Why the HIV Reservoir Never Runs Dry: Clonal Expansion and the Characteristics of HIV-Infected Cells Challenge Strategies to Cure and Control HIV Infection

Chuen-Yen Lau, Matthew A Adan, Frank Maldarelli, Chuen-Yen Lau, Matthew A Adan, Frank Maldarelli

Abstract

Antiretroviral therapy (ART) effectively reduces cycles of viral replication but does not target proviral populations in cells that persist for prolonged periods and that can undergo clonal expansion. Consequently, chronic human immunodeficiency virus (HIV) infection is sustained during ART by a reservoir of long-lived latently infected cells and their progeny. This proviral landscape undergoes change over time on ART. One of the forces driving change in the landscape is the clonal expansion of infected CD4 T cells, which presents a key obstacle to HIV eradication. Potential mechanisms of clonal expansion include general immune activation, antigenic stimulation, homeostatic proliferation, and provirus-driven clonal expansion, each of which likely contributes in varying, and largely unmeasured, amounts to maintaining the reservoir. The role of clinical events, such as infections or neoplasms, in driving these mechanisms remains uncertain, but characterizing these forces may shed light on approaches to effectively eradicate HIV. A limited number of individuals have been cured of HIV infection in the setting of bone marrow transplant; information from these and other studies may identify the means to eradicate or control the virus without ART. In this review, we describe the mechanisms of HIV-1 persistence and clonal expansion, along with the attempts to modify these factors as part of reservoir reduction and cure strategies.

Keywords: HIV; clonal expansion; cure; persistence; reservoir.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A) Mechanism of HIV integration. HIV proviruses integrate into host DNA via a nucleophilic attack, staggered by 5 host base pairs. This staggering of base pairs allows for integration site analysis to determine true clonal expansion from the results of polymerase chain reaction (PCR) amplification. HIV integration favors transcriptionally active regions of the chromosome and, therefore, typically does not take place within tightly bound heterochromatin. LEDGF/p75 is a transcriptional activator that guides integration towards transcriptionally active regions and AT-rich regions. A simplified representation of the HIV intasome is depicted. It is likely comprised of a multimer of integrase molecules. Bp: base pair; IN: integrase tetramer. Adapted from [64]. (B) Phases of the productive HIV replication cycle. HIV proviruses also replicate through clonal expansion, not depicted here. RT: reverse transcription.
Figure 2
Figure 2
(A) Multiphasic model of viral decay. The four phases of HIV RNA decay after starting ART are shown. (B) Phase 1 viral load decay is greater in INSTI-containing regimens. The greater rate of phase 1 decay is likely due to the existence of two distinct populations of HIV-infected cells, some that integrate DNA slowly, and others that integrate more quickly. HIV RNA rapidly declines as INSTIs prevent integration in faster-integrating cell populations. This trend may also be explained by the later stage in the HIV lifecycle at which integrase inhibitors act. (Adapted from [65].).
Figure 3
Figure 3
Clonal expansion vs. viral replication. HIV infection may persist via multiple mechanisms. Without ART, or with inadequate ART, cycles of active viral replication continue, leading to the infection of new susceptible cells. New cycles of infection result in new mutations and genetic variation. Even while on effective ART, HIV proviruses persist via the clonal expansion of HIV-infected cells. Clonally expanded cells may be replication-competent, periodically reactivate from a latent state, and may produce infectious virus, leading to low-level viremia. With effective ART, this low-level viral production is unlikely to infect new cells. Adapted from [87].
Figure 4
Figure 4
Mechanisms of clonal expansion. (A) Homeostatic proliferation maintains existing CD4 T cells. (B) Generalized immune activation can stimulate CD4 T-cell proliferation. (C) Antigen-binding to a CD4 T-cell receptor can stimulate clonal expansion. This stimulus for clonal expansion can create larger clones than the other mechanisms. (D) In rare instances, the site of proviral integration into the host genome can stimulate clonal expansion.
Figure 5
Figure 5
Receptors and coreceptors on CD4 T cells. Tropism of HIV is determined by receptors and coreceptors that allow for binding to the cell surface. LFA-1: lymphocyte-function-associated antigen. Adapted from [207].
Figure 6
Figure 6
HIV DNA by Anatomic Compartment. This figure depicts copies of HIV DNA-per-million cells quantified by ddPCR at various anatomic sites, as described by two research groups. HIV DNA serves as an estimate of the number of proviruses present. A total of 10 individuals are represented in this figure, 8 of whom had undetectable plasma viral RNA until death and 2 of whom discontinued ART in the days or weeks before death. Each dot represents mean HIV DNA copies across all participants in that study at each anatomic site, with bars that extend to one SD above and below the mean value. Dots that do not have SD bars represent data from one individual, and thus SD could not be calculated. Data are from Bozzi et al. [3] and Chaillon [227].

References

    1. Hammer S.M., Ribaudo H., Bassett R., Mellors J.W., Demeter L.M., Coombs R.W., Currier J., Morse G.D., Geber J.G., Martinez A.I., et al. A randomized, placebo-controlled trial of abacavir intensification in HIV-1-infected adults with virologic suppression on a protease inhibitor-containing regimen. HIV Clin. Trials. 2010;11:312–324. doi: 10.1310/hct1105-312.
    1. Kearney M.F., Spindler J., Shao W., Yu S., Anderson E.M., O’Shea A., Rehm C., Poethke C., Kovacs N., Mellors J.W., et al. Lack of Detectable HIV-1 Molecular Evolution during Suppressive Antiretroviral Therapy. PLoS Pathog. 2014;10:e1004010. doi: 10.1371/journal.ppat.1004010.
    1. Bozzi G., Simonetti F.R., Watters S.A., Anderson E.M., Gouzoulis M., Kearney M.F., Rote P., Lange C., Shao W., Gorelick R., et al. No evidence of ongoing HIV replication or compartmentalization in tissues during combination antiretroviral therapy: Implications for HIV eradication. Sci. Adv. 2019;5:eaav2045. doi: 10.1126/sciadv.aav2045.
    1. Chun T.-W., Moir S., Fauci A.S. HIV reservoirs as obstacles and opportunities for an HIV cure. Nat. Immunol. 2015;16:584–589. doi: 10.1038/ni.3152.
    1. Croxford S., Kitching A., Desai S., Kall M., Edelstein M., Skingsley A., Burns F., Copas A., Brown E.A., Sullivan A.K., et al. Mortality and causes of death in people diagnosed with HIV in the era of highly active antiretroviral therapy compared with the general population: An analysis of a national observational cohort. Lancet Public Health. 2017;2:e35–e46. doi: 10.1016/S2468-2667(16)30020-2.
    1. Michaels S.H., Clark R., Kissinger P. Declining Morbidity and Mortality among Patients with Advanced Human Immunodeficiency Virus Infection. N. Engl. J. Med. 1998;339:405–406. doi: 10.1056/NEJM199808063390612.
    1. Imamichi H., Dewar R.L., Adelsberger J.W., Rehm C.A., O’Doherty U., Paxinos E.E., Fauci A.S., Lane H.C. Defective HIV-1 proviruses produce novel protein-coding RNA species in HIV-infected patients on combination antiretroviral therapy. Proc. Natl. Acad. Sci. USA. 2016;113:8783–8788. doi: 10.1073/pnas.1609057113.
    1. Currier J.S., Baden L.R. Getting Smarter—The Toxicity of Undertreated HIV Infection. N. Engl. J. Med. 2006;355:2359–2361. doi: 10.1056/NEJMe068250.
    1. Pollack R.A., Jones R.B., Pertea M., Bruner K.M., Martin A.R., Thomas A., Capoferri A.A., Beg S.A., Huang S.-H., Karandish S., et al. Defective HIV-1 Proviruses Are Expressed and Can Be Recognized by Cytotoxic T Lymphocytes, which Shape the Proviral Landscape. Cell Host Microbe. 2017;21:494–506.e4. doi: 10.1016/j.chom.2017.03.008.
    1. Rodari A., Darcis G., Van Lint C.M. The Current Status of Latency Reversing Agents for HIV-1 Remission. Annu. Rev. Virol. 2021;8:491–514. doi: 10.1146/annurev-virology-091919-103029.
    1. Rasmussen T.A., McMahon J., Chang J.J., Audsley J., Rhodes A., Tennakoon S., Dantanarayana A., Spelman T., Schmidt T., Kent S.J., et al. The effect of antiretroviral intensification with dolutegravir on residual virus replication in HIV-infected individuals: A randomised, placebo-controlled, double-blind trial. Lancet HIV. 2018;5:e221–e230. doi: 10.1016/S2352-3018(18)30040-7.
    1. Jones R.B., Walker B.D. HIV-specific CD8+ T cells and HIV eradication. J. Clin. Investig. 2016;126:455–463. doi: 10.1172/JCI80566.
    1. Vansant G., Bruggemans A., Janssens J., Debyser Z. Block-And-Lock Strategies to Cure HIV Infection. Viruses. 2020;12:84. doi: 10.3390/v12010084.
    1. Yeh Y.-H.J., Ho Y.-C. Shock-and-kill versus block-and-lock: Targeting the fluctuating and heterogeneous HIV-1 gene expression. Proc. Natl. Acad. Sci. USA. 2021;118:e2103692118. doi: 10.1073/pnas.2103692118.
    1. Jiang C., Lian X., Gao C., Sun X., Einkauf K.B., Chevalier J.M., Chen S.M.Y., Hua S., Rhee B., Chang K., et al. Distinct viral reservoirs in individuals with spontaneous control of HIV-1. Nature. 2020;585:261–267. doi: 10.1038/s41586-020-2651-8.
    1. Blazkova J., Gao F., Marichannegowda M.H., Justement J.S., Shi V., Whitehead E.J., Schneck R.F., Huiting E.D., Gittens K., Cottrell M., et al. Distinct mechanisms of long-term virologic control in two HIV-infected individuals after treatment interruption of anti-retroviral therapy. Nat. Med. 2021;27:1893–1898. doi: 10.1038/s41591-021-01503-6.
    1. Parikh U.M., McCormick K., van Zyl G., Mellors J.W. Future technologies for monitoring HIV drug resistance and cure. Curr. Opin. HIV AIDS. 2017;12:182–189. doi: 10.1097/COH.0000000000000344.
    1. Abdel-Mohsen M., Richman D., Siliciano R.F., Nussenzweig M.C., Howell B., Martinez-Picado J., Chomont N., Bar K.J., Yu X.G., Lichterfeld M., et al. Recommendations for measuring HIV reservoir size in cure-directed clinical trials. Nat. Med. 2020;26:1339–1350. doi: 10.1038/s41591-020-1022-1.
    1. Siliciano J.D., Siliciano R.F. Assays to Measure Latency, Reservoirs, and Reactivation. HIV-1 Latency. 2017;417:23–41. doi: 10.1007/82_2017_75.
    1. Rosenbloom D.I.S., Elliott O., Hill A.L., Henrich T.J., Siliciano J.M., Siliciano R.F. Designing and Interpreting Limiting Dilution Assays: General Principles and Applications to the Latent Reservoir for Human Immunodeficiency Virus-1. Open Forum Infect. Dis. 2015;2:ofv123. doi: 10.1093/ofid/ofv123.
    1. Falcinelli S.D., Ceriani C., Margolis D.M., Archin N.M. New Frontiers in Measuring and Characterizing the HIV Reservoir. Front. Microbiol. 2019;10:2878. doi: 10.3389/fmicb.2019.02878.
    1. Lusic M., Siliciano R.F. Nuclear landscape of HIV-1 infection and integration. Nat. Rev. Genet. 2016;15:69–82. doi: 10.1038/nrmicro.2016.162.
    1. Engelman A.N., Singh P.K. Cellular and molecular mechanisms of HIV-1 integration targeting. Cell. Mol. Life Sci. 2018;75:2491–2507. doi: 10.1007/s00018-018-2772-5.
    1. Symons J., Cameron P.U., Lewin S.R. HIV integration sites and implications for maintenance of the reservoir. Curr. Opin. HIV AIDS. 2018;13:152–159. doi: 10.1097/COH.0000000000000438.
    1. Deruaz M., Tager A.M. Humanized mouse models of latent HIV infection. Curr. Opin. Virol. 2017;25:97–104. doi: 10.1016/j.coviro.2017.07.027.
    1. Masse-Ranson G., Mouquet H., Di Santo J.P. Humanized mouse models to study pathophysiology and treatment of HIV infection. Curr. Opin. HIV AIDS. 2018;13:143–151. doi: 10.1097/COH.0000000000000440.
    1. Whitney J.B., Jones R.B. In Vitro and In Vivo Models of HIV Latency. HIV Vaccines Cure. 2018;1075:241–263. doi: 10.1007/978-981-13-0484-2_10.
    1. Del Prete G.Q., Lifson J.D., Keele B.F. Nonhuman primate models for the evaluation of HIV-1 preventive vaccine strategies: Model parameter considerations and consequences. Curr. Opin. HIV AIDS. 2016;11:546–554. doi: 10.1097/COH.0000000000000311.
