[en] PURPOSE OF REVIEW: Despite suppressive antiretroviral therapy (ART), HIV-1 reservoirs persist and reignite viral replication if therapy is interrupted. Persistence of the viral reservoir in people with HIV-1 (PWH) is the main obstacle to an HIV-1 cure. The reservoirs are not transcriptionally silent, and viral transcripts can be detected in most ART-treated individuals. Here, we review the recent progress in the characterization of persistent HIV-1 transcription during ART.
RECENT FINDINGS: Evidence from several studies indicates that, although cell-associated unspliced (US) HIV-1 RNA is abundantly expressed in ART-treated PWH, intact full-length US transcripts are rare and most US RNA is derived from defective proviruses. The transcription- and translation-competent defective proviruses, previously considered irrelevant, are increasingly being linked to residual HIV-1 pathogenesis under suppressive ART. Recent data suggest a continuous crosstalk between the residual HIV-1 activity under ART and the immune system. Persistent HIV-1 transcription on ART, despite being mostly derived from defective proviruses, predicts viral rebound upon therapy interruption, suggesting its role as an indicator of the strength of the host antiviral immune response that is shaping the viral rebound.
SUMMARY: In light of the recent findings, the significance of persistent HIV-1 transcription during ART for the long-term health of PWH and the cure research should be reassessed.
Disciplines :
Immunology & infectious disease
Author, co-author :
Fombellida-Lopez, Céline ; Université de Liège - ULiège > Département des sciences cliniques ; Laboratory of Experimental Virology, Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
Berkhout, Ben; Laboratory of Experimental Virology, Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
Darcis, Gilles ; Université de Liège - ULiège > Département des sciences cliniques
Pasternak, Alexander O; Laboratory of Experimental Virology, Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
Language :
English
Title :
Persistent HIV-1 transcription during ART: time to reassess its significance?
Publication date :
07 March 2024
Journal title :
Current Opinion in HIV and AIDS
ISSN :
1746-630X
Publisher :
Ovid Technologies (Wolters Kluwer Health), United States
Deeks SG, Lewin SR, Havlir DV,. The end of AIDS: HIV infection as a chronic disease. Lancet 2013; 382: 1525-1533.
Trickey A, Sabin CA, Burkholder G,. Life expectancy after 2015 of adults with HIV on long-term antiretroviral therapy in Europe and North America: a collaborative analysis of cohort studies. Lancet HIV 2023; 10: e295-e307.
Darcis G, Berkhout B, Pasternak AO,. The quest for cellular markers of HIV reservoirs: any color you like. Front Immunol 2019; 10: 2251.
Veenhuis RT, Abreu CM, Costa PAG,. Monocyte-derived macrophages contain persistent latent HIV reservoirs. Nat Microbiol 2023; 8: 833-844.
Ganor Y, Real F, Sennepin A,. HIV-1 reservoirs in urethral macrophages of patients under suppressive antiretroviral therapy. Nat Microbiol 2019; 4: 633-644.
Siliciano JD, Kajdas J, Finzi D,. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+T cells. Nat Med 2003; 9: 727-728.
Crooks AM, Bateson R, Cope AB,. Precise quantitation of the latent HIV-1 reservoir: implications for eradication strategies. J Infect Dis 2015; 212: 1361-1365.
Chomont N, El-Far M, Ancuta P,. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med 2009; 15: 893-900.
Maldarelli F, Wu X, Su L,. HIV latency. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science 2014; 345: 179-183.
Wagner TA, McLaughlin S, Garg K,. HIV latency. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection. Science 2014; 345: 570-573.
Bailey JR, Sedaghat AR, Kieffer T,. Residual human immunodeficiency virus type 1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in circulating CD4+T cells. J Virol 2006; 80: 6441-6457.
Simonetti FR, Sobolewski MD, Fyne E,. Clonally expanded CD4+T cells can produce infectious HIV-1 in vivo. Proc Natl Acad Sci USA 2016; 113: 1883-1888.
Lorenzo-Redondo R, Fryer HR, Bedford T,. Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature 2016; 530: 51-56.
Pasternak AO, Vroom J, Kootstra NA,. Nonnucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy is associated with lower cell-associated HIV RNA and DNA levels as compared with therapy based on protease inhibitors. Elife 2021; 10: e68174.
