments, the first delay in viral rebound in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine is about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 1.5 years, about 2 years, about 3 years or longer compared to the second delay in viral rebound in a second HIV-infected person after treatment with ART and a TLR7 modifier. In some embodiments, the first delay in viral rebound in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine is about 3 months longer compared to the second delay in viral rebound in a second HIV-infected person after treatment with ART and a TLR7 modifier.

[0107] In some embodiments, the first delay in viral rebound in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine is longer than the second delay in viral rebound in a second HIV-infected person after treatment with ART and an HIV vaccine. In some embodiments, the first delay in viral rebound in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine is longer than the second delay in viral rebound in a second HIV-infected person after treatment with ART and an HIV vaccine, ranging from about 1 day to about 10 years, for example, about 1 week to about 1 year, about 2 weeks to about 1 year, about 3 weeks to about 1 year, about 1 month to about 1 year, about 2 months to about 1 year, about 3 months to about 1 year, about 3 months to about 2 years, etc. In some embodiments, the first delay in viral rebound in a first HIV-infected person after treatment with ART, a TLR7 modulating compound, and an HIV vaccine is longer by 1 day, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 1.5 years, 2 years, 3 years or more compared to the second delay in viral rebound in a second HIV-infected person after treatment with ART and an HIV vaccine. In some embodiments, the first delay in viral rebound in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine is about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 1.5 years, about 2 years, about 3 years or longer compared to the second delay in viral rebound in a second HIV-infected person after treatment with ART and an HIV vaccine. In some embodiments, the first delay in viral rebound in a first HIV-infected person after treatment with ART, a TLR7 modifier, and an HIV vaccine is about 1 month longer compared to the second delay in viral rebound in a second HIV-infected person after treatment with ART and an HIV vaccine. VII. Administration

[0108] The TLR7 modifiers of this disclosure, for example, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the HIV vaccine described herein are administered in combination to humans to increase the likelihood of achieving the desired biological effect and to minimize adverse effects. In some embodiments, the TLR7 modifiers and the HIV vaccine are administered in parallel. In some embodiments, the TLR7 modifiers and the HIV vaccine are administered sequentially, for example, on different days or in different weeks.

[0109] The HIV vaccines described herein may be administered by any means known in the art, including but not limited to intravenous, intramuscular, intrathecal, intraperitoneal, intranasal, or oral administration. In some embodiments, the HIV vaccine is administered intramuscularly. In some embodiments, the HIV vaccine is administered once every 8, 10, 12, 14, or 16 weeks. In some embodiments, the HIV vaccine is administered once every 12 weeks. In some embodiments, the HIV vaccine comprises a first virus and a second virus. In some embodiments, the first virus is administered once or more times, followed by the second virus once or more times. In some embodiments, the first virus is administered twice, and the second virus is administered twice. In some embodiments, the first virus is administered in weeks 0 and 12, and the second virus is administered in weeks 24 and 36.

[0110] The TLR7 modulated compounds of this disclosure may be administered by any means known in the art, including but not limited to intravenous, intramuscular, intrathecal, intraperitoneal, or oral administration. In some embodiments, the TLR7 modulated compounds are administered orally.

[0111] In some embodiments, the TLR7 modulating compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once every week, every two weeks, or every three weeks. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once every two weeks, for example, every 12–16, 13–15, or 14 days. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered every two weeks after the third dose of the virus. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered sequentially, for example, once every two weeks over eight weeks, for a total of five doses, i.e., in weeks 26, 28, 30, 32, and 34, with week 0 being the first dose of the virus. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered intermittently. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in weeks 26, 28, 30, 32, 34, 38, 40, 42, 44 and 46, with week 0 being the first dose of the first virus.

[0112] In some embodiments, the compound of formula (I) is administered as a single tablet. In some embodiments, the compound of formula (I) is administered in two or more tablets, for example, three, four, or five tablets. When administered in two or more tablets, the compound of formula (I) can be present in the same dose, for example, 6 mg in three tablets of 2 mg of the compound of formula (I) (i.e., 3 × 2 mg), or 8 mg in two tablets of 4 mg of the compound of formula (I), or in different doses, for example, 6 mg in one tablet of 4 mg of the compound of formula (I) and one tablet of 2 mg of the compound of formula (I).