    1. Sharma A., Overbaugh J. CD4–HIV-1 Envelope Interactions: Critical Insights for the Simian/HIV/Macaque Model. AIDS Res. Hum. Retrovir. 2018;34:778–779. doi: 10.1089/aid.2018.0110.
    1. Cilento M.E., Kirby K.A., Sarafianos S.G. Avoiding Drug Resistance in HIV Reverse Transcriptase. Chem. Rev. 2021;121:3271–3296. doi: 10.1021/acs.chemrev.0c00967.
    1. Giacomelli A., Pezzati L., Rusconi S. The crosstalk between antiretrovirals pharmacology and HIV drug resistance. Expert Rev. Clin. Pharmacol. 2020;13:739–760. doi: 10.1080/17512433.2020.1782737.
    1. Rhee S.-Y., Grant P.M., Tzou P.L., Barrow G., Harrigan P.R., Ioannidis J.P.A., Shafer R.W. A systematic review of the genetic mechanisms of dolutegravir resistance. J. Antimicrob. Chemother. 2019;74:3135–3149. doi: 10.1093/jac/dkz256.
    1. Rhee S.Y., Gonzales M.J., Kantor R., Betts B.J., Ravela J., Shafer R.W. Human immunodeficiency virus reverse transcriptase and protease sequence database. Nucleic Acids Res. 2003;31:298–303. doi: 10.1093/nar/gkg100.
    1. Mansky L.M., Temin H.M. Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J. Virol. 1995;69:5087–5094. doi: 10.1128/jvi.69.8.5087-5094.1995.
    1. Rhodes T.D., Nikolaitchik O., Chen J., Powell D., Hu W.-S. Genetic Recombination of Human Immunodeficiency Virus Type 1 in One Round of Viral Replication: Effects of Genetic Distance, Target Cells, Accessory Genes, and Lack of High Negative Interference in Crossover Events. J. Virol. 2005;79:1666–1677. doi: 10.1128/JVI.79.3.1666-1677.2005.
    1. Rawson O.J.M., Nikolaitchik A.O., Keele B.F., Pathak V., Hu W.-S. Recombination is required for efficient HIV-1 replication and the maintenance of viral genome integrity. Nucleic Acids Res. 2018;46:10535–10545. doi: 10.1093/nar/gky910.
    1. Hu W.-S., Hughes S.H. HIV-1 Reverse Transcription. Cold Spring Harb. Perspect. Med. 2012;2:a006882. doi: 10.1101/cshperspect.a006882.
    1. Schlub T., Grimm A.J., Smyth R.P., Cromer D., Chopra A., Mallal S., Venturi V., Waugh C., Mak J., Davenport M.P. Fifteen to Twenty Percent of HIV Substitution Mutations Are Associated with Recombination. J. Virol. 2014;88:3837–3849. doi: 10.1128/JVI.03136-13.
    1. Smyth R., Schlub T., Grimm A.J., Waugh C., Ellenberg P., Chopra A., Mallal S., Cromer D., Mak J., Davenport M.P., et al. Identifying Recombination Hot Spots in the HIV-1 Genome. J. Virol. 2013;88:2891–2902. doi: 10.1128/JVI.03014-13.
    1. Rawson J.M., Mansky L.M. Retroviral Vectors for Analysis of Viral Mutagenesis and Recombination. Viruses. 2014;6:3612–3642. doi: 10.3390/v6093612.
    1. Batorsky R., Kearney M.F., Palmer S.E., Maldarelli F., Rouzine I.M., Coffin J.M. Estimate of effective recombination rate and average selection coefficient for HIV in chronic infection. Proc. Natl. Acad. Sci. USA. 2011;108:5661–5666. doi: 10.1073/pnas.1102036108.
    1. Coffin J.M. HIV population dynamics in vivo: Implications for genetic variation, pathogenesis, and therapy. Science. 1995;267:483–489. doi: 10.1126/science.7824947.
    1. Bruner K.M., Murray A.J., Pollack R.A., Soliman M.G., Laskey S.B., Capoferri A.A., Lai J., Strain M.C., Lada S.M., Hoh R., et al. Defective proviruses rapidly accumulate during acute HIV-1 infection. Nat. Med. 2016;22:1043–1049. doi: 10.1038/nm.4156.
    1. Burdick R.C., Li C., Munshi M., Rawson J.M.O., Nagashima K., Hu W.-S., Pathak V.K. HIV-1 uncoats in the nucleus near sites of integration. Proc. Natl. Acad. Sci. USA. 2020;117:5486–5493. doi: 10.1073/pnas.1920631117.
    1. Burdick R.C., Pathak V.K. Efficient HIV-1 in vitro reverse transcription: Optimal capsid stability is required. Signal Transduct. Target. Ther. 2021;6:1–2. doi: 10.1038/s41392-020-00458-3.
    1. Li C., Burdick R.C., Nagashima K., Hu W.-S., Pathak V.K. HIV-1 cores retain their integrity until minutes before uncoating in the nucleus. Proc. Natl. Acad. Sci. USA. 2021;118:e2019467118. doi: 10.1073/pnas.2019467118.
    1. Koh Y., Wu X., Ferris A.L., Matreyek K., Smith S.J., Lee K., KewalRamani V.N., Hughes S.H., Engelman A. Differential Effects of Human Immunodeficiency Virus Type 1 Capsid and Cellular Factors Nucleoporin 153 and LEDGF/p75 on the Efficiency and Specificity of Viral DNA Integration. J. Virol. 2012;87:648–658. doi: 10.1128/JVI.01148-12.
    1. Achuthan V., Perreira J.M., Sowd G.A., Puray-Chavez M., McDougall W.M., Paulucci-Holthauzen A., Wu X., Fadel H.J., Poeschla E.M., Multani A.S., et al. Capsid-CPSF6 Interaction Licenses Nuclear HIV-1 Trafficking to Sites of Viral DNA Integration. Cell Host Microbe. 2018;24:392–404.e8. doi: 10.1016/j.chom.2018.08.002.
    1. Santos da Silva E., Shanmugapriya S., Malikov V., Gu F., Delaney M.K., Naghavi M.H. HIV -1 Capsids Mimic a Microtubule Regulator to Coordinate Early Stages of Infection. EMBO J. 2020;39:1043–1049. doi: 10.15252/embj.2020104870.
    1. Lesbats P., Engelman A.N., Cherepanov P. Retroviral DNA Integration. Chem. Rev. 2016;116:12730–12757. doi: 10.1021/acs.chemrev.6b00125.
    1. Coffin J.M., Bale M.J., Wells D., Guo S., Luke B., Zerbato J.M., Sobolewski M.D., Sia T., Shao W., Wu X., et al. Integration in oncogenes plays only a minor role in determining the in vivo distribution of HIV integration sites before or during suppressive antiretroviral therapy. PLoS Pathog. 2021;17:e1009141. doi: 10.1371/journal.ppat.1009141.
    1. Maldarelli F., Wu X., Su L., Simonetti F.R., Shao W., Hill S., Spindler J., Ferris A.L., Mellors J.W., Kearney M.F., et al. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science. 2014;345:179–183. doi: 10.1126/science.1254194.
    1. Geis F.K., Goff S.P. Unintegrated HIV-1 DNAs are loaded with core and linker histones and transcriptionally silenced. Proc. Natl. Acad. Sci. USA. 2019;116:23735–23742. doi: 10.1073/pnas.1912638116.
    1. Chen J., Umunnakwe C., Sun D.Q., Nikolaitchik O.A., Pathak V.K., Berkhout B., Das A.T., Hu W.-S. Impact of Nuclear Export Pathway on Cytoplasmic HIV-1 RNA Transport Mechanism and Distribution. mBio. 2020;11:e01578-20. doi: 10.1128/mBio.01578-20.
    1. Lassen K.G., Ramyar K.X., Bailey J.R., Zhou Y., Siliciano R.F. Nuclear Retention of Multiply Spliced HIV-1 RNA in Resting CD4+ T Cells. PLoS Pathog. 2006;2:e68. doi: 10.1371/journal.ppat.0020068.
    1. Byun S., Han S., Zheng Y., Planelles V., Lee Y. The landscape of alternative splicing in HIV-1 infected CD4 T-cells. BMC Med. Genom. 2020;13:38. doi: 10.1186/s12920-020-0680-7.
    1. Sundquist W.I., Kräusslich H.-G. HIV-1 Assembly, Budding, and Maturation. Cold Spring Harb. Perspect. Med. 2012;2:a006924. doi: 10.1101/cshperspect.a006924.
    1. Hataye J.M., Casazza J.P., Best K., Liang C.J., Immonen T.T., Ambrozak D.R., Darko S., Henry A.R., Laboune F., Maldarelli F., et al. Principles Governing Establishment versus Collapse of HIV-1 Cellular Spread. Cell Host Microbe. 2019;26:748–763.e20. doi: 10.1016/j.chom.2019.10.006.
    1. Chun T.-W., Carruth L., Finzi D., Shen X., DiGiuseppe J.A., Taylor H., Hermankova M., Chadwick K., Margolick J., Quinn T.C., et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature. 1997;387:183–188. doi: 10.1038/387183a0.
    1. Chun T.-W., Finzi D., Margolick J., Chadwick K., Schwartz D., Siliciano R.F. In vivo fate of HIV-1-infected T cells: Quantitative analysis of the transition to stable latency. Nat. Med. 1995;1:1284–1290. doi: 10.1038/nm1295-1284.
    1. Finzi D., Blankson J.N., Siliciano J.D., Margolick J.B., Chadwick K., Pierson T.C., Smith A.K., Lisziewicz J., Lori F., Flexner C., et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat. Med. 1999;5:512–517. doi: 10.1038/8394.
    1. Finzi D., Hermankova M., Pierson T., Carruth L.M., Buck C., Chaisson R.E., Quinn T.C., Chadwick K., Margolick J., Brookmeyer R., et al. Identification of a Reservoir for HIV-1 in Patients on Highly Active Antiretroviral Therapy. Science. 1997;278:1295–1300. doi: 10.1126/science.278.5341.1295.
    1. Roche M., Tumpach C., Symons J., Gartner M., Anderson J.L., Khoury G., Cashin K., Cameron P.U., Churchill M.J., Deeks S.G., et al. CXCR4-Using HIV Strains Predominate in Naive and Central Memory CD4+ T Cells in People Living with HIV on Antiretroviral Therapy: Implications for How Latency Is Established and Maintained. J. Virol. 2020;94:01736-19. doi: 10.1128/JVI.01736-19.
    1. Anderson E.M., Maldarelli F. The role of integration and clonal expansion in HIV infection: Live long and prosper. Retrovirology. 2018;15:71. doi: 10.1186/s12977-018-0448-8.
    1. Hill A.L., Rosenbloom D.I.S., Nowak M.A., Siliciano R.F. Insight into treatment of HIV infection from viral dynamics models. Immunol. Rev. 2018;285:9–25. doi: 10.1111/imr.12698.
    1. Palmer S., Wiegand A.P., Maldarelli F., Bazmi H., Mican J.M., Polis M., Dewar R.L., Planta A., Liu S., Metcalf J.A., et al. New Real-Time Reverse Transcriptase-Initiated PCR Assay with Single-Copy Sensitivity for Human Immunodeficiency Virus Type 1 RNA in Plasma. J. Clin. Microbiol. 2003;41:4531–4536. doi: 10.1128/JCM.41.10.4531-4536.2003.
    1. Cillo A.R., Vagratian D., Bedison M.A., Anderson E.M., Kearney M., Fyne E., Koontz D., Coffin J.M., Piatak M., Mellors J.W. Improved Single-Copy Assays for Quantification of Persistent HIV-1 Viremia in Patients on Suppressive Antiretroviral Therapy. J. Clin. Microbiol. 2014;52:3944–3951. doi: 10.1128/JCM.02060-14.
    1. Somsouk M., Dunham R.M., Cohen M., Albright R., Abdel-Mohsen M., Liegler T., Lifson J., Piatak M., Gorelick R., Huang Y., et al. The Immunologic Effects of Mesalamine in Treated HIV-Infected Individuals with Incomplete CD4+ T Cell Recovery: A Randomized Crossover Trial. PLoS ONE. 2014;9:e116306. doi: 10.1371/journal.pone.0116306.
    1. Tosiano M.A., Jacobs J.L., Shutt K.A., Cyktor J.C., Mellors J.W. A Simpler and More Sensitive Single-Copy HIV-1 RNA Assay for Quantification of Persistent HIV-1 Viremia in Individuals on Suppressive Antiretroviral Therapy. J. Clin. Microbiol. 2019;57:e01714-18. doi: 10.1128/JCM.01714-18.
    1. Riddler S.A., Dragavon J., Bosch R.J., Bastow B., Bedison A.M., Vagratian D., Vaida F., Eron J.J., Gandhi R.T., Mellors J.W. Continued Slow Decay of the Residual Plasma Viremia Level in HIV-1–Infected Adults Receiving Long-term Antiretroviral Therapy. J. Infect. Dis. 2015;213:556–560. doi: 10.1093/infdis/jiv433.