Martinez-Picado J, Deeks SG,. Persistent HIV-1 replication during antiretroviral therapy. Curr Opin HIV AIDS 2016; 11: 417-423.
Cohn LB, Chomont N, Deeks SG,. The biology of the HIV-1 latent reservoir and implications for cure strategies. Cell Host Microbe 2020; 27: 519-530.
Dufour C, Gantner P, Fromentin R, Chomont N,. The multifaceted nature of HIV latency. J Clin Invest 2020; 130: 3381-3390.
Margolis DM, Archin NM, Cohen MS,. Curing HIV: seeking to target and clear persistent infection. Cell 2020; 181: 189-206.
Rausch JW, Parvez S, Pathak S,. HIV expression in infected T cell clones. Viruses 2024; 16: 108.
Pasternak AO, Berkhout B,. What do we measure when we measure cell-associated HIV RNA. Retrovirology 2018; 15: 13.
Pasternak AO, Berkhout B,. HIV persistence: silence or resistance? Curr Opin Virol 2023; 59: 101301.
Astorga-Gamaza A, Buzon MJ,. The active human immunodeficiency virus reservoir during antiretroviral therapy: emerging players in viral persistence. Curr Opin HIV AIDS 2021; 16: 193-199.
Lichterfeld M, Gao C, Yu XG,. An ordeal that does not heal: understanding barriers to a cure for HIV-1 infection. Trends Immunol 2022; 43: 608-616.
Collora JA, Ho YC,. The loud minority: transcriptionally active HIV-1-infected cells survive, proliferate, and persist. Cell 2022; 185: 227-229.
Lewin SR, Vesanen M, Kostrikis L,. Use of real-time PCR and molecular beacons to detect virus replication in human immunodeficiency virus type 1-infected individuals on prolonged effective antiretroviral therapy. J Virol 1999; 73: 6099-6103.
Fischer M, Wong JK, Russenberger D,. Residual cell-associated unspliced HIV-1 RNA in peripheral blood of patients on potent antiretroviral therapy represents intracellular transcripts. Antivir Ther 2002; 7: 91-103.
Kaiser P, Joos B, Niederost B,. Productive human immunodeficiency virus type 1 infection in peripheral blood predominantly takes place in CD4/CD8 double-negative T lymphocytes. J Virol 2007; 81: 9693-9706.
Pasternak AO, Jurriaans S, Bakker M,. Cellular levels of HIV unspliced RNA from patients on combination antiretroviral therapy with undetectable plasma viremia predict the therapy outcome. PLoS One 2009; 4: e8490.
Pasternak AO, de Bruin M, Jurriaans S,. Modest nonadherence to antiretroviral therapy promotes residual HIV-1 replication in the absence of virological rebound in plasma. J Infect Dis 2012; 206: 1443-1452.
Wiegand A, Spindler J, Hong FF,. 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.
McManus WR, Bale MJ, Spindler J,. HIV-1 in lymph nodes is maintained by cellular proliferation during antiretroviral therapy. J Clin Invest 2019; 129: 4629-4642.
Einkauf KB, Osborn MR, Gao C,. Parallel analysis of transcription, integration, and sequence of single HIV-1 proviruses. Cell 2022; 185: 266-282. e15. A pioneering study that assessed in parallel a number of virological parameters, including proviral genetic intactness, chromatin context of the integration site, and transcriptional activity at the single-proviral level. This study strongly suggests that transcriptionally active proviruses are selected against during prolonged ART and that large clones of infected cells may outcompete negative selection forces through elevated intrinsic proliferative activity.
Dubé M, Tastet O, Dufour C,. Spontaneous HIV expression during suppressive ART is associated with the magnitude and function of HIV-specific CD4+and CD8+T cells. Cell Host Microbe 2023; 31: 1507-1522. e5. This study identified phenotypically diverse HIV-infected cells that spontaneously express viral RNA, and occasionally protein, during ART. Despite carrying defective proviruses, active reservoirs correlated with HIV-specific CD4+ and CD8+ T-cell responses. These results suggest that ongoing viral gene expression maintains HIV-specific immune responses during suppressive ART.
Purcell DF, Martin MA,. Alternative splicing of human immunodeficiency virus type 1 mRNA modulates viral protein expression, replication, and infectivity. J Virol 1993; 67: 6365-6378.