[0113] In some embodiments, approximately 4 mg to approximately 12 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, such as approximately 4, 5, 6, 7, 8, 9, 10, 11, or approximately 12 mg, is administered. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in 10 doses. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in 10 doses, with one 4 mg tablet administered in doses 1-2 and 3 x 2 mg tablets administered in doses 3-10. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in 10 doses, with one 4 mg tablet administered in doses 1-3 and 3 x 2 mg tablets administered in doses 4-10. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in 10 doses, with one 4 mg tablet administered for doses 1-4 and 3 × 2 mg tablets administered for doses 5-10. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in 10 doses, with 3 × 2 mg tablets administered for doses 1-10. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in 10 doses, with 3 × 2 mg tablets administered for doses 1-2 and 2 × 4 mg tablets administered for doses 3-10. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in 10 doses, with 5 × 2 mg tablets administered for doses 1-3 and 3 × 4 mg tablets administered for doses 4-10.

[0114] In some embodiments, the TLR7 modulating compound of formula (I) or a pharmaceutically acceptable salt thereof and the HIV vaccine are administered concurrently with ART. In some embodiments, the therapeutic agent of ART is the same before and during administration of the compound of formula (I) and the HIV vaccine. In some embodiments, the therapeutic agent of ART differs before and during administration of the compound of formula (I) and the HIV vaccine.

[0115] In some embodiments, the method involves a therapeutically effective amount of the compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, The method involves administering to a human being an immunogenic polypeptide, or a first virus containing a nucleic acid encoding an immunogenic polypeptide, wherein the immunogenic polypeptide is (i) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 1, (ii) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 2, (iii) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 3, (iv) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 4, (v) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 5, (vi) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 6, (vii) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 7, (viii) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 8, (ix) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 9, (x) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 10, (xi) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 11, (xii) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 12, (xiii) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 13, (xiv) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 14, (xv) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 15, (xvi) A sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with sequence number 16, At least two of (i) to (xvi) are linked by single, double, or triple alanine amino acid linkers, the linkers resulting in the formation of AAA sequences in the binding region between adjacent sequences, and each of sequences (i) to (xvi) is 11 to 85 amino acids in length, e.g., 11 to 82, 11 to 80, or 11 to 78. In some embodiments, the immunogenic polypeptide includes a sequence having an amino acid sequence with 1, 2, or 3 or fewer substitutions in any one of SEQ ID NOs. 1 to 16.

[0116] In some embodiments, an immunogenic polypeptide is administered that contains an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 17. In some embodiments, the immunogenic polypeptide contains the amino acid sequence of SEQ ID NO: 17.

[0117] In some embodiments, a nucleic acid encoding an immunogenic polypeptide is administered, which comprises a nucleic acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 18. In some embodiments, the nucleic acid encoding the immunogenic polypeptide comprises the nucleic acid sequence of SEQ ID NO: 18.

[0118] In some embodiments, the method involves a compound of formula (I) and: [ka] 5 × 10⁶ copies of replication-deficient chimpanzee adenovirus containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 10 The first virus contains individual virus particles, 2 × 10⁶ modified vaccinia virus Ankara (MVA) containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 8 The procedure involves administering a second virus containing plaque-forming units to a human, The first virus is administered in weeks 0 and 12, the second virus in weeks 24 and 36, 4 mg of compound (I) is administered in weeks 26 and 28, and 6 mg of compound (I) is administered in weeks 30, 32, 34, 38, 40, 42, 44 and 46.

[0119] In some embodiments, the method involves a compound of formula (I) and: [ka] 5 × 10⁶ copies of replication-deficient chimpanzee adenovirus containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 10 The first virus contains individual virus particles, 2 × 10⁶ modified vaccinia virus Ankara (MVA) containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 8The procedure involves administering a second virus containing plaque-forming units to a human, The first virus was administered in weeks 0 and 12, the second virus in weeks 24 and 36, 4 mg of compound (I) in weeks 26, 28 and 30, and 6 mg of compound (I) in weeks 32, 34, 38, 40, 42, 44 and 46.