    1. Andrade A., Rosenkranz S.L., Cillo A.R., Lu D., Daar E.S., Jacobson J.M., Lederman M., Acosta E.P., Campbell T., Feinberg J., et al. Three Distinct Phases of HIV-1 RNA Decay in Treatment-Naive Patients Receiving Raltegravir-Based Antiretroviral Therapy: ACTG A5248. J. Infect. Dis. 2013;208:884–891. doi: 10.1093/infdis/jit272.
    1. Palmer S., Maldarelli F., Wiegand A., Bernstein B., Hanna G., Brun S.C., Kempf D.J., Mellors J.W., Coffin J.M., King M.S. Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc. Natl. Acad. Sci. USA. 2008;105:3879–3884. doi: 10.1073/pnas.0800050105.
    1. Perelson A.S., Ribeiro R.M. Modeling the within-host dynamics of HIV infection. BMC Biol. 2013;11:96. doi: 10.1186/1741-7007-11-96.
    1. Sedaghat A.R., Dinoso J.B., Shen L., Wilke C.O., Siliciano R.F. Decay dynamics of HIV-1 depend on the inhibited stages of the viral life cycle. Proc. Natl. Acad. Sci. USA. 2008;105:4832–4837. doi: 10.1073/pnas.0711372105.
    1. Cardozo E.F., Andrade A., Mellors J.W., Kuritzkes D.R., Perelson A.S., Ribeiro R.M. Treatment with integrase inhibitor suggests a new interpretation of HIV RNA decay curves that reveals a subset of cells with slow integration. PLoS Pathog. 2017;13:e1006478. doi: 10.1371/journal.ppat.1006478.
    1. Andrade A., Guedj J., Rosenkranz S.L., Lu D., Mellors J., Kuritzkes D.R., Perelson A.S., Ribeiro R.M. Early HIV RNA decay during raltegravir-containing regimens exhibits two distinct subphases (1a and 1b) AIDS. 2015;29:2419–2426. doi: 10.1097/QAD.0000000000000843.
    1. Smith R. Adherence to antiretroviral HIV drugs: How many doses can you miss before resistance emerges? Proc. R. Soc. B Boil. Sci. 2005;273:617–624. doi: 10.1098/rspb.2005.3352.
    1. Winters M.A., Lloyd R.M., Jr., Shafer R.W., Kozal M.J., Miller M.D., Holodniy M. Development of elvitegravir resistance and linkage of integrase inhibitor mutations with protease and reverse transcriptase resistance mutations. PLoS ONE. 2012;7:e40514. doi: 10.1371/journal.pone.0040514.
    1. Wensing A.M., Calvez V., Ceccherini-Silberstein F., Charpentier C., Gunthard H.F., Paredes R., Shafer R.W., Richman D.D. 2019 update of the drug resistance mutations in HIV-1. Top Antivir. Med. 2019;27:111–121.
    1. Pingen M., Wensing A.M., Fransen K., De Bel A., de Jong D., Hoepelman A.I., Magiorkinis E., Paraskevis D., Lunar M.M., Poljak M., et al. Persistence of frequently transmitted drug-resistant HIV-1 variants can be explained by high viral replication capacity. Retrovirology. 2014;11:1–15. doi: 10.1186/s12977-014-0105-9.
    1. Puertas M.C., Ploumidis G., Ploumidis M., Fumero E., Clotet B., Walworth C.M., Petropoulos C.J., Martinez-Picado J. Pan-resistant HIV-1 emergence in the era of integrase strand-transfer inhibitors: A case report. Lancet Microbe. 2020;1:e130–e135. doi: 10.1016/S2666-5247(20)30006-9.
    1. Panel on Antiretroviral Guidelines for Adults and Adolescents Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services 2020. [(accessed on 4 November 2020)]; Available online: .
    1. Hare S., Vos A., Clayton R.F., Thuring J.W., Cummings M.D., Cherepanov P. Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc. Natl. Acad. Sci. USA. 2010;107:20057–20062. doi: 10.1073/pnas.1010246107.
    1. Anstett K., Brenner B., Mesplede T., Wainberg M.A. HIV drug resistance against strand transfer integrase inhibitors. Retrovirology. 2017;14:1–16. doi: 10.1186/s12977-017-0360-7.
    1. Goethals O., Clayton R., Van Ginderen M., Vereycken I., Wagemans E., Geluykens P., Dockx K., Strijbos R., Smits V., Vos A., et al. Resistance Mutations in Human Immunodeficiency Virus Type 1 Integrase Selected with Elvitegravir Confer Reduced Susceptibility to a Wide Range of Integrase Inhibitors. J. Virol. 2008;82:10366–10374. doi: 10.1128/JVI.00470-08.
    1. Cattaneo D., Gervasoni C. Pharmacokinetics and Pharmacodynamics of Cabotegravir, a Long-Acting HIV Integrase Strand Transfer Inhibitor. Eur. J. Drug Metab. Pharmacokinet. 2018;44:319–327. doi: 10.1007/s13318-018-0526-2.
    1. Jacobs J.L., Halvas E.K., Tosiano M.A., Mellors J.W. Persistent HIV-1 Viremia on Antiretroviral Therapy: Measurement and Mechanisms. Front. Microbiol. 2019;10:2383. doi: 10.3389/fmicb.2019.02383.
    1. Horsburgh B.A., Palmer S. Measuring HIV Persistence on Antiretroviral Therapy. Adv. Exp. Med. Biol. 2018;1075:265–284. doi: 10.1007/978-981-13-0484-2_11.
    1. Fujinaga K., Cary D.C. Experimental Systems for Measuring HIV Latency and Reactivation. Viruses. 2020;12:1279. doi: 10.3390/v12111279.
    1. Estes J.D., Kityo C., Ssali F., Swainson L., Makamdop K.N., Del Prete G.Q., Deeks S.G., Luciw P.A., Chipman J.G., Beilman G.J., et al. Defining total-body AIDS-virus burden with implications for curative strategies. Nat. Med. 2017;23:1271–1276. doi: 10.1038/nm.4411.
    1. Hawkins S.F.C., Guest P.C. Multiplex Analyses Using Real-Time Quantitative PCR. Methods Mol. Biol. 2016;1546:125–133. doi: 10.1007/978-1-4939-6730-8_8.
    1. Anderson E.M., Maldarelli F. Quantification of HIV DNA Using Droplet Digital PCR Techniques. Curr. Protoc. Microbiol. 2018;51:e62. doi: 10.1002/cpmc.62.
    1. Margot N., Koontz D., McCallister S., Mellors J.W., Callebaut C. Measurement of plasma HIV-1 RNA below the limit of quantification (<20 copies/mL) of commercial assays with the integrase HIV RNA single-copy assay. J. Clin. Virol. 2018;108:50–52. doi: 10.1016/j.jcv.2018.09.003.
    1. Avettand-Fènoël V., Hocqueloux L., Ghosn J., Cheret A., Frange P., Melard A., Viard J.-P., Rouzioux C. Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications. Clin. Microbiol. Rev. 2016;29:859–880. doi: 10.1128/CMR.00015-16.
    1. Hong F., Aga E., Cillo A.R., Yates A.L., Besson G., Fyne E., Koontz D.L., Jennings C., Zheng L., Mellors J.W. Novel Assays for Measurement of Total Cell-Associated HIV-1 DNA and RNA. J. Clin. Microbiol. 2016;54:902–911. doi: 10.1128/JCM.02904-15.
    1. Sannier G., Dubé M., Kaufmann D.E. Single-Cell Technologies Applied to HIV-1 Research: Reaching Maturity. Front. Microbiol. 2020;11:297. doi: 10.3389/fmicb.2020.00297.
    1. Grau-Expósito J., Serra-Peinado C., Miguel L., Navarro J., Curran A., Burgos J., Ocaña I., Ribera E., Torrella A., Planas B., et al. A Novel Single-Cell FISH-Flow Assay Identifies Effector Memory CD4 + T cells as a Major Niche for HIV-1 Transcription in HIV-Infected Patients. mBio. 2017;8:e00876-17. doi: 10.1128/mBio.00876-17.
    1. Wiegand A., Spindler J., Hong F.F., Shao W., Cyktor J.C., Cillo A.R., Halvas E.K., Coffin J.M., Mellors J.W., Kearney M.F. Single-cell analysis of HIV-1 transcriptional activity reveals expression of proviruses in expanded clones during ART. Proc. Natl. Acad. Sci. USA. 2017;114:E3659–E3668. doi: 10.1073/pnas.1617961114.
    1. Liu R., Yeh Y.-H.J., Varabyou A., Collora J.A., Sherrill-Mix S., Talbot C.C., Mehta S., Albrecht K., Hao H., Zhang H., et al. Single-cell transcriptional landscapes reveal HIV-1–driven aberrant host gene transcription as a potential therapeutic target. Sci. Transl. Med. 2020;12:eaaz0802. doi: 10.1126/scitranslmed.aaz0802.
    1. Deleage C., Chan C.N., Busman-Sahay K., Estes J.D. Next-generation in situ hybridization approaches to define and quantify HIV and SIV reservoirs in tissue microenvironments. Retrovirology. 2018;15:1–10. doi: 10.1186/s12977-017-0387-9.
    1. Vasquez J.J., Hussien R., Aguilar-Rodriguez B., Junger H., Dobi D., Henrich T.J., Thanh C., Gibson E., Hogan L., McCune J., et al. Elucidating the Burden of HIV in Tissues Using Multiplexed Immunofluorescence and In Situ Hybridization: Methods for the Single-Cell Phenotypic Characterization of Cells Harboring HIV In Situ. J. Histochem. Cytochem. 2018;66:427–446. doi: 10.1369/0022155418756848.
    1. Wonderlich E.R., Subramanian K., Cox B., Wiegand A., Lackman-Smith C., Bale M., Stone M., Hoh R., Kearney M., Maldarelli F., et al. Effector memory differentiation increases detection of replication-competent HIV-l in resting CD4+ T cells from virally suppressed individuals. PLoS Pathog. 2019;15:e1008074. doi: 10.1371/journal.ppat.1008074.
    1. Bruner K.M., Wang Z., Simonetti F.R., Bender A.M., Kwon K.J., Sengupta S., Fray E.J., Beg S.A., Antar A.A.R., Jenike K.M., et al. A quantitative approach for measuring the reservoir of latent HIV-1 proviruses. Nature. 2019;566:120–125. doi: 10.1038/s41586-019-0898-8.
    1. Antar A., Jenike K.M., Jang S., Rigau D.N., Reeves D.B., Hoh R., Krone M.R., Keruly J.C., Moore R.D., Schiffer J.T., et al. Longitudinal study reveals HIV-1–infected CD4+ T cell dynamics during long-term antiretroviral therapy. J. Clin. Investig. 2020;130:3543–3559. doi: 10.1172/JCI135953.
    1. Hughes S.H. Reverse Transcription of Retroviruses and LTR Retrotransposons. Microbiol. Spectr. 2015;3:1051–1077. doi: 10.1128/microbiolspec.MDNA3-0027-2014.
    1. Bale M.J., Kearney M. Review: HIV-1 phylogeny during suppressive antiretroviral therapy. Curr. Opin. HIV AIDS. 2019;14:188–193. doi: 10.1097/COH.0000000000000535.
    1. Maldarelli F., Kearney M., Palmer S., Stephens R., Mican J., Polis M.A., Davey R.T., Kovacs J., Shao W., Rock-Kress D., et al. HIV Populations Are Large and Accumulate High Genetic Diversity in a Nonlinear Fashion. J. Virol. 2013;87:10313–10323. doi: 10.1128/JVI.01225-12.
    1. Lorenzo-Redondo R., Fryer H.R., Bedford T., Kim E.Y., Archer J., Pond S.L.K., Chung Y.S., Penugonda S., Chipman J.G., Fletcher C.V., et al. Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature. 2016;530:51–56. doi: 10.1038/nature16933.
    1. Jones B.R., Miller R.L., Kinloch N.N., Tsai O., Rigsby H., Sudderuddin H., Shahid A., Ganase B., Brumme C.J., Harris M., et al. Genetic Diversity, Compartmentalization, and Age of HIV Proviruses Persisting in CD4 + T Cell Subsets during Long-Term Combination Antiretroviral Therapy. J. Virol. 2020;94:e01786-19. doi: 10.1128/JVI.01786-19.
    1. Josefsson L., Palmer S., Faria N.R., Lemey P., Casazza J., Ambrozak D., Kearney M., Shao W., Kottilil S., Sneller M., et al. Single Cell Analysis of Lymph Node Tissue from HIV-1 Infected Patients Reveals that the Majority of CD4+ T-cells Contain One HIV-1 DNA Molecule. PLoS Pathog. 2013;9:e1003432. doi: 10.1371/journal.ppat.1003432.
    1. Delviks-Frankenberry K., Galli A., Nikolaitchik O., Mens H., Pathak V.K., Hu W.-S. Mechanisms and Factors that Influence High Frequency Retroviral Recombination. Viruses. 2011;3:1650–1680. doi: 10.3390/v3091650.