Ocwieja KE, Sherrill-Mix S, Mukherjee R,. Dynamic regulation of HIV-1 mRNA populations analyzed by single-molecule enrichment and long-read sequencing. Nucleic Acids Res 2012; 40: 10345-10355.
Emery A, Swanstrom R,. HIV-1: to splice or not to splice, that is the question. Viruses 2021; 13: 181.
Sertznig H, Hillebrand F, Erkelenz S,. Behind the scenes of HIV-1 replication: alternative splicing as the dependency factor on the quiet. Virology 2018; 516: 176-188.
Kim SY, Byrn R, Groopman J, Baltimore D,. Temporal aspects of DNA and RNA synthesis during human immunodeficiency virus infection: evidence for differential gene expression. J Virol 1989; 63: 3708-3713.
Karn J, Stoltzfus CM,. Transcriptional and posttranscriptional regulation of HIV-1 gene expression. Cold Spring Harb Perspect Med 2012; 2: a006916.
Malim MH, Cullen BR,. HIV-1 structural gene expression requires the binding of multiple Rev monomers to the viral RRE: implications for HIV-1 latency. Cell 1991; 65: 241-248.
Malim MH, Hauber J, Le SY,. The HIV-1 rev trans-activator acts through a structured target sequence to activate nuclear export of unspliced viral mRNA. Nature 1989; 338: 254-257.
Yukl SA, Kaiser P, Kim P,. HIV latency in isolated patient CD4+ T cells may be due to blocks in HIV transcriptional elongation, completion, and splicing. Sci Transl Med 2018; 10: eaa9927.
Fischer M, Joos B, Wong JK,. Attenuated and nonproductive viral transcription in the lymphatic tissue of HIV-1-infected patients receiving potent antiretroviral therapy. J Infect Dis 2004; 189: 273-285.
Scherpenisse M, Kootstra NA, Bakker M,. Cell-associated HIV-1 unspliced-to-multiply-spliced RNA ratio at 12 weeks of ART predicts immune reconstitution on therapy. mBio 2021; 12:e00099-21. This study demonstrated that persistent HIV-1 transcription during ART correlates with markers of immune activation, exhaustion, and apoptosis, and identified an HIV-1 marker that outperformed more than 50 host and viral markers in the prediction of the immunological response to ART.
Pasternak AO, Jurriaans S, Bakker M,. Steady increase in cellular HIV-1 load during the asymptomatic phase of untreated infection despite stable plasma viremia. AIDS 2010; 24: 1641-1649.
Gao H, Ozantürk AN, Wang Q,. Evaluation of HIV-1 latency reversal and antibody-dependent viral clearance by quantification of singly spliced HIV-1 vpu/env mRNA. J Virol 2021; 95:e02124-20.
Schmid A, Gianella S, von Wyl V,. Profound depletion of HIV-1 transcription in patients initiating antiretroviral therapy during acute infection. PLoS One 2010; 5: e13310.
Vesanen M, Markowitz M, Cao Y,. Human immunodeficiency virus type-1 mRNA splicing pattern in infected persons is determined by the proportion of newly infected cells. Virology 1997; 236: 104-109.
Uprety P, Chadwick EG, Rainwater-Lovett K,. Cell-associated HIV-1 DNA and RNA decay dynamics during early combination antiretroviral therapy in HIV-1-infected infants. Clin Infect Dis 2015; 61: 1862-1870.
Telwatte S, Lee S, Somsouk M,. Gut and blood differ in constitutive blocks to HIV transcription, suggesting tissue-specific differences in the mechanisms that govern HIV latency. PLoS Pathog 2018; 14: e1007357.
Kamieniarz-Gdula K, Proudfoot NJ,. Transcriptional control by premature termination: a forgotten mechanism. Trends Genet 2019; 35: 553-64.
Noe Gonzalez M, Blears D, Svejstrup JQ,. Causes and consequences of RNA polymerase II stalling during transcript elongation. Nat Rev Mol Cell Biol 2021; 22: 3-21.
Ho YC, Shan L, Hosmane NN,. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 2013; 155: 540-51.
Bruner KM, Murray AJ, Pollack RA,. Defective proviruses rapidly accumulate during acute HIV-1 infection. Nat Med 2016; 22: 1043-9.