[0120] In some embodiments, the method involves a compound of formula (I) and: [ka] 5 × 10⁶ copies of replication-deficient chimpanzee adenovirus containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 10 The first virus contains individual virus particles, 2 × 10⁶ modified vaccinia virus Ankara (MVA) containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 8 The procedure involves administering a second virus containing plaque-forming units to a human, The first virus was administered in weeks 0 and 12, the second virus in weeks 24 and 36, 4 mg of compound (I) in weeks 26, 28, 30 and 32, and 6 mg of compound (I) in weeks 34, 38, 40, 42, 44 and 46.

[0121] In some embodiments, the method involves a compound of formula (I) and: [ka] 5 × 10⁶ copies of replication-deficient chimpanzee adenovirus containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 10 The first virus contains individual virus particles, 2 × 10⁶ modified vaccinia virus Ankara (MVA) containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 8The procedure involves administering a second virus containing plaque-forming units to a human, The first virus is administered in weeks 0 and 12, the second virus in weeks 24 and 36, and 6 mg of the compound of formula (I) is administered in weeks 26, 28, 30, 32, 34, 38, 40, 42, 44 and 46.

[0122] In some embodiments, the method involves a compound of formula (I) and: [ka] 5 × 10⁶ copies of replication-deficient chimpanzee adenovirus containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 10 The first virus contains individual virus particles, 2 × 10⁶ modified vaccinia virus Ankara (MVA) containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 8 The procedure involves administering a second virus containing plaque-forming units to a human, The first virus is administered in weeks 0 and 12, the second virus in weeks 24 and 36, 6 mg of compound (I) is administered in weeks 26 and 28, and 8 mg of compound (I) is administered in weeks 30, 32, 34, 38, 40, 42, 44 and 46. VIII. Kit

[0123] This disclosure provides a kit comprising a TLR7 modulated compound of formula (I) or a pharmaceutically acceptable salt thereof, and an HIV vaccine as described herein. The kit may further include instructions for use, for example, for the treatment of a viral infection. The instructions are generally in writing, but an electronic storage medium (e.g., a magnetic diskette or optical disk) containing the instructions is also acceptable.

[0124] This disclosure also provides a pharmaceutical kit comprising one or more containers containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, and an HIV vaccine. Such containers may optionally be accompanied by a notice in the form prescribed by a government agency regulating the manufacture, use, or sale of a medicinal product, such notice reflecting the agency's approval for manufacture, use, or sale for human administration. Each component may be packaged in a separate container, or some components may be combined in a single container, provided that cross-reactivity and shelf life are acceptable. The kit may be in unit dosage forms, bulk packages (e.g., multi-dose packages), or subunit doses. The kit may also contain multiple unit doses of the compound and the HIV vaccine, along with instructions for use, and may be packaged in quantities sufficient for storage and use in a pharmacy (e.g., hospital pharmacies and dispensing pharmacies).

[0125] Articles comprising a unit dose of the compounds of this disclosure or pharmaceutically acceptable salts thereof, and an HIV vaccine, in packaging suitable for use in the manner described herein are also provided. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, jars, flexible packaging, etc. The articles may further be sterile and / or sealed. IX.Example HIV treatment protocol for TLR7 modulated compounds and HIV vaccines in Example 1(I) [Examples]

[0126] This example describes a Phase IIa randomized, double-blind, double-dummy, placebo-controlled trial evaluating the safety and tolerability of a sequential regimen of HIV vaccine and compound (I) in early-diagnosed and treated HIV-1 infection. The trial screens HIV-1 infected participants who initiated ART within 180 days (6 months) of estimated HIV-1 infection and achieved virological suppression for at least one year. Participants who provide informed consent and meet the trial inclusion criteria are randomized to one of four parallel treatment groups. The trial is conducted in three periods: Period 1 lasts 48 weeks, during which participants receive and continue their ART regimen; Period 2 lasts up to 24 weeks, during which participants discontinue their ART regimen (i.e., an analytical treatment interruption period); Period 3 lasts up to 12 weeks, during which participants are monitored after resuming ART.