    1. Wagner T.A., McLaughlin S., Garg K., Cheung C.Y.K., Larsen B.B., Styrchak S., Huang H.C., Edlefsen P.T., Mullins J.I., Frenkel L.M. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection. Science. 2014;345:570–573. doi: 10.1126/science.1256304.
    1. Cohn L.B., Silva I., Oliveira T., Rosales R., Parrish E.H., Learn G.H., Hahn B., Czartoski J.L., McElrath M.J., Lehmann C., et al. HIV-1 Integration Landscape during Latent and Active Infection. Cell. 2015;160:420–432. doi: 10.1016/j.cell.2015.01.020.
    1. Ferreira R.-C., Prodger J.L., Redd A.D., Poon A.F.Y. Quantifying the clonality and dynamics of the within-host HIV-1 latent reservoir. Virus Evol. 2021;7:veaa104. doi: 10.1093/ve/veaa104.
    1. Sunshine S., Kirchner R., Amr S.S., Mansur L., Shakhbatyan R., Kim M., Bosque A., Siliciano R.F., Planelles V., Hofmann O., et al. HIV Integration Site Analysis of Cellular Models of HIV Latency with a Probe-Enriched Next-Generation Sequencing Assay. J. Virol. 2016;90:4511–4519. doi: 10.1128/JVI.01617-15.
    1. Bedwell G.J., Jang S., Li W., Singh P.K., Engelman A.N. rigrag: High-resolution mapping of genic targeting preferences during HIV-1 integration in vitro and in vivo. Nucleic Acids Res. 2021;49:7330–7346. doi: 10.1093/nar/gkab514.
    1. Einkauf K.B., Lee G.Q., Gao C., Sharaf R., Sun X., Hua S., Chen S.M., Jiang C., Lian X., Chowdhury F.Z., et al. Intact HIV-1 proviruses accumulate at distinct chromosomal positions during prolonged antiretroviral therapy. J. Clin. Investig. 2019;129:988–998. doi: 10.1172/JCI124291.
    1. Patro S.C., Brandt L.D., Bale M., Halvas E.K., Joseph K.W., Shao W., Wu X., Guo S., Murrell B., Wiegand A., et al. Combined HIV-1 sequence and integration site analysis informs viral dynamics and allows reconstruction of replicating viral ancestors. Proc. Natl. Acad. Sci. USA. 2019;116:25891–25899. doi: 10.1073/pnas.1910334116.
    1. Pierson T., McArthur J., Siliciano R.F. Reservoirs for HIV-1: Mechanisms for Viral Persistence in the Presence of Antiviral Immune Responses and Antiretroviral Therapy. Annu. Rev. Immunol. 2000;18:665–708. doi: 10.1146/annurev.immunol.18.1.665.
    1. Hermankova M., Ray S.C., Ruff C., Powell-Davis M., Ingersoll R., D’Aquila R.T., Quinn T.C., Siliciano J.D., Siliciano R.F., Persaud D. HIV-1 Drug Resistance Profiles in Children and Adults with Viral Load of <50 copies/mL receiving combination therapy. JAMA. 2001;286:196–207. doi: 10.1001/jama.286.2.196.
    1. Von Wyl V., Gianella S., Fischer M., Niederoest B., Kuster H., Battegay M., Bernasconi E., Cavassini M., Rauch A., Hirschel B., et al. Early Antiretroviral Therapy During Primary HIV-1 Infection Results in a Transient Reduction of the Viral Setpoint upon Treatment Interruption. PLoS ONE. 2011;6:e27463. doi: 10.1371/journal.pone.0027463.
    1. Gianella S., von Wyl V., Fischer M., Niederoest B., Battegay M., Bernasconi E., Cavassini M., Rauch A., Hirschel B., Vernazza P., et al. Effect of early antiretroviral therapy during primary HIV-1 infection on cell-associated HIV-1 DNA and plasma HIV-1 RNA. Antivir. Ther. 2011;16:535–545. doi: 10.3851/IMP1776.
    1. Ananworanich J., Schuetz A., Vandergeeten C., Sereti I., De Souza M., Rerknimitr R., Dewar R., Marovich M., Van Griensven F., Sekaly R., et al. Impact of Multi-Targeted Antiretroviral Treatment on Gut T Cell Depletion and HIV Reservoir Seeding during Acute HIV Infection. PLoS ONE. 2012;7:e33948. doi: 10.1371/journal.pone.0033948.
    1. Thornhill J., Inshaw J., Kaleebu P., Cooper D., Ramjee G., Schechter M., Tambussi G., Fox J., Samuel M., Miro J.M., et al. Brief Report: Enhanced Normalization of CD4/CD8 Ratio with Earlier Antiretroviral Therapy at Primary HIV Infection. JAIDS J. Acquir. Immune Defic. Syndr. 2016;73:69–73. doi: 10.1097/QAI.0000000000001013.
    1. Wan C., Bachmann N., Mitov V., Blanquart F., Céspedes S.P., Turk T., Neumann K., Beerenwinkel N., Bogojeska J., Fellay J., et al. Heritability of the HIV-1 reservoir size and decay under long-term suppressive ART. Nat. Commun. 2020;11:1–11. doi: 10.1038/s41467-020-19198-7.
    1. Thorball C.W., Borghesi A., Bachmann N., Von Siebenthal C., Vongrad V., Turk T., Neumann K., Beerenwinkel N., Bogojeska J., Roth V., et al. Host Genomics of the HIV-1 Reservoir Size and Its Decay Rate During Suppressive Antiretroviral Treatment. JAIDS J. Acquir. Immune Defic. Syndr. 2020;85:517–524. doi: 10.1097/QAI.0000000000002473.
    1. Bachmann N., Von Siebenthal C., Vongrad V., Turk T., Neumann K., Beerenwinkel N., Bogojeska J., Fellay J., Roth V., The Swiss HIV Cohort Study et al. Determinants of HIV-1 reservoir size and long-term dynamics during suppressive ART. Nat. Commun. 2019;10:1–11. doi: 10.1038/s41467-019-10884-9.
    1. Anderson E.M., Simonetti F.R., Gorelick R.J., Hill S., Gouzoulis M.A., Bell J., Rehm C., Pérez L., Boritz E., Wu X., et al. Dynamic Shifts in the HIV Proviral Landscape During Long Term Combination Antiretroviral Therapy: Implications for Persistence and Control of HIV Infections. Viruses. 2020;12:136. doi: 10.3390/v12020136.
    1. Peluso M.J., Bacchetti P., Ritter K.D., Beg S., Lai J., Martin J.N., Hunt P.W., Henrich T.J., Siliciano J.D., Siliciano R.F., et al. Differential decay of intact and defective proviral DNA in HIV-1–infected individuals on suppressive antiretroviral therapy. JCI Insight. 2020;5:e13297. doi: 10.1172/jci.insight.132997.
    1. Maldarelli F. Targeting viral reservoirs: Ability of antiretroviral therapy to stop viral replication. Curr. Opin. HIV AIDS. 2011;6:49–56. doi: 10.1097/COH.0b013e32834134ea.
    1. Buzon M.J., Massanella M., Llibre J.M., Esteve A., Dahl V., Puertas M.C., Gatell J.M., Domingo P., Paredes R., Sharkey M., et al. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat. Med. 2010;16:460–465. doi: 10.1038/nm.2111.
    1. Thierry E., Deprez E., Delelis O. Different Pathways Leading to Integrase Inhibitors Resistance. Front. Microbiol. 2017;7:2165. doi: 10.3389/fmicb.2016.02165.
    1. Martinez-Picado J., Zurakowski R., Buzón M.J., Stevenson M. Episomal HIV-1 DNA and its relationship to other markers of HIV-1 persistence. Retrovirology. 2018;15:15. doi: 10.1186/s12977-018-0398-1.
    1. López-Huertas M.R., Gutiérrez C., Madrid-Elena N., Hernández-Novoa B., Olalla-Sierra J., Plana M., Delgado R., Rubio R., Muñoz-Fernández M., Moreno S. Prolonged administration of maraviroc reactivates latent HIV in vivo but it does not prevent antiretroviral-free viral rebound. Sci. Rep. 2020;10:1–13. doi: 10.1038/s41598-020-79002-w.
    1. Kityo C., Szubert A.J., Siika A., Heyderman R., Bwakura-Dangarembizi M., Lugemwa A., Mwaringa S., Griffiths A., Nkanya I., Kabahenda S., et al. Raltegravir-intensified initial antiretroviral therapy in advanced HIV disease in Africa: A randomised controlled trial. PLoS Med. 2018;15:e1002706. doi: 10.1371/journal.pmed.1002706.
    1. Chaillon A., Gianella S., Lada S.M., Perez-Santiago J., Jordan P., Ignacio C., Karris M., Richman D.D., Mehta S.R., Little S.J., et al. Size, Composition, and Evolution of HIV DNA Populations during Early Antiretroviral Therapy and Intensification with Maraviroc. J. Virol. 2018;92:e01589-17. doi: 10.1128/JVI.01589-17.
    1. Henrich T.J. Dolutegravir intensification and HIV persistence: 3 + 1 = 3. Lancet HIV. 2018;5:e201–e202. doi: 10.1016/S2352-3018(18)30064-X.
    1. Puertas M.C., Gómez-Mora E., Santos J.R., Molto J., Urrea V., Moron-Lopez S., Hernandez-Rodriguez A., Marfil S., Martínez-Bonet M., Matas L., et al. Impact of intensification with raltegravir on HIV-1-infected individuals receiving monotherapy with boosted PIs. J. Antimicrob. Chemother. 2018;73:1940–1948. doi: 10.1093/jac/dky106.
    1. Kim C.J., Rousseau R., Huibner S., Kovacs C., Benko E., Shahabi K., Kandel G., Ostrowski M., Kaul R. Impact of intensified antiretroviral therapy during early HIV infection on gut immunology and inflammatory blood biomarkers. AIDS. 2017;31:1529–1534. doi: 10.1097/QAD.0000000000001515.
    1. Wang X., Mink G., Lin D., Song X., Rong L. Influence of raltegravir intensification on viral load and 2-LTR dynamics in HIV patients on suppressive antiretroviral therapy. J. Theor. Biol. 2017;416:16–27. doi: 10.1016/j.jtbi.2016.12.015.
    1. Lafeuillade A., Assi A., Poggi C., Bresson-Cuquemelle C., Jullian E., Tamalet C. Failure of combined antiretroviral therapy intensification with maraviroc and raltegravir in chronically HIV-1 infected patients to reduce the viral reservoir: The IntensHIV randomized trial. AIDS Res. Ther. 2014;11:1–6. doi: 10.1186/1742-6405-11-33.
    1. Puertas M.C., Massanella M., Llibre J.M., Ballestero M., Buzon M.J., Ouchi D., Esteve A., Boix J., Manzardo C., Miró J.M., et al. Intensification of a raltegravir-based regimen with maraviroc in early HIV-1 infection. AIDS. 2014;28:325–334. doi: 10.1097/QAD.0000000000000066.
    1. Gutiérrez C., Hernández-Novoa B., Vallejo A., Serrano-Villar S., Abad-Fernández M., Madrid N., Díaz L., Moreno A., Dronda F., Zamora J., et al. Dynamics of the HIV-1 latent reservoir after discontinuation of the intensification of antiretroviral treatment: Results of two clinical trials. AIDS. 2013;27:2081–2088. doi: 10.1097/QAD.0b013e328361d0e1.
    1. Negredo E., Massanella M., Puertas M.C., Buzon M.J., Puig J., Pérez-Alvárez N., Pérez-Santiago J., Bonjoch A., Moltó J., Jou A., et al. Early but limited effects of raltegravir intensification on CD4 T cell reconstitution in HIV-infected patients with an immunodiscordant response to antiretroviral therapy. J. Antimicrob. Chemother. 2013;68:2358–2362. doi: 10.1093/jac/dkt183.
    1. Sharkey M. Tracking episomal HIV DNA: Implications for viral persistence and eradication of HIV. Curr. Opin. HIV AIDS. 2013;8:93–99. doi: 10.1097/COH.0b013e32835d08c2.
    1. Chege D., Kovacs C., La Porte C., Ostrowski M., Raboud J., Su D., Kandel G., Brunetta J., Kim C.J., Sheth P.M., et al. Effect of raltegravir intensification on HIV proviral DNA in the blood and gut mucosa of men on long-term therapy: A randomized controlled trial. AIDS. 2012;26:167–174. doi: 10.1097/QAD.0b013e32834e8955.
    1. Hatano H., Scherzer R., Wu Y., Harvill K., Maka K., Hoh R., Sinclair E., Palmer S., Martin J.N., Busch M.P., et al. A Randomized Controlled Trial Assessing the Effects of Raltegravir Intensification on Endothelial Function in Treated HIV Infection. JAIDS J. Acquir. Immune Defic. Syndr. 2012;61:317–325. doi: 10.1097/QAI.0b013e31826e7d0f.