Hiener B, Horsburgh BA, Eden JS,. Identification of genetically intact HIV-1 proviruses in specific CD4(+) T cells from effectively treated participants. Cell Rep 2017; 21: 813-22.
Pinzone MR, VanBelzen DJ, Weissman S,. Longitudinal HIV sequencing reveals reservoir expression leading to decay which is obscured by clonal expansion. Nat Commun 2019; 10: 728.
Martin HA, Kadiyala GN, Telwatte S,. New assay reveals vast excess of defective over intact HIV-1 transcripts in antiretroviral therapy-suppressed individuals. J Virol 2022; 96: e0160522. This study developed a new assay that can distinguish and quantify intact as well as defective HIV-1 RNA. In ART-treated PWH, they found that the vast majority of all HIV-1 cell-associated unspliced RNA is defective, due to the scarcity of the intact proviruses combined with incomplete HIV-1 transcriptional processivity.
Singh K, Natarajan V, Dewar R,. Long-term persistence of transcriptionally-active "defective" HIV-1 proviruses: Implications for persistent immune activation during antiretroviral therapy. AIDS 2023; 37: 2119-2130. By performing near-full-length single-genome sequencing of HIV-1 DNA and cell-associated unspliced RNA in peripheral blood of a combined cohort of ART-treated PWH, the authors found that an overwhelming majority of CA HIV RNA transcripts were derived from defective proviruses. Despite this, they found a strong association between CA US and the western blot score, as well as with the CD8+T-cell count.
Imamichi H, Smith M, Adelsberger JW,. Defective HIV-1 proviruses produce viral proteins. Proc Natl Acad Sci USA 2020; 117: 3704-10.
Imamichi H, Dewar RL, Adelsberger JW,. 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: 8783-8.
Bruner KM, Wang Z, Simonetti FR,. A quantitative approach for measuring the reservoir of latent HIV-1 proviruses. Nature 2019; 566: 120-5.
Scrimieri F, Bastian E, Smith M,. Transcriptionally-active "defective" HIV-1 proviruses and their association with immunological nonresponse to antiretroviral therapy. J Infect Dis 2024; jiae009. This study found an association between the US RNA copy number and the immunological nonresponse.
White JA, Kufera JT, Bachmann N,. Measuring the latent reservoir for HIV-1: quantification bias in near full-length genome sequencing methods. PLoS Pathog 2022; 18: e1010845.
Tumpach C, Rhodes A, Kim Y,. Adaptation of droplet digital PCR-based HIV transcription profiling to digital PCR and association of HIV transcription and total or intact HIV DNA. Viruses 2023; 15: 1606.
Pasternak AO, Berkhout B,. The splice of life: does RNA processing have a role in HIV-1 persistence? Viruses 2021; 13: 1751.
Massanella M, Yek C, Lada SM,. Improved assays to measure and characterize the inducible HIV reservoir. EBioMedicine 2018; 36: 113-121.
Zerbato JM, Khoury G, Zhao W,. Multiply spliced HIV RNA is a predictive measure of virus production ex vivo and in vivo following reversal of HIV latency. EBioMedicine 2021; 65: 103241.
Zicari S, Sessa L, Cotugno N,. Immune activation, inflammation, and non-AIDS co-morbidities in HIV-infected patients under long-term ART. Viruses 2019; 11: E200.
Pasternak AO, Tsukamoto T, Berkhout B,. 'Zombie' proviruses in the spotlight: exploring the dark side of HIV persistence. AIDS 2023; 37: 2239-41.
Kuniholm J, Coote C, Henderson AJ,. Defective HIV-1 genomes and their potential impact on HIV pathogenesis. Retrovirology 2022; 19: 13.
Hatano H, Jain V, Hunt PW,. Cell-based measures of viral persistence are associated with immune activation and programmed cell death protein 1 (PD-1)-expressing CD4+T cells. J Infect Dis 2013; 208: 50-56.
Gandhi RT, McMahon DK, Bosch RJ,. Levels of HIV-1 persistence on antiretroviral therapy are not associated with markers of inflammation or activation. PLoS Pathog 2017; 13: e1006285.
Olson A, Coote C, Snyder-Cappione JE,. HIV-1 transcription but not intact provirus levels are associated with systemic inflammation. J Infect Dis 2021; 223: 1934-1942.