[0127] The following criteria for participants to be enrolled in the trial include patients who meet the following criteria: (1) Individuals aged 18-60 who have been diagnosed with HIV-1 infection. (2) The patient has received ART, i.e., three or more antiretroviral drugs, which was initiated within six months of the estimated date of HIV-1 infection. Early initiation of treatment must be demonstrated by at least one of the following criteria (a) to (h): (a) HIV-1 / 2 negative and positive plasma HIV-1 up to 160 days prior to the start of ART Third or fourth-generation assays for RNA, (b) Third-generation assays for HIV1 / 2-negative and positive plasma HIV-1 p24Ag and positive plasma HIV-1 RNA up to 158 days prior to the start of ART. (c) HIV1 / 2 positive and negative HIV-1 and HIV-2 antibody discrimination immunoassays and fourth-generation assays for positive HIV-1 RNA up to 158 days prior to the start of ART. (d) HIV-1 / 2 positive and negative Western blot (WB) tests (no bands detected) and third or fourth-generation assays for positive HIV-1 RNA up to 157 days prior to the start of ART. (e) Third or fourth generation assay for HIV-1 / 2 positivity and inconclusive WB testing (less than two envelope bands) and positive HIV-1 RNA up to 151 days prior to the start of ART. (f) HIV-1 / 2 positive and uncertain HIV-1 and 2 antibody-recognition immunoassays and third or fourth-generation assays for positive HIV-1 RNA, (g) HIV seroconversion (negative HIV test up to 160 days prior to the first positive HIV test) and ART initiated within 90 days of HIV-1 diagnosis, (h) Third or fourth-generation assay for HIV-1 / 2 positivity and positive WB testing without p31 banding up to 90 days prior to ART initiation, in a qualifying medical history up to 151 days prior to ART initiation (due to either a clearly reported transmissibility risk and / or demonstrated acute retroviral syndrome up to 5 months prior to HIV diagnosis). (3) The virologically suppressed pVL population, defined as less than 50 copies / mL, for at least one year prior to screening, with an acceptable isolated blip (less than 200 copies / mL, discontinuous, less than 10% of all measurements, or representing no more than two occurrences per year). (4) Six months prior to screening, 450 cells / mm 3 It has a stable number of CD4s as described above. (5) 200 cells / mm³ after HIV diagnosis 3 Having the minimum CD4 count mentioned above, and low values ​​isolated at the time of acute HIV-1 infection, are acceptable only if adequate immune recovery continues after initiation of ART (see inclusion criteria #4).

[0128] Participants are screened to enroll in the trial. After providing informed consent, participants are randomly assigned in a 5:1:1:2 ratio using interactive automated response technology (IRT) to receive either the HIV vaccine and compound (I), the HIV vaccine alone, compound (I) alone, or a placebo. Randomization is stratified by sentinel and non-sentinel participants. The sentinel cohort, consisting of the first nine participants, is randomized in a 5:1:1:2 ratio and administered. A blinded, independent Safety Monitoring Committee (SMC) reviews sentinel cohort data collected over the week following the first injection of the last sentinel participant before enrollment of the remaining 81 participants (non-sentinel cohort). The SMC reviews safety data for all participants for the remainder of the trial. Sentinel participants who discontinue the study within one week of the first dose of the investigational drug (IMP) for reasons unrelated to safety will be replaced. Sentinel participants who discontinue the study after this point, and non-sentinel participants who discontinue the study after the first dose of IMP, will not be replaced. The IMP administration schedule will be managed by the Investigative Rehabilitation Team (IRT).