    1. Llibre J.M., Buzón M.J., Massanella M., Esteve A., Dahl V., Puertas M.C., Domingo P., Gatell J.M., Larrouse M., Gutierrez M., et al. Treatment intensification with raltegravir in subjects with sustained HIV-1 viraemia suppression: A randomized 48-week study. Antivir. Ther. 2011;17:355–364. doi: 10.3851/IMP1917.
    1. Buzon M.J., Codoñer F.M., Frost S.D.W., Pou C., Puertas M.C., Massanella M., Dalmau J., Llibre J.M., Stevenson M., Blanco J., et al. Deep Molecular Characterization of HIV-1 Dynamics under Suppressive HAART. PLoS Pathog. 2011;7:e1002314. doi: 10.1371/journal.ppat.1002314.
    1. Dahl V., Lee E., Peterson J., Spudich S.S., Leppla I., Sinclair E., Fuchs D., Palmer S., Price R.W. Raltegravir Treatment Intensification Does Not Alter Cerebrospinal Fluid HIV-1 Infection or Immunoactivation in Subjects on Suppressive Therapy. J. Infect. Dis. 2011;204:1936–1945. doi: 10.1093/infdis/jir667.
    1. Archin N.M., Cheema M., Parker D., Wiegand A., Bosch R.J., Coffin J.M., Eron J., Cohen M., Margolis D.M. Antiretroviral Intensification and Valproic Acid Lack Sustained Effect on Residual HIV-1 Viremia or Resting CD4+ Cell Infection. PLoS ONE. 2010;5:e9390. doi: 10.1371/journal.pone.0009390.
    1. McMahon D., Jones J., Wiegand A., Gange S., Kearney M., Palmer S., McNulty S., Metcalf J.A., Acosta E., Rehm C., et al. Short-Course Raltegravir Intensification Does Not Reduce Persistent Low-Level Viremia in Patients with HIV-1 Suppression during Receipt of Combination Antiretroviral Therapy. Clin. Infect. Dis. 2010;50:912–919. doi: 10.1086/650749.
    1. Yilmaz A., Verhofstede C., D’Avolio A., Watson V., Hagberg L., Fuchs D., Svennerholm B., Gisslén M. Treatment Intensification Has no Effect on the HIV-1 Central Nervous System Infection in Patients on Suppressive Antiretroviral Therapy. JAIDS J. Acquir. Immune Defic. Syndr. 2010;55:590–596. doi: 10.1097/QAI.0b013e3181f5b3d1.
    1. Dinoso J.B., Kim S.Y., Wiegand A.M., Palmer S.E., Gange S., Cranmer L., O’Shea A., Callender M., Spivak A., Brennan T., et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc. Natl. Acad. Sci. USA. 2009;106:9403–9408. doi: 10.1073/pnas.0903107106.
    1. Havlir D.V., Strain M.C., Clerici M., Ignacio C., Trabattoni D., Ferrante P., Wong J.K. Productive Infection Maintains a Dynamic Steady State of Residual Viremia in Human Immunodeficiency Virus Type 1-Infected Persons Treated with Suppressive Antiretroviral Therapy for Five Years. J. Virol. 2003;77:11212–11219. doi: 10.1128/JVI.77.20.11212-11219.2003.
    1. Ait- ar A., Kula A., Darcis G., Verdikt R., De Wit S., Gautier V., Mallon P.W.G., Marcello A., Rohr O., Van Lint C. Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs. Front. Microbiol. 2020;10:3060. doi: 10.3389/fmicb.2019.03060.
    1. Sgarbanti M., Battistini A. Therapeutics for HIV-1 reactivation from latency. Curr. Opin. Virol. 2013;3:394–401. doi: 10.1016/j.coviro.2013.06.001.
    1. Mok H.P., Lever A. Waking Up the Sleepers: HIV Latency and Reactivation. J. Formos. Med Assoc. 2008;107:909–914. doi: 10.1016/S0929-6646(09)60013-9.
    1. Dahl V., Josefsson L., Palmer S. HIV reservoirs, latency, and reactivation: Prospects for eradication. Antivir. Res. 2010;85:286–294. doi: 10.1016/j.antiviral.2009.09.016.
    1. Gulick R.M. Structured Treatment Interruption in Patients Infected with HIV: A new approach to therapy. Drugs. 2002;62:245–253. doi: 10.2165/00003495-200262020-00001.
    1. Davey R.T., Bhat N., Yoder C., Chun T.-W., Metcalf J.A., Dewar R., Natarajan V., Lempicki R., Adelsberger J.W., Miller K.D., et al. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc. Natl. Acad. Sci. USA. 1999;96:15109–15114. doi: 10.1073/pnas.96.26.15109.
    1. Martin G.E., Frater J. Post-treatment and spontaneous HIV control. Curr. Opin. HIV AIDS. 2018;13:402–407. doi: 10.1097/COH.0000000000000488.
    1. Joos B., Fischer M., Kuster H., Pillai S.K., Wong J.K., Böni J., Hirschel B., Weber R., Trkola A., Günthard H.F., et al. HIV rebounds from latently infected cells, rather than from continuing low-level replication. Proc. Natl. Acad. Sci. USA. 2008;105:16725–16730. doi: 10.1073/pnas.0804192105.
    1. Rothenberger M.K., Keele B.F., Wietgrefe S.W., Fletcher C.V., Beilman G., Chipman J., Khoruts A., Estes J.D., Anderson J., Callisto S.P., et al. Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption. Proc. Natl. Acad. Sci. USA. 2015;112:E1126–E1134. doi: 10.1073/pnas.1414926112.
    1. Bednar M.M., Hauser B., Zhou S., Jacobson J.M., Eron J.J., Frank I., Swanstrom R. Diversity and Tropism of HIV-1 Rebound Virus Populations in Plasma Level After Treatment Discontinuation. J. Infect. Dis. 2016;214:403–407. doi: 10.1093/infdis/jiw172.
    1. Vibholm L.K., Lorenzi J.C.C., Pai J.A., Cohen Y.Z., Oliveira T., Barton J.P., Noceda M.G., Lu C.-L., Ablanedo-Terrazas Y., Estrada P.M.D.R., et al. Characterization of Intact Proviruses in Blood and Lymph Node from HIV-Infected Individuals Undergoing Analytical Treatment Interruption. J. Virol. 2019;93:e01920-18. doi: 10.1128/JVI.01920-18.
    1. De Scheerder M.-A., Vrancken B., Dellicour S., Schlub T., Lee E., Shao W., Rutsaert S., Verhofstede C., Kerre T., Malfait T., et al. HIV Rebound Is Predominantly Fueled by Genetically Identical Viral Expansions from Diverse Reservoirs. Cell Host Microbe. 2019;26:347–358.e7. doi: 10.1016/j.chom.2019.08.003.
    1. Kearney M.F., Wiegand A., Shao W., Coffin J.M., Mellors J.W., Lederman M., Gandhi R.T., Keele B.F., Li J.Z. Origin of Rebound Plasma HIV Includes Cells with Identical Proviruses That Are Transcriptionally Active before Stopping of Antiretroviral Therapy. J. Virol. 2016;90:1369–1376. doi: 10.1128/JVI.02139-15.
    1. Fehér C., Leal L., Plana M., Climent N., Guardo A.C., Martínez E., Castro P., Díaz-Brito V., Mothe B., De Quirós J.C.L.B., et al. Virological Outcome Measures During Analytical Treatment Interruptions in Chronic HIV-1-Infected Patients. Open Forum Infect. Dis. 2019;6:ofz485. doi: 10.1093/ofid/ofz485.
    1. Fajnzylber J., Sharaf R., Hutchinson J.N., Aga E., Bosch R.J., Hartogensis W., Jacobson J.M., Connick E., Volberding P., Skiest D.J., et al. Frequency of Post Treatment Control Varies by ART Restart and Viral Load Criteria. AIDS. 2021;35:2225–2227. doi: 10.1097/QAD.0000000000002978.
    1. Li J.Z., Etemad B., Ahmed H., Aga E., Bosch R.J., Mellors J.W., Kuritzkes D.R., Lederman M.M., Para M., Gandhi R.T. The size of the expressed HIV reservoir predicts timing of viral rebound after treatment interruption. AIDS. 2015;30:343–353. doi: 10.1097/QAD.0000000000000953.
    1. Bar K.J., Sneller M.C., Harrison L.J., Justement J.S., Overton E.T., Petrone M.E., Salantes D.B., Seamon C.A., Scheinfeld B., Kwan R.W., et al. Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption. N. Engl. J. Med. 2016;375:2037–2050. doi: 10.1056/NEJMoa1608243.
    1. Li J.Z., Aga E., Bosch R.J., Pilkinton M., Kroon E., MacLaren L., Keefer M., Fox L., Barr L., Acosta E., et al. Time to Viral Rebound After Interruption of Modern Antiretroviral Therapies. Clin. Infect. Dis. 2021:ciab541. doi: 10.1093/cid/ciab541.
    1. Clarridge K.E., Blazkova J., Einkauf K., Petrone M., Refsland E.W., Justement J.S., Shi V., Huiting E.D., Seamon C.A., Lee G.Q., et al. Effect of analytical treatment interruption and reinitiation of antiretroviral therapy on HIV reservoirs and immunologic parameters in infected individuals. PLoS Pathog. 2018;14:e1006792. doi: 10.1371/journal.ppat.1006792.
    1. Liu R., Simonetti F.R., Ho Y.-C. The forces driving clonal expansion of the HIV-1 latent reservoir. Virol. J. 2020;17:1–13. doi: 10.1186/s12985-019-1276-8.
    1. Buzon M.J., Martin-Gayo E., Pereyra F., Ouyang Z., Sun H., Li J.Z., Piovoso M., Shaw A., Dalmau J., Zangger N., et al. Long-Term Antiretroviral Treatment Initiated at Primary HIV-1 Infection Affects the Size, Composition, and Decay Kinetics of the Reservoir of HIV-1-Infected CD4 T Cells. J. Virol. 2014;88:10056–10065. doi: 10.1128/JVI.01046-14.
    1. Garcia-Broncano P., Maddali S., Einkauf K.B., Jiang C., Gao C., Chevalier J., Chowdhury F.Z., Maswabi K., Ajibola G., Moyo S., et al. Early antiretroviral therapy in neonates with HIV-1 infection restricts viral reservoir size and induces a distinct innate immune profile. Sci. Transl. Med. 2019;11:eaax7350. doi: 10.1126/scitranslmed.aax7350.
    1. Woldemeskel B.A., Kwaa A.K., Blankson J.N. Viral reservoirs in elite controllers of HIV-1 infection: Implications for HIV cure strategies. EBioMedicine. 2020;62:103118. doi: 10.1016/j.ebiom.2020.103118.
    1. Besson G.J., Lalama C.M., Bosch R.J., Gandhi R.T., Bedison M.A., Aga E., Riddler S.A., McMahon D.K., Hong F., Mellors J.W. HIV-1 DNA Decay Dynamics in Blood During More Than a Decade of Suppressive Antiretroviral Therapy. Clin. Infect. Dis. 2014;59:1312–1321. doi: 10.1093/cid/ciu585.
    1. Vider-Shalit T., Almani M., Sarid R., Louzoun Y. The HIV hide and seek game: An immunogenomic analysis of the HIV epitope repertoire. AIDS. 2009;23:1311–1318. doi: 10.1097/QAD.0b013e32832c492a.
    1. Garcia-Bates T.M., Palma M.L., Anderko R.R., Hsu D.C., Ananworanich J., Korber B.T., Gaiha G.D., Phanuphak N., Thomas R., Tovanabutra S., et al. Dendritic cells focus CTL responses toward highly conserved and topologically important HIV-1 epitopes. EBioMedicine. 2021;63:103175. doi: 10.1016/j.ebiom.2020.103175.
    1. Murakoshi H., Zou C., Kuse N., Akahoshi T., Chikata T., Gatanaga H., Oka S., Hanke T., Takiguchi M. CD8+ T cells specific for conserved, cross-reactive Gag epitopes with strong ability to suppress HIV-1 replication. Retrovirology. 2018;15:1–14. doi: 10.1186/s12977-018-0429-y.
    1. Graf E.H., Pace M., Peterson B.A., Lynch L.J., Chukwulebe S.B., Mexas A.M., Shaheen F., Martin J.N., Deeks S.G., Connors M., et al. Gag-Positive Reservoir Cells Are Susceptible to HIV-Specific Cytotoxic T Lymphocyte Mediated Clearance In Vitro and Can Be Detected In Vivo. PLoS ONE. 2013;8:e71879. doi: 10.1371/annotation/3aa92c3d-b6dd-4c6e-8cee-9587ce80a9c9.
    1. Coffin J.M., Wells D.W., Zerbato J.M., Kuruc J.D., Guo S., Luke B.T., Eron J.J., Bale M., Spindler J., Simonetti F.R., et al. Clones of infected cells arise early in HIV-infected individuals. JCI Insight. 2019;4:e128432. doi: 10.1172/jci.insight.128432.