Pacheco YM, Jarrin I, Rosado I,. Increased risk of non-AIDS-related events in HIV subjects with persistent low CD4 counts despite cART in the CoRIS cohort. Antiviral Res 2015; 117: 69-74.
van Lelyveld SF, Gras L, Kesselring A,. Long-term complications in patients with poor immunological recovery despite virological successful HAART in Dutch ATHENA cohort. AIDS 2012; 26: 465-474.
Lapadula G, Cozzi-Lepri A, Marchetti G,. Risk of clinical progression among patients with immunological nonresponse despite virological suppression after combination antiretroviral treatment. AIDS 2013; 27: 769-779.
Pollack RA, Jones RB, Pertea M,. 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.
Takata H, Mitchell JL, Pacheco J,. An active HIV reservoir during ART is associated with maintenance of HIV-specific CD8+ T cell magnitude and short-lived differentiation status. Cell Host Microbe 2023; 31: 1494-1506. e4. This study found that the residual antigen expression by the active HIV-1 reservoir during suppressive ART correlated with increased HIV-specific CD8+ T-cell magnitude but prevented differentiation into functional cells.
Lian X, Seiger KW, Parsons EM,. Progressive transformation of the HIV-1 reservoir cell profile over two decades of antiviral therapy. Cell Host Microbe 2023; 31: 83-96. e5. This study found that following two decades of continuous ART, the integration site profile of intact HIV-1 proviruses is heavily biased toward heterochromatin locations, likely as a result of immune selection mechanisms; such proviruses are less transcriptionally active and possibly, less rebound competent.
Jiang C, Lian X, Gao C,. Distinct viral reservoirs in individuals with spontaneous control of HIV-1. Nature 2020; 585: 261-267.
Stevenson EM, Ward AR, Truong R,. HIV-specific T cell responses reflect substantive in vivo interactions with antigen despite long-term therapy. JCI Insight 2021; 6: e142640.
Peluso MJ, Bacchetti P, Ritter KD,. Differential decay of intact and defective proviral DNA in HIV-1-infected individuals on suppressive antiretroviral therapy. JCI Insight 2020; 5: e132997.
Falcinelli SD, Kilpatrick KW, Read J,. Longitudinal dynamics of intact HIV proviral DNA and outgrowth virus frequencies in a cohort of ART-treated individuals. J Infect Dis 2021; 224: 92-100.
Gandhi RT, Cyktor JC, Bosch RJ,. Selective decay of intact HIV-1 proviral DNA on antiretroviral therapy. J Infect Dis 2021; 223: 225-233.
Halvas EK, Joseph KW, Brandt LD,. HIV-1 viremia not suppressible by antiretroviral therapy can originate from large T cell clones producing infectious virus. J Clin Invest 2020; 130: 5847-5857.
White JA, Wu F, Yasin S,. Clonally expanded HIV-1 proviruses with 5'-leader defects can give rise to nonsuppressible residual viremia. J Clin Invest 2023; 133: e165245.
Ren Y, Huang SH, Patel S,. BCL-2 antagonism sensitizes cytotoxic T cell-resistant HIV reservoirs to elimination ex vivo. J Clin Invest 2020; 130: 2542-2559.
Huang SH, Ren Y, Thomas AS,. Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+T cells. J Clin Invest 2018; 128: 876-889.
Astorga-Gamaza A, Grau-Expósito J, Burgos J,. Identification of HIV-reservoir cells with reduced susceptibility to antibody-dependent immune response. Elife 2022; 11: e78294. This study demonstrates that HIV-infected cells expressing CD32 have reduced susceptibility to natural killer cell-mediated ADCC, suggesting a possible mechanism behind the previously observed high enrichment for HIV DNA in CD32+ cells.
Duette G, Hiener B, Morgan H,. The HIV-1 proviral landscape reveals that Nef contributes to HIV-1 persistence in effector memory CD4+T cells. J Clin Invest 2022; 132: e154422. This study provides evidence that intact HIV proviruses persisting in effector memory CD4+ T cells may be better protected from the host immune surveillance than in other maturation subsets, which might be associated with superior Nef-mediated MHC-I downregulation in the effector memory cells relative to less mature CD4+ T-cell populations.
Klatt NR, Chomont N, Douek DC, Deeks SG,. Immune activation and HIV persistence: implications for curative approaches to HIV infection. Immunol Rev 2013; 254: 326-342.