[0129] The compound of formula (I) is primarily metabolized by the cytochrome P450 (CYP) 3A4 enzyme (CYP3A), with only minor contributions from CYP2C8 and CYP2D6 in vitro. Since the compound of formula (I) is a substrate of P-glycoprotein and breast cancer resistance protein in vitro, plasma exposure to the compound may increase or decrease when used in combination with inhibitors or inducers of CYP3A, P-glycoprotein, or breast cancer resistance protein. Any ART agents known to inhibit or induce CYP3A, P-glycoprotein, or breast cancer resistance protein are excluded from use in this study during treatment (period 1). For these participants, who may be in regimens containing one of these agents, a regimen switch from one of the contraindicated agents to an approved agent is permitted between screening and baseline visit. The following agents are excluded from ART regimens during the study: HIV protease inhibitors (including low-dose ritonavir), cobicistat-containing regimens, elvitegravir, efavirenz, etravirine, and nevirapine.

[0130] Participants will undergo a screening visit within 28 days prior to their first dose of the HIV vaccine. In Period 1 (Weeks 0-48), participants will be randomly assigned to Week 0 (baseline) treatment, on which they will receive either their first dose of the HIV vaccine or a compatible vaccine placebo. Participants who need to switch their ART from a contraindicated drug to an approved one during the trial will switch between screening and baseline, and for these participants, the screening period will be extended up to 45 days prior to their first dose.

[0131] Participants continued ART during Period 1. Sentinel cohort participants had additional Period 1 visits for additional monitoring and evaluation compared to the non-sentinel cohort. Participants received HIV vaccine containing the first and second viruses: 5 × 10⁶ doses in 0.5 mL formulation buffer of replication-deficient chimpanzee adenovirus containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 during Period 1. 10 Up to two doses of the first virus containing individual virus particles, and 2 × 10⁶ modified vaccinia virus Ankara (MVA) containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 in 0.5 mL Tris buffer. 8 Participants receive two doses of a second virus containing 1 plaque-forming units and ten doses of the compound of formula (I), or a suitable placebo. All participants have their HIV-1 viral load monitored throughout Period 1. At the end of Period 1, participants will meet the eligibility criteria for an Analytical Treatment Interruption (ATI) before entering Period 2 and will initiate an ATI. If the ATI eligibility criteria are not met, enrollment in Period 2 will be postponed, or the participant will be withdrawn from the study and undergo the early termination procedure for Period 1. Participants who discontinue the vaccine early in Period 1 will leave the study and complete the early termination evaluation for Period 1, while participants who discontinue the compound early have the option to continue the study and proceed to Period 2.

[0132] The first virus comprises a replication-deficient recombinant chimpanzee adenovirus (ChAd) vector based on the chimpanzee adenovirus isolate ChAdY25, described in U.S. Patent No. 9,714,435 (which is incorporated herein by reference in its entirety), the vector encoding the immunogenic polypeptide of Sequence ID No. 17. The vector is induced by subcloning the immunogenic polypeptide sequence into a common ChAdOx1 bacterial artificial chromosome (BAC) system (University of Oxford, Oxford, UK). The plasmid obtained from this subcloning (pC255, 40,483 kbp) is linearized and transfected into commercially available HEK293 T-REx® cells (Thermo Fisher Scientific, Waltham, Massachusetts, USA) to produce the first virus, which is then formulated as a suspension for intramuscular injection. The injection buffer contains 10 mM L-histidine, 35 mM NaCl, 7.5% (w / v) sucrose, 1 mM MgCl2, 0.1 mM disodium EDTA, 0.1% (w / v) polysorbate-80, and 0.5% (v / v) ethanol. Adjust the pH to 6.6 with HCl. Store the vial at -80°C.

[0133] The administration schedule for Period 1 is as follows: In weeks 0 and 12, 5 × 10¹⁶ doses of replication-deficient chimpanzee adenovirus containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 are administered in 0.5 mL of formulation buffer. 10 Administer the first virus containing 10⁶ virus particles. At weeks 24 and 36, administer 2 × 10⁶ modified vaccinia virus Ankara (MVA) containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 in 0.5 mL Tris buffer (10 mM Tris HCl, pH 7.7, 140 mM NaCl). 8A second virus containing 1 plaque-forming unit is administered. 6 mg of compound (I) is administered at weeks 26 and 28. 8 mg of compound (I) is administered at weeks 30, 32, 34, 38, 40, 42, 44, and 46, provided that no grade 3 / 4 adverse events related to the compound occur after administration of 6 mg of the compound.