    1. Hughes S.H., Coffin J.M. What Integration Sites Tell Us about HIV Persistence. Cell Host Microbe. 2016;19:588–598. doi: 10.1016/j.chom.2016.04.010.
    1. Chomont N., El-Far M., Ancuta P., Trautmann L., Procopio A.F., Yassine-Diab B., Boucher G., Boulassel M.-R., Ghattas G., Brenchley J.M., et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat. Med. 2009;15:893–900. doi: 10.1038/nm.1972.
    1. Wang Z., Gurule E.E., Brennan T.P., Gerold J.M., Kwon K.J., Hosmane N.N., Kumar M., Beg S.A., Capoferri A.A., Ray S.C., et al. Expanded cellular clones carrying replication-competent HIV-1 persist, wax, and wane. Proc. Natl. Acad. Sci. USA. 2018;115:E2575–E2584. doi: 10.1073/pnas.1720665115.
    1. Simonetti F.R., Zhang H., Soroosh G.P., Duan J., Rhodehouse K., Hill A.L., Beg S.A., McCormick K., Raymond H.E., Nobles C.L., et al. Antigen-driven clonal selection shapes the persistence of HIV-1–infected CD4+ T cells in vivo. J. Clin. Investig. 2021;131:e145254. doi: 10.1172/JCI145254.
    1. Mendoza P., Jackson J.R., Oliveira T.Y., Gaebler C., Ramos V., Caskey M., Jankovic M., Nussenzweig M.C., Cohn L.B. Antigen-responsive CD4+ T cell clones contribute to the HIV-1 latent reservoir. J. Exp. Med. 2020;217:e20200051. doi: 10.1084/jem.20200051.
    1. Ferdin J., Goričar K., Dolžan V., Plemenitaš A., Martin J.N., Peterlin B.M., Deeks S., Lenassi M. Viral protein Nef is detected in plasma of half of HIV-infected adults with undetectable plasma HIV RNA. PLoS ONE. 2018;13:e0191613. doi: 10.1371/journal.pone.0191613.
    1. Imamichi H., Smith M., Adelsberger J.W., Izumi T., Scrimieri F., Sherman B.T., Rehm C.A., Imamichi T., Pau A., Catalfamo M., et al. Defective HIV-1 proviruses produce viral proteins. Proc. Natl. Acad. Sci. USA. 2020;117:3704–3710. doi: 10.1073/pnas.1917876117.
    1. Grund B., Baker J.V., Deeks S., Wolfson J., Wentworth D., Cozzi-Lepri A., Cohen C.J., Phillips A., Lundgren J.D., Neaton J.D., et al. Relevance of Interleukin-6 and D-Dimer for Serious Non-AIDS Morbidity and Death among HIV-Positive Adults on Suppressive Antiretroviral Therapy. PLoS ONE. 2016;11:e0155100. doi: 10.1371/journal.pone.0155100.
    1. Sandler N.G., Wand H., Roque A., Law M., Nason M.C., Nixon D.E., Pedersen C., Ruxrungtham K., Lewin S.R., Emery S., et al. Plasma Levels of Soluble CD14 Independently Predict Mortality in HIV Infection. J. Infect. Dis. 2011;203:780–790. doi: 10.1093/infdis/jiq118.
    1. Nasi M., De Biasi S., Gibellini L., Bianchini E., Pecorini S., Bacca V., Guaraldi G., Mussini C., Pinti M., Cossarizza A. Ageing and inflammation in patients with HIV infection. Clin. Exp. Immunol. 2016;187:44–52. doi: 10.1111/cei.12814.
    1. Marconi V.C., Moser C., Gavegnano C., Deeks S.G., Lederman M.M., Overton E.T., Tsibris A., Hunt P.W., Kantor A., Sekaly R.-P., et al. Randomized Trial of Ruxolitinib in Antiretroviral-Treated Adults with HIV. Clin. Infect. Dis. 2021:ciab212. doi: 10.1093/cid/ciab212.
    1. Adan M., Lau C.-Y., Dewar R., Higgins J., Rehm C., Ganesan A., McMahon D., Anderson E., Maldarelli F. Role of Host Immune Activation in Enrichment in Proportion of Deleted Proviruses During ART; Proceedings of the Retroviruses at Cold Spring Harbor Laboratory; Laurel Hollow, NY, USA. 22–27 May 2017.
    1. Katlama C., Lambert-Niclot S., Assoumou L., Papagno L., Lecardonnel F., Zoorob R., Tambussi G., Clotet B., Youle M., Achenbach C., et al. Treatment intensification followed by interleukin-7 reactivates HIV without reducing total HIV DNA: A randomized trial. AIDS. 2016;30:221–230. doi: 10.1097/QAD.0000000000000894.
    1. Vandergeeten C., Fromentin R., DaFonseca S., Lawani M.B., Sereti I., Lederman M.M., Ramgopal M., Routy J.-P., Sékaly R.-P., Chomont N. Interleukin-7 promotes HIV persistence during antiretroviral therapy. Blood. 2013;121:4321–4329. doi: 10.1182/blood-2012-11-465625.
    1. Boyman O., Purton J.F., Surh C.D., Sprent J. Cytokines and T-cell homeostasis. Curr. Opin. Immunol. 2007;19:320–326. doi: 10.1016/j.coi.2007.04.015.
    1. Bosque A., Famiglietti M., Weyrich A.S., Goulston C., Planelles V. Homeostatic Proliferation Fails to Efficiently Reactivate HIV-1 Latently Infected Central Memory CD4+ T Cells. PLoS Pathog. 2011;7:e1002288. doi: 10.1371/journal.ppat.1002288.
    1. Bosinger S.E., Sodora D.L., Silvestri G. Generalized immune activation and innate immune responses in simian immunodeficiency virus infection. Curr. Opin. HIV AIDS. 2011;6:411–418. doi: 10.1097/COH.0b013e3283499cf6.
    1. Klatt N.R., Chomont N., Douek D.C., Deeks S.G. Immune activation and HIV persistence: Implications for curative approaches to HIV infection. Immunol. Rev. 2013;254:326–342. doi: 10.1111/imr.12065.
    1. Bushman F.D. Retroviral Insertional Mutagenesis in Humans: Evidence for Four Genetic Mechanisms Promoting Expansion of Cell Clones. Mol. Ther. 2020;28:352–356. doi: 10.1016/j.ymthe.2019.12.009.
    1. Stevenson E.M., Ward A.R., Truong R., Thomas A.S., Huang S.-H., Dilling T.R., Terry S., Bui J.K., Mota T.M., Danesh A., et al. HIV-specific T cell responses reflect substantive in vivo interactions with antigen despite long-term therapy. JCI Insight. 2021;6:e142640. doi: 10.1172/jci.insight.142640.
    1. Zaunders J., Munier C.M.L., McGuire H.M., Law H., Howe A., Xu Y., Groth B.F.D.S., Schofield P., Christ D., Milner B., et al. Mapping the extent of heterogeneity of human CCR5+ CD4+ T cells in peripheral blood and lymph nodes. AIDS. 2020;34:833–848. doi: 10.1097/QAD.0000000000002503.
    1. Leong Y.A., Atnerkar A., Yu D. Human Immunodeficiency Virus Playing Hide-and-Seek: Understanding the TFH Cell Reservoir and Proposing Strategies to Overcome the Follicle Sanctuary. Front. Immunol. 2017;8:622. doi: 10.3389/fimmu.2017.00622.
    1. Woodham A.W., Skeate J.G., Sanna A.M., Taylor J.R., Da Silva D.M., Cannon P.M., Kast W.M. Human Immunodeficiency Virus Immune Cell Receptors, Coreceptors, and Cofactors: Implications for Prevention and Treatment. AIDS Patient Care STDs. 2016;30:291–306. doi: 10.1089/apc.2016.0100.
    1. Koppensteiner H., Brack-Werner R., Schindler M. Macrophages and their relevance in Human Immunodeficiency Virus Type I infection. Retrovirology. 2012;9:1–11. doi: 10.1186/1742-4690-9-82.
    1. Koppensteiner H., Banning C., Schneider C., Hohenberg H., Schindler M. Macrophage Internal HIV-1 Is Protected from Neutralizing Antibodies. J. Virol. 2011;86:2826–2836. doi: 10.1128/JVI.05915-11.
    1. Martin-Gayo E., Yu X.G. Role of Dendritic Cells in Natural Immune Control of HIV-1 Infection. Front. Immunol. 2019;10:1306. doi: 10.3389/fimmu.2019.01306.
    1. Preza G.C., Tanner K., Elliott J., Yang O.O., Anton P.A., Ochoa M.-T. Antigen-Presenting Cell Candidates for HIV-1 Transmission in Human Distal Colonic Mucosa Defined by CD207 Dendritic Cells and CD209 Macrophages. AIDS Res. Hum. Retroviruses. 2014;30:241–249. doi: 10.1089/aid.2013.0145.
    1. De Witte L., Nabatov A., Pion M., Fluitsma D., Jong M.A.W.P.D., De Gruijl T., Piguet V., Van Kooyk Y., Geijtenbeek T.B.H. Langerin is a natural barrier to HIV-1 transmission by Langerhans cells. Nat. Med. 2007;13:367–371. doi: 10.1038/nm1541.
    1. West H.C., Bennett C.L. Redefining the Role of Langerhans Cells as Immune Regulators within the Skin. Front. Immunol. 2018;8:1941. doi: 10.3389/fimmu.2017.01941.
    1. Mayr L., Su B., Moog C. Langerhans Cells: The ‘Yin and Yang’ of HIV Restriction and Transmission. Trends Microbiol. 2017;25:170–172. doi: 10.1016/j.tim.2017.01.009.
    1. Ribeiro C.M., Sarrami-Forooshani R., Geijtenbeek T.B. HIV-1 border patrols: Langerhans cells control antiviral responses and viral transmission. Futur. Virol. 2015;10:1231–1243. doi: 10.2217/fvl.15.79.
    1. Wacleche V.S., Tremblay C.L., Routy J.-P., Ancuta P. The Biology of Monocytes and Dendritic Cells: Contribution to HIV Pathogenesis. Viruses. 2018;10:65. doi: 10.3390/v10020065.
    1. Cavrois M., Neidleman J., Kreisberg J., Greene W.C. In Vitro Derived Dendritic Cells trans-Infect CD4 T Cells Primarily with Surface-Bound HIV-1 Virions. PLoS Pathog. 2007;3:e4. doi: 10.1371/journal.ppat.0030004.
    1. Rappocciolo G., Sluis-Cremer N., Rinaldo C.R. Open Forum Infectious Diseases. Oxford University Press; Oxford, UK: 2019. Efficient HIV-1 Trans Infection of CD4+ T Cells Occurs in the Presence of Antiretroviral Therapy; p. ofz253.
    1. Wu L., KewalRamani V.N. Dendritic-cell interactions with HIV: Infection and viral dissemination. Nat. Rev. Immunol. 2006;6:859–868. doi: 10.1038/nri1960.
    1. Jiang A.-P., Jiang J.-F., Guo M.-G., Jin Y.-M., Li Y.-Y., Wang J.-H. Human Blood-Circulating Basophils Capture HIV-1 and Mediate Viral trans -Infection of CD4 + T Cells. J. Virol. 2015;89:8050–8062. doi: 10.1128/JVI.01021-15.
    1. Jiang A.-P., Jiang J.-F., Wei J.-F., Guo M.-G., Qin Y., Guo Q.-Q., Ma L., Liu B.-C., Wang X., Veazey R.S., et al. Human Mucosal Mast Cells Capture HIV-1 and Mediate Viral trans -Infection of CD4 + T Cells. J. Virol. 2016;90:2928–2937. doi: 10.1128/JVI.03008-15.
    1. DeLucia D.C., Rinaldo C.R., Rappocciolo G. Inefficient HIV-1 trans Infection of CD4 + T Cells by Macrophages from HIV-1 Nonprogressors Is Associated with Altered Membrane Cholesterol and DC-SIGN. J. Virol. 2018;92:e00092-18. doi: 10.1128/JVI.00092-18.
    1. Castellano P., Prevedel L., Eugenin E.A. HIV-infected macrophages and microglia that survive acute infection become viral reservoirs by a mechanism involving Bim. Sci. Rep. 2017;7:1–16. doi: 10.1038/s41598-017-12758-w.
    1. Herskovitz J., Gendelman H.E. HIV and the Macrophage: From Cell Reservoirs to Drug Delivery to Viral Eradication. J. Neuroimmune Pharmacol. 2018;14:52–67. doi: 10.1007/s11481-018-9785-6.
    1. Hertoghs N., Nijmeijer B.M., Van Teijlingen N.H., Fenton-May A.E., Kaptein T.M., Van Hamme J.L., Kappes J.C., Kootstra N.A., Hahn B.H., Borrow P., et al. Sexually transmitted founder HIV-1 viruses are relatively resistant to Langerhans cell-mediated restriction. PLoS ONE. 2019;14:e0226651. doi: 10.1371/journal.pone.0226651.