Massanella M, Fromentin R, Chomont N,. Residual inflammation and viral reservoirs: alliance against an HIV cure. Curr Opin HIV AIDS 2016; 11: 234-241.
Etemad B, Esmaeilzadeh E, Li JZ,. Learning from the exceptions: HIV remission in posttreatment controllers. Front Immunol 2019; 10: 1749.
Giron LB, Abdel-Mohsen M,. Viral and host biomarkers of HIV remission post treatment interruption. Curr HIV/AIDS Rep 2022; 19: 217-233.
Adams P, Berkhout B, Pasternak AO,. Towards a molecular profile of antiretroviral therapy-free HIV remission. Curr Opin HIV AIDS 2022; 17: 301-307.
Pasternak AO, Psomas CK, Berkhout B,. Predicting posttreatment HIV remission: does size of the viral reservoir matter? Front Microbiol 2021; 12: 648434.
Li JZ, Etemad B, Ahmed H,. The size of the expressed HIV reservoir predicts timing of viral rebound after treatment interruption. AIDS 2016; 30: 343-353.
Sneller MC, Justement JS, Gittens KR,. A randomized controlled safety/efficacy trial of therapeutic vaccination in HIV-infected individuals who initiated antiretroviral therapy early in infection. Sci Transl Med 2017; 9: eaan8848.
Pasternak AO, Grijsen ML, Wit FW,. Cell-associated HIV-1 RNA predicts viral rebound and disease progression after discontinuation of temporary early ART. JCI Insight 2020; 5: e134196.
Giron LB, Palmer CS, Liu Q,. Noninvasive plasma glycomic and metabolic biomarkers of posttreatment control of HIV. Nat Commun 2021; 12: 3922.
Bartsch YC, Loos C, Rossignol E,. Viral rebound kinetics correlate with distinct HIV antibody features. mBio 2021; 12: e00170-221.
Wedrychowski A, Martin HA, Li Y,. Transcriptomic signatures of human immunodeficiency virus post-treatment control. J Virol 2023; 97: e0125422. This study provides new insights into how HIV-1 transcription changes after ART interruption in both noncontrollers and posttreatment controllers.
Einkauf KB, Lee GQ, Gao C,. Intact HIV-1 proviruses accumulate at distinct chromosomal positions during prolonged antiretroviral therapy. J Clin Invest 2019; 129: 988-998.
Janssens J, De Wit F, Parveen N, Debyser Z,. Single-cell imaging shows that the transcriptional state of the HIV-1 provirus and its reactivation potential depend on the integration site. mBio 2022; 13: e0000722.
Vansant G, Chen HC, Zorita E,. The chromatin landscape at the HIV-1 provirus integration site determines viral expression. Nucleic Acids Res 2020; 48: 7801-7817.
Vibholm LK, Lorenzi JCC, Pai JA,. Characterization of intact proviruses in blood and lymph node from HIV-infected individuals undergoing analytical treatment interruption. J Virol 2019; 93:e01920-18.
Cohen YZ, Lorenzi JCC, Krassnig L,. Relationship between latent and rebound viruses in a clinical trial of anti-HIV-1 antibody 3BNC117. J Exp Med 2018; 215: 2311-2324.
Lu CL, Pai JA, Nogueira L,. Relationship between intact HIV-1 proviruses in circulating CD4+ T cells and rebound viruses emerging during treatment interruption. Proc Natl Acad Sci USA 2018; 115: E11341-E11348.
Bertagnolli LN, Varriale J, Sweet S,. Autologous IgG antibodies block outgrowth of a substantial but variable fraction of viruses in the latent reservoir for HIV-1. Proc Natl Acad Sci USA 2020; 117: 32066-32077.
Gondim MVP, Sherrill-Mix S, Bibollet-Ruche F,. Heightened resistance to host type 1 interferons characterizes HIV-1 at transmission and after antiretroviral therapy interruption. Sci Transl Med 2021; 13: eabd8179.
Akiyama H, Miller CM, Ettinger CR,. HIV-1 intron-containing RNA expression induces innate immune activation and T cell dysfunction. Nat Commun 2018; 9: 3450.
McCauley SM, Kim K, Nowosielska A,. Intron-containing RNA from the HIV-