[0134] During Period 2 (Weeks 48-72), participants were instructed to discontinue ART after their visit at Week 48. Participants were monitored weekly for rebound in HIV-1 plasma viremia. Participants resumed ART during Period 2 if certain criteria were met. Participants with a viral load of less than 50 copies / mL at the end of Period 2 who did not resume ART during Period 2 underwent an additional evaluation at their visit at Week 72. Participants who met the criteria for resuming ART during Period 2 resumed ART and were enrolled in Period 3. If a participant discontinued the study early during Period 2, their ART regimen should be restarted, and the participant should undergo the Period 2 early termination procedure.

[0135] Period 2, consisting of 24 weeks, will consist of weekly visits. Participants will discontinue ART use at week 48. All participants will resume ART after meeting the criteria for doing so, or at the latest at the visit in week 72. All participants who resume ART before the end of Period 2 will continue ART until Period 3 from the time of resumption. Regardless of whether it is during or at the end of Period 2 (i.e., during week 72), all participants who resume ART during Period 2 will have their viral load monitored after resuming ART.

[0136] During Period 2, careful clinical monitoring of symptoms will be performed by the principal investigator. Participants will provide periodic blood samples to determine HIV-1 pVL (i.e., plasma viral load), CD4 and CD8 counts, and for ART pharmacokinetics. Participants whose viral load was less than 50 copies / mL after completing 12 weeks of ATI (i.e., Week 60) and who did not resume ART will undergo additional evaluations, specifically blood sampling for immunological and virological assays, at their visit in Week 72.

[0137] During Period 3 (Weeks 72-84), all participants who resumed ART during Period 2 had their viral load monitored 4 and 12 weeks after resuming ART (Weeks 76 and 84), regardless of whether it was during Period 2 or after completing Period 2 (i.e., at the Week 72 visit). Participants made a final trial visit at Week 84. The Week 84 visit also served as an early termination visit for participants who discontinued the trial early during Period 3.

[0138] Efficacy endpoints are assessed by changes in peripheral and gut-associated lymphoid tissue (GALT) in the viral reservoir, along with changes in HIV-1 pVL over time. Participants will be monitored for viremia throughout the study.

[0139] Blood samples collected to evaluate HIV-1 pVL are used to determine virological control and viral rebound, for example, when the viral load is less than 50 copies / mL or less than 2000 copies / mL. Sustained virological control is generally less than 50 copies / mL during ATI (period 2, weeks 48-72).

[0140] Immunogenicity and pharmacodynamic endpoints are evaluated based on the following laboratory tests: (1) an interferon-γ ELISPOT assay to determine the width and magnitude of the de novo T cell response to the HIV vaccine target region of the HIV-1 protein and the total vaccine-induced HIV-1 specific response; (2) changes in the following from before administration of compound (I) to 24 hours after administration: (a) serum / plasma cytokines, (b) gene expression in whole blood (including interferon-stimulated genes), (c) changes in immune cell phenotype / activation in peripheral blood; (3) microbiome based on fecal sample collection; and (4) changes in baseline GALT immune cell phenotype / activation, gene expression (including interferon-stimulated genes), HIV-1 specific T cell response, and HIV-1 reservoir.

[0141] Fecal samples will be collected in week 0 and week 26, and at the early termination of the protocol, if applicable, for microbiome analysis. Example 2: Medication for HIV patients

[0142] A 40-year-old human male patient with confirmed HIV-1 infection and receiving ART is administered the HIV vaccine according to Example 1 and the compound of formula (I) to thus treat the HIV-1 infection. X.array

[0143] In addition to the sequences disclosed elsewhere in this disclosure, the following sequences are provided for reference or use in various exemplary embodiments of the disclosure, provided for illustrative purposes. [Table 3]