    1. Wong J.K., Yukl S.A. Tissue reservoirs of HIV. Curr Opin HIV AIDS. 2016;11:362–370. doi: 10.1097/COH.0000000000000293.
    1. Chaillon A., Gianella S., Dellicour S., Rawlings S.A., Schlub T.E., de Oliveira M.F., Ignacio C., Porrachia M., Vrancken B., Smith D.M. HIV persists throughout deep tissues with repopulation from multiple anatomical sources. J. Clin. Investig. 2020;130:1699–1712. doi: 10.1172/JCI134815.
    1. Spudich S., González-Scarano F. HIV-1-Related Central Nervous System Disease: Current Issues in Pathogenesis, Diagnosis, and Treatment. Cold Spring Harb. Perspect. Med. 2012;2:a007120. doi: 10.1101/cshperspect.a007120.
    1. Dahl V., Peterson J., Spudich S., Lee E., Shacklett B.L., Price R.W., Palmer S. Single-copy assay quantification of HIV-1 RNA in paired cerebrospinal fluid and plasma samples from elite controllers. AIDS. 2013;27:1145–1149. doi: 10.1097/QAD.0b013e32835cf235.
    1. Winston A., Antinori A., Cinque P., Fox H.S., Gisslen M., Henrich T.J., Letendre S., Persaud D., Price R.W., Spudich S. Defining cerebrospinal fluid HIV RNA escape. AIDS. 2019;33:S107–S111. doi: 10.1097/QAD.0000000000002252.
    1. Joseph S.B., Kincer L.P., Bowman N.M., Evans C., Vinikoor M.J., Lippincott C.K., Gisslén M., Spudich S., Menezes P., Robertson K., et al. Human Immunodeficiency Virus Type 1 RNA Detected in the Central Nervous System (CNS) After Years of Suppressive Antiretroviral Therapy Can Originate from a Replicating CNS Reservoir or Clonally Expanded Cells. Clin. Infect. Dis. 2018;69:1345–1352. doi: 10.1093/cid/ciy1066.
    1. Joseph S.B., Arrildt K.T., Sturdevant C.B., Swanstrom R. HIV-1 target cells in the CNS. J. Neurovirol. 2014;21:276–289. doi: 10.1007/s13365-014-0287-x.
    1. Schnell G., Joseph S., Spudich S., Price R.W., Swanstrom R. HIV-1 Replication in the Central Nervous System Occurs in Two Distinct Cell Types. PLoS Pathog. 2011;7:e1002286. doi: 10.1371/journal.ppat.1002286.
    1. Sturdevant C.B., Joseph S.B., Schnell G., Price R.W., Swanstrom R., Spudich S. Compartmentalized Replication of R5 T Cell-Tropic HIV-1 in the Central Nervous System Early in the Course of Infection. PLoS Pathog. 2015;11:e1004720. doi: 10.1371/journal.ppat.1004720.
    1. Lutgen V., Narasipura S.D., Barbian H.J., Richards M., Wallace J., Razmpour R., Buzhdygan T., Ramirez S., Prevedel L., Eugenin E.A., et al. HIV infects astrocytes in vivo and egresses from the brain to the periphery. PLoS Pathog. 2020;16:e1008381. doi: 10.1371/journal.ppat.1008381.
    1. Maldarelli F. The gift of a lifetime: Analysis of HIV at autopsy. J. Clin. Investig. 2020;130:1611–1614. doi: 10.1172/JCI135905.
    1. Eggers C., Arendt G., Hahn K., Husstedt I.W., Maschke M., Neuen-Jacob E., Obermann M., Rosenkranz T., Schielke E., For the German Association of Neuro-AIDS und Neuro-Infectiology (DGNANI) et al. HIV-1-associated neurocognitive disorder: Epidemiology, pathogenesis, diagnosis, and treatment. J. Neurol. 2017;264:1715–1727. doi: 10.1007/s00415-017-8503-2.
    1. Hellmuth J., Valcour V., Spudich S. CNS reservoirs for HIV: Implications for eradication. J. Virus Erad. 2015;1:67–71. doi: 10.1016/S2055-6640(20)30489-1.
    1. Henderson L.J., Johnson T.P., Smith B.R., Reoma L., Santamaria U.A., Bachani M., DeMarino C., Barclay R.A., Snow J., Sacktor N., et al. Presence of Tat and transactivation response element in spinal fluid despite antiretroviral therapy. AIDS. 2019;33:S145–S157. doi: 10.1097/qad.0000000000002268.
    1. Marino J., Maubert M.E., Mele A.R., Spector C., Wigdahl B., Nonnemacher M.R. Functional impact of HIV-1 Tat on cells of the CNS and its role in HAND. Cell. Mol. Life Sci. 2020;77:5079–5099. doi: 10.1007/s00018-020-03561-4.
    1. Marino J., Wigdahl B., Nonnemacher M.R. Extracellular HIV-1 Tat Mediates Increased Glutamate in the CNS Leading to Onset of Senescence and Progression of HAND. Front. Aging Neurosci. 2020;12:168. doi: 10.3389/fnagi.2020.00168.
    1. Cowley D., Gray L.R., Wesselingh S.L., Gorry P.R., Churchill M.J. Genetic and functional heterogeneity of CNS-derived tat alleles from patients with HIV-associated dementia. J. NeuroVirology. 2010;17:70–81. doi: 10.1007/s13365-010-0002-5.
    1. Kearney M.F., Wiegand A., Shao W., McManus W., Bale M., Luke B., Maldarelli F., Mellors J.W., Coffin J.M. Ongoing HIV Replication During ART Reconsidered. Open Forum Infect. Dis. 2017;4:ofx173. doi: 10.1093/ofid/ofx173.
    1. Boritz E.A., Darko S., Swaszek L., Wolf G., Wells D., Wu X., Henry A.R., Laboune F., Hu J., Ambrozak D., et al. Multiple Origins of Virus Persistence during Natural Control of HIV Infection. Cell. 2016;166:1004–1015. doi: 10.1016/j.cell.2016.06.039.
    1. Guadalupe M., Reay E., Sankaran S., Prindiville T., Flamm J., McNeil A., Dandekar S. Severe CD4 + T-Cell Depletion in Gut Lymphoid Tissue during Primary Human Immunodeficiency Virus Type 1 Infection and Substantial Delay in Restoration following Highly Active Antiretroviral Therapy. J. Virol. 2003;77:11708–11717. doi: 10.1128/JVI.77.21.11708-11717.2003.
    1. Brenchley J.M., Douek D.C. HIV infection and the gastrointestinal immune system. Mucosal Immunol. 2007;1:23–30. doi: 10.1038/mi.2007.1.
    1. Macal M., Sankaran S., Chun T.-W., Reay E., Flamm J., Prindiville T.J., Dandekar S. Effective CD4+ T-cell restoration in gut-associated lymphoid tissue of HIV-infected patients is associated with enhanced Th17 cells and polyfunctional HIV-specific T-cell responses. Mucosal Immunol. 2008;1:475–488. doi: 10.1038/mi.2008.35.
    1. Imamichi H., DeGray G., Dewar R.L., Mannon P., Yao M., Chairez C., Sereti I., Kovacs J.A. Lack of Compartmentalization of HIV-1 Quasispecies Between the Gut and Peripheral Blood Compartments. J. Infect. Dis. 2011;204:309–314. doi: 10.1093/infdis/jir259.
    1. Moron-Lopez S., Puertas M.C., Gálvez C., Navarro J., Carrasco A., Esteve M., Manyé J., Crespo M., Salgado M., Martinez-Picado J. Sensitive quantification of the HIV-1 reservoir in gut-associated lymphoid tissue. PLoS ONE. 2017;12:e0175899. doi: 10.1371/journal.pone.0175899.
    1. Bull M.E., McKernan J.L., Styrchak S., Kraft K., Hitti J., Cohn S.E., Tapia K., Deng W., Holte S., Mullins J.I., et al. Phylogenetic Analyses Comparing HIV Sequences from Plasma at Virologic Failure to Cervix Versus Blood Sequences from Antecedent Antiretroviral Therapy Suppression. AIDS Res. Hum. Retroviruses. 2019;35:557–566. doi: 10.1089/aid.2018.0211.
    1. Mabvakure B.M., Lambson B.E., Ramdayal K., Masson L., Kitchin D., Allam M., Karim S.A., Williamson C., Passmore J.-A., Martin D.P., et al. Evidence for both Intermittent and Persistent Compartmentalization of HIV-1 in the Female Genital Tract. J. Virol. 2019;93:e00311-19. doi: 10.1128/JVI.00311-19.
    1. Bull M., Learn G., Genowati I., McKernan J., Hitti J., Lockhart D., Tapia K., Holte S., Dragavon J., Coombs R., et al. Compartmentalization of HIV-1 within the Female Genital Tract Is Due to Monotypic and Low-Diversity Variants Not Distinct Viral Populations. PLoS ONE. 2009;4:e7122. doi: 10.1371/journal.pone.0007122.
    1. Klein K., Nickel G., Nankya I., Kyeyune F., Demers K., Ndashimye E., Kwok C., Chen P.-L., Rwambuya S., Poon A., et al. Higher sequence diversity in the vaginal tract than in blood at early HIV-1 infection. PLoS Pathog. 2018;14:e1006754. doi: 10.1371/journal.ppat.1006754.
    1. Kariuki S.M., Selhorst P., Anthony C., Matten D., Abrahams M.-R., Martin D.P., Ariën K.K., Rebe K., Williamson C., Dorfman J.R. Compartmentalization and Clonal Amplification of HIV-1 in the Male Genital Tract Characterized Using Next-Generation Sequencing. J. Virol. 2020;94:e00229-20. doi: 10.1128/JVI.00229-20.
    1. Kovacs A., Wasserman S.S., Burns D., Wright D.J., Cohn J., Landay A., Weber K., Cohen M., Levine A., Minkoff H., et al. Determinants of HIV-1 shedding in the genital tract of women. Lancet. 2001;358:1593–1601. doi: 10.1016/S0140-6736(01)06653-3.
    1. Zaikos T.D., Terry V.H., Kettinger N.T.S., Lubow J., Painter M.M., Virgilio M., Neevel A., Taschuk F., Onafuwa-Nuga A., McNamara L.A., et al. Hematopoietic Stem and Progenitor Cells Are a Distinct HIV Reservoir that Contributes to Persistent Viremia in Suppressed Patients. Cell Rep. 2018;25:3759–3773. doi: 10.1016/j.celrep.2018.11.104.
    1. McNamara L., Collins K.L. Hematopoietic stem/precursor cells as HIV reservoirs. Curr. Opin. HIV AIDS. 2011;6:43–48. doi: 10.1097/COH.0b013e32834086b3.
    1. Sebastian N.T., Zaikos T.D., Terry V., Taschuk F., McNamara L.A., Onafuwa-Nuga A., Yucha R., Signer R.A.J., Iv J.R., Bixby D., et al. CD4 is expressed on a heterogeneous subset of hematopoietic progenitors, which persistently harbor CXCR4 and CCR5-tropic HIV proviral genomes in vivo. PLoS Pathog. 2017;13:e1006509. doi: 10.1371/journal.ppat.1006509.
    1. Durand C.M., Ghiaur G., Siliciano J.D., Rabi S.A., Eisele E.E., Salgado M., Shan L., Lai J.F., Zhang H., Margolick J., et al. HIV-1 DNA Is Detected in Bone Marrow Populations Containing CD4+ T Cells but Is not Found in Purified CD34+ Hematopoietic Progenitor Cells in Most Patients on Antiretroviral Therapy. J. Infect. Dis. 2012;205:1014–1018. doi: 10.1093/infdis/jir884.
    1. Alexaki A., Wigdahl B. HIV-1 Infection of Bone Marrow Hematopoietic Progenitor Cells and Their Role in Trafficking and Viral Dissemination. PLoS Pathog. 2008;4:e1000215. doi: 10.1371/journal.ppat.1000215.
    1. Henrich T.J., Beckford-Vera D., Martinez-Ortiz E., Aslam M., Thanh C., Kumar S., Wu I.-W., Hoh R., Flavell R., Seo Y., et al. Whole-body PET imaging of the HIV reservoir using radiolabeled VRC01; Proceedings of the Conference on Retroviruses and Opportunistic Infections; Boston, MA, USA. 8–11 March 2020.
    1. Aamer H.A., McClure J., Ko D., Maenza J., Collier A.C., Coombs R.W., Mullins J.I., Frenkel L.M. Cells producing residual viremia during antiretroviral treatment appear to contribute to rebound viremia following interruption of treatment. PLoS Pathog. 2020;16:e1008791. doi: 10.1371/journal.ppat.1008791.
    1. Thomas J., Ruggiero A., Paxton W.A., Pollakis G. Measuring the Success of HIV-1 Cure Strategies. Front. Cell. Infect. Microbiol. 2020;10:134. doi: 10.3389/fcimb.2020.00134.