[0144] While the foregoing disclosures are described in some detail as explanations and examples to clarify understanding, those skilled in the art will understand that certain changes and modifications may be made within the scope of the appended claims. In addition, each reference provided herein is incorporated as a whole by reference, as each reference is incorporated individually by reference. In the event of any conflict between this application and the references provided herein, this application shall prevail. The present invention provides, for example, the following items: (Item 1) A method for treating or preventing HIV infection in a person who has HIV infection or is at risk of developing HIV infection and requires treatment or prevention of HIV infection, wherein the method comprises a therapeutically effective amount of a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, (i) A sequence having at least 90% sequence identity with sequence number 1, (ii) A sequence having at least 90% sequence identity with sequence number 2, (iii) A sequence having at least 90% sequence identity with sequence number 3, (iv) A sequence having at least 90% sequence identity with sequence number 4, (v) A sequence having at least 90% sequence identity with sequence number 5, (vi) A sequence having at least 90% sequence identity with sequence number 6, (vii) Sequences having at least 90% sequence identity with sequence number 7, (viii) Sequences having at least 90% sequence identity with sequence number 8, (ix) A sequence having at least 90% sequence identity with sequence number 9, (x) A sequence having at least 90% sequence identity with sequence number 10, (xi) A sequence having at least 90% sequence identity with sequence number 11, (xii) A sequence having at least 90% sequence identity with sequence number 12, (xiii) Sequences having at least 90% sequence identity with sequence number 13, (xiv) Sequences having at least 90% sequence identity with sequence number 14, (xv) A sequence having at least 90% sequence identity with sequence number 15, and (xvi) The administration of a first virus to a human being comprising a nucleic acid encoding an immunogenic polypeptide having at least 90% sequence identity with sequence number 16, At least two of (i) to (xvi) are linked by single, double, or triple alanine amino acid linkers, the linkers resulting in the formation of AAA sequences in the binding region between adjacent sequences, A method wherein each of the sequences (i) to (xvi) is 11 to 85 amino acids in length. (Item 2) The immunogenic polypeptide is (i) A sequence having at least 95% sequence identity with sequence number 1, (ii) A sequence having at least 95% sequence identity with sequence number 2, (iii) A sequence having at least 95% sequence identity with sequence number 3, (iv) A sequence having at least 95% sequence identity with sequence number 4, (v) A sequence having at least 95% sequence identity with sequence number 5, (vi) A sequence having at least 95% sequence identity with sequence number 6, (vii) A sequence having at least 95% sequence identity with sequence number 7, (viii) A sequence having at least 95% sequence identity with sequence number 8, (ix) A sequence having at least 95% sequence identity with sequence number 9, (x) A sequence having at least 95% sequence identity with sequence number 10, (xi) A sequence having at least 95% sequence identity with sequence number 11, (xii) A sequence having at least 95% sequence identity with sequence number 12, (xiii) A sequence having at least 95% sequence identity with sequence number 13, (xiv) A sequence having at least 95% sequence identity with sequence number 14, (xv) A sequence having at least 95% sequence identity with sequence number 15, (xvi) The method according to item 1, comprising a sequence having at least 95% sequence identity with sequence number 16. (Item 3) The method according to item 1 or 2, wherein the immunogenic polypeptide comprises the sequences of SEQ ID NOs. 1 to 16, and at least two of SEQ ID NOs. 1 to 16 are linked by the single, double, or triple alanine amino acid linker, the linker resulting in the formation of an AAA sequence in the binding region between adjacent sequences. (Item 4) The method according to any one of items 1 to 3, wherein the immunogenic polypeptide has the amino acid sequence of SEQ ID NO: 17. (Item 5) The method according to any one of items 1 to 4, wherein the nucleic acid has the nucleic acid sequence of sequence number 18. (Item 6) The method according to any one of items 1 to 5, wherein the first virus comprises a viral vector of the family Adenoviridae or Poxviridae. (Item 7) The method according to any one of items 1 to 6, wherein the first virus comprises an adenovirus viral vector. (Item 8) The method according to item 7, wherein the first virus is chimpanzee adenovirus. (Item 9) The method according