    1. Shan L., Deng K., Shroff N.S., Durand C.M., Rabi S.A., Yang H.-C., Zhang H., Margolick J.B., Blankson J.N., Siliciano R.F. Stimulation of HIV-1-Specific Cytolytic T Lymphocytes Facilitates Elimination of Latent Viral Reservoir after Virus Reactivation. Immunity. 2012;36:491–501. doi: 10.1016/j.immuni.2012.01.014.
    1. Maina E.K., Adan A.A., Mureithi H., Muriuki J., Lwembe R.M. A Review of Current Strategies Towards the Elimination of Latent HIV-1 and Subsequent HIV-1 Cure. Curr. HIV Res. 2021;19:14–26. doi: 10.2174/1570162X18999200819172009.
    1. McBrien J.B., Mavigner M., Franchitti L., Smith S.A., White E., Tharp G.K., Walum H., Busman-Sahay K., Aguilera-Sandoval C.R., Thayer W.O., et al. Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells. Nature. 2020;578:154–159. doi: 10.1038/s41586-020-1946-0.
    1. Nixon C.C., Mavigner M., Sampey G.C., Brooks A.D., Spagnuolo R.A., Irlbeck D.M., Mattingly C., Ho P.T., Schoof N., Cammon C.G., et al. Systemic HIV and SIV latency reversal via non-canonical NF-κB signalling in vivo. Nature. 2020;578:160–165. doi: 10.1038/s41586-020-1951-3.
    1. Abner E., Jordan A. HIV "shock and kill" therapy: In need of revision. Antiviral Res. 2019;166:19–34. doi: 10.1016/j.antiviral.2019.03.008.
    1. Lichterfeld M. Reactivation of latent HIV moves shock-and-kill treatments forward. Nature. 2020;578:42–43. doi: 10.1038/d41586-020-00010-x.
    1. Clutton G.T., Jones R.B. Diverse Impacts of HIV Latency-Reversing Agents on CD8+ T-Cell Function: Implications for HIV Cure. Front. Immunol. 2018;9:1452. doi: 10.3389/fimmu.2018.01452.
    1. Zhao M., De Crignis E., Rokx C., Verbon A., van Gelder T., Mahmoudi T., Katsikis P.D., Mueller Y.M. T cell toxicity of HIV latency reversing agents. Pharmacol. Res. 2018;139:524–534. doi: 10.1016/j.phrs.2018.10.023.
    1. Subramanian S., Bates S.E., Wright J.J., Espinoza-Delgado I., Piekarz R.L. Clinical Toxicities of Histone Deacetylase Inhibitors. Pharmaceuticals. 2010;3:2751–2767. doi: 10.3390/ph3092751.
    1. Jones R.B., O’Connor R., Mueller S., Foley M.H., Szeto G., Karel D., Lichterfeld M., Kovacs C., Ostrowski M.A., Trocha A., et al. Histone Deacetylase Inhibitors Impair the Elimination of HIV-Infected Cells by Cytotoxic T-Lymphocytes. PLoS Pathog. 2014;10:e1004287. doi: 10.1371/journal.ppat.1004287.
    1. Kim Y., Anderson J.L., Lewin S.R. Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV. Cell Host Microbe. 2018;23:14–26. doi: 10.1016/j.chom.2017.12.004.
    1. Sarabia I., Bosque A. HIV-1 Latency and Latency Reversal: Does Subtype Matter? Viruses. 2019;11:1104. doi: 10.3390/v11121104.
    1. Cullen H., Schorn A.J. Endogenous Retroviruses Walk a Fine Line between Priming and Silencing. Viruses. 2020;12:792. doi: 10.3390/v12080792.
    1. Ahlenstiel C.L., Symonds G., Kent S.J., Kelleher A.D. Block and Lock HIV Cure Strategies to Control the Latent Reservoir. Front. Cell. Infect. Microbiol. 2020;10:424. doi: 10.3389/fcimb.2020.00424.
    1. Christ F., Voet A., Marchand A., Nicolet S., Desimmie B., Marchand D., Bardiot D., Van Der Veken N.J., Van Remoortel B., Strelkov S.V., et al. Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nat. Chem. Biol. 2010;6:442–448. doi: 10.1038/nchembio.370.
    1. Debyser Z., VanSant G., Bruggemans A., Janssens J., Christ F. Insight in HIV Integration Site Selection Provides a Block-and-Lock Strategy for a Functional Cure of HIV Infection. Viruses. 2018;11:12. doi: 10.3390/v11010012.
    1. Orphanides G., LeRoy G., Chang C.-H., Luse D.S., Reinberg D. FACT, a Factor that Facilitates Transcript Elongation through Nucleosomes. Cell. 1998;92:105–116. doi: 10.1016/S0092-8674(00)80903-4.
    1. Chang H.-W., Valieva M.E., Safina A., Chereji R.V., Wang J., Kulaeva O.I., Morozov A.V., Kirpichnikov M.P., Feofanov A.V., Gurova K.V., et al. Mechanism of FACT removal from transcribed genes by anticancer drugs curaxins. Sci. Adv. 2018;4:eaav2131. doi: 10.1126/sciadv.aav2131.
    1. Joshi P., Stoddart C.A. Impaired Infectivity of Ritonavir-resistant HIV Is Rescued by Heat Shock Protein 90AB1. J. Biol. Chem. 2011;286:24581–24592. doi: 10.1074/jbc.M111.248021.
    1. Gavegnano C., Detorio M., Montero C., Bosque A., Planelles V., Schinazi R.F. Ruxolitinib and Tofacitinib Are Potent and Selective Inhibitors of HIV-1 Replication and Virus Reactivation In Vitro. Antimicrob. Agents Chemother. 2014;58:1977–1986. doi: 10.1128/AAC.02496-13.
    1. Noël N., Jacquelin B., Huot N., Goujard C., Lambotte O., Müller-Trutwin M. Interferon-associated therapies toward HIV control: The back and forth. Cytokine Growth Factor Rev. 2018;40:99–112. doi: 10.1016/j.cytogfr.2018.03.004.
    1. Utay N.S., Douek D.C. Interferons and HIV Infection: The Good, the Bad, and the Ugly. Pathog. Immun. 2016;1:107–116. doi: 10.20411/pai.v1i1.125.
    1. Papasavvas E., Azzoni L., Kossenkov A.V., Dawany N., Morales K.H., Fair M., Ross B.N., Lynn K., Mackiewicz A., Mounzer K., et al. NK Response Correlates with HIV Decrease in Pegylated IFN-α2a–Treated Antiretroviral Therapy–Suppressed Subjects. J. Immunol. 2019;203:705–717. doi: 10.4049/jimmunol.1801511.
    1. Azzoni L., Foulkes A.S., Papasavvas E., Mexas A.M., Lynn K.M., Mounzer K., Tebas P., Jacobson J.M., Frank I., Busch M.P., et al. Pegylated Interferon Alfa-2a Monotherapy Results in Suppression of HIV Type 1 Replication and Decreased Cell-Associated HIV DNA Integration. J. Infect. Dis. 2012;207:213–222. doi: 10.1093/infdis/jis663.
    1. Papasavvas E., Azzoni L., Pagliuzza M.A., Abdel-Mohsen M., Ross B.N., Fair M., Howell B.J., Hazuda D.J., Chomont N., Li Q., et al. Safety, Immune, and Antiviral Effects of Pegylated Interferon Alpha 2b Administration in Antiretroviral Therapy-Suppressed Individuals: Results of Pilot Clinical Trial. AIDS Res. Hum. Retroviruses. 2021;37:433–443. doi: 10.1089/aid.2020.0243.
    1. Rivero-Juárez A., Frias M., Rivero A. Current views on interferon therapy for HIV. Expert Opin. Biol. Ther. 2016;16:1135–1142. doi: 10.1080/14712598.2016.1196180.
    1. Liu Y., Cao W., Sun M., Li T. Broadly neutralizing antibodies for HIV-1: Efficacies, challenges and opportunities. Emerg. Microbes Infect. 2020;9:194–206. doi: 10.1080/22221751.2020.1713707.
    1. Nishimura Y., Martin M.A. Of Mice, Macaques, and Men: Broadly Neutralizing Antibody Immunotherapy for HIV-1. Cell Host Microbe. 2017;22:207–216. doi: 10.1016/j.chom.2017.07.010.
    1. Das A.T., Binda C.S., Berkhout B. Elimination of infectious HIV DNA by CRISPR–Cas9. Curr. Opin. Virol. 2019;38:81–88. doi: 10.1016/j.coviro.2019.07.001.
    1. Nerys-Junior A., Braga-Dias L.P., Pezzuto P., Cotta-de-Almeida V., Tanuri A. Comparison of the editing patterns and editing efficiencies of TALEN and CRISPR-Cas9 when targeting the human CCR5 gene. Genet. Mol. Biol. 2018;41:167–179. doi: 10.1590/1678-4685-gmb-2017-0065.
    1. Tebas P., Jadlowsky J.K., Shaw P.A., Tian L., Esparza E., Brennan A.L., Kim S., Naing S.Y., Richardson M.W., Vogel A.N., et al. CCR5-edited CD4+ T cells augment HIV-specific immunity to enable post-rebound control of HIV replication. J. Clin. Investig. 2021;131:e144486. doi: 10.1172/JCI144486.
    1. Sullivan N.T., Allen A.G., Atkins A.J., Chung C.H., Dampier W., Nonnemacher M.R., Wigdahl B. Designing Safer CRISPR/Cas9 Therapeutics for HIV: Defining Factors That Regulate and Technologies Used to Detect Off-Target Editing. Front. Microbiol. 2020;11:1872. doi: 10.3389/fmicb.2020.01872.
    1. Jilg N., Li J.Z. On the Road to a HIV Cure: Moving Beyond Berlin and London. Infect. Dis. Clin. North Am. 2019;33:857–868. doi: 10.1016/j.idc.2019.04.007.
    1. Lopalco L. CCR5: From Natural Resistance to a New Anti-HIV Strategy. Viruses. 2010;2:574–600. doi: 10.3390/v2020574.
    1. Chalmet K., Van Wanzeele F., Demecheleer E., Dauwe K., Pelgrom J., Van Der Gucht B., Vogelaers D., Plum J., Stuyver L., Vandekerckhove L., et al. Impact of Δ32-CCR5 heterozygosity on HIV-1 genetic evolution and variability—A study of 4 individuals infected with closely related HIV-1 strains. Virology. 2008;379:213–222. doi: 10.1016/j.virol.2008.06.036.
    1. Hütter G., Nowak D., Mossner M., Ganepola S., Müssig A., Allers K., Schneider T., Hofmann J., Kücherer C., Blau O., et al. Long-Term Control of HIV byCCR5Delta32/Delta32 Stem-Cell Transplantation. N. Engl. J. Med. 2009;360:692–698. doi: 10.1056/NEJMoa0802905.
    1. Hütter G., Thiel E. Allogeneic transplantation of CCR5-deficient progenitor cells in a patient with HIV infection: An update after 3 years and the search for patient no. 2. AIDS. 2011;25:273–274. doi: 10.1097/QAD.0b013e328340fe28.
    1. Gupta R., Peppa D., Hill A.L., Gálvez C., Salgado M., Pace M., McCoy E.L., Griffith A.S., Thornhill J., Alrubayyi A., et al. Evidence for HIV-1 cure after CCR5Δ32/Δ32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: A case report. Lancet HIV. 2020;7:e340–e347. doi: 10.1016/S2352-3018(20)30069-2.
    1. Gupta R.K., Abdul-Jawad S., McCoy L.E., Mok H.P., Peppa D., Salgado M., Martinez-Picado J., Nijhuis M., Wensing A.M.J., Lee H., et al. HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation. Nature. 2019;568:244–248. doi: 10.1038/s41586-019-1027-4.
    1. Marban C., Forouzanfar F., Ait-Ammar A., Fahmi F., El Mekdad H., Daouad F., Rohr O., Schwartz C. Targeting the Brain Reservoirs: Toward an HIV Cure. Front. Immunol. 2016;7:397. doi: 10.3389/fimmu.2016.00397.
    1. Migueles A.S., Connors M. Success and failure of the cellular immune response against HIV-1. Nat. Immunol. 2015;16:563–570. doi: 10.1038/ni.3161.
    1. Etemad B., Esmaeilzadeh E., Li J.Z. Learning from the Exceptions: HIV Remission in Post-treatment Controllers. Front. Immunol. 2019;10:1749. doi: 10.3389/fimmu.2019.01749.
    1. Gonzalo-Gil E., Ikediobi U., Sutton R.E. Mechanisms of Virologic Control and Clinical Characteristics of HIV+ Elite/Viremic Controllers. Yale J. Boil. Med. 2017;90:245–259.
    1. Uruena A., Cassetti I., Kashyap N., Deleage C., Estes J.D., Trindade C., Hammoud A.D., Burbelo P.D., Natarajan V., Dewar R., et al. Prolonged Posttreatment Virologic Control and Complete Seroreversion After Advanced Human Immunodeficiency Virus-1 Infection. Open Forum Infect. Dis. 2020;8:ofaa613. doi: 10.1093/ofid/ofaa613.

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