to item 7 or 8, wherein the first virus is a replication-deficient chimpanzee adenovirus. (Item 10) Approximately 5 × 10 of the first virus 10 The method according to any one of items 7 to 9, wherein a number of virus particles are administered. (Item 11) The method according to any one of items 1 to 10, wherein the first virus is administered once every 12 weeks. (Item 12) The method according to item 11, wherein the first virus is administered twice. (Item 13) The method according to any one of items 1 to 12, further comprising administering a second virus comprising the nucleic acid encoding the immunogenic polypeptide. (Item 14) The method according to item 13, wherein the second virus comprises a modified vaccinia virus ankara (MVA) vector. (Item 15) Approximately 2 × 10⁻⁶ of the second virus mentioned above. 8 The method according to item 14, wherein a plaque-forming unit is administered. (Item 16) The method described in any one of items 13-15, wherein the second virus is administered once every 12 weeks. (Item 17) The method according to item 16, wherein the second virus is administered twice. (Item 18) The method according to any one of items 13 to 17, wherein the first virus and the second virus are administered intramuscularly. (Item 19) The method according to any one of items 13 to 18, wherein the first virus is administered in weeks 0 and 12, and the second virus is administered in weeks 24 and 36. (Item 20) The method according to item 19, wherein approximately 6 mg to approximately 8 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered. (Item 21) The method according to item 20, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered every two weeks after the third dose of the virus. (Item 22) The method according to any one of items 19 to 21, wherein the compound of formula (I) is administered at weeks 26, 28, 30, 32, 34, 38, 40, 42, 44 and 46. (Item 23) The method according to any one of items 1 to 22, wherein the aforementioned human is virologically suppressed. (Item 24) The method according to item 23, wherein the virologically suppressed human has a viral load of approximately 200, 100, less than 50, or approximately 20 copies of HIV-1 RNA per mL of plasma or blood. (Item 25) The method according to item 23 or 24, wherein the virological suppression results from the administration of antiretroviral therapy. (Item 26) The aforementioned antiretroviral therapies include raltegravir, elvitegravir, solutegravir, cabotegravir, dolutegravir, abacavir, didanosine, tenofovir disoproxil fumarate, tenofovir alafenamide, emtricitabine, lamivudine, stabudine, zidovudine, abacavir, erubcitabine, tenofovir exalidex, festinavir, nevirapine, efavirenz, etravirine, rilpivirine, fosdevine, doravirine, relcivirine, atazanavir, darunavir, indinavir, lopinavir, nelfinavirine, saquinavirine, tipranavirine, ritonavir, fosamprenavir, maraviroc, enfuvirtide, fostesavir, bevirimat, cobicistat, and bictegravir. The method according to item 25, comprising one or more agents selected from the group consisting of or pharmaceutically acceptable salts thereof. (Item 27) A method for treating HIV infection in a virologically suppressed human being who has HIV infection and requires treatment for HIV infection, wherein the method comprises a compound of formula (I) and: [ka] 5 × 10⁶ copies of replication-deficient chimpanzee adenovirus containing nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17 10 The first virus contains individual virus particles, A nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17, and 2×10 8 plaque forming units of a second virus, comprising administering the same to the human, where the first virus is administered at week 0 and week 12, where the second virus is administered at week 24 and week 36, 6 mg of the compound of formula (I) is administered at week 26 and week 28, 8 mg of the compound of formula (I) is administered at weeks 30, 32, 34, 38, 40, 42, 44 and 46, a method. (Item 28) A compound of formula (I) and: [Chemical formula] A first virus comprising 5×10 10 virus particles of a replication-defective chimpanzee adenovirus, containing a nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17, and a second virus comprising 2×10 8 plaque forming units of a modified vaccinia virus Ankara (MVA), containing a nucleic acid encoding an immunogenic polypeptide having the amino acid sequence of SEQ ID NO: 17, comprising administering the same to a human, a method wherein the first virus is administered at week 0 and week 12, the second virus is administered at week 24 and week 36, 6 mg of the compound of formula (I) is administered at week 26 and week 28, 8 mg of the compound of formula (I) is administered at weeks 30, 32, 34, 38, 40, 42, 44 and 46, a method.

Claims

[Claim 1] The method or combination described in the specification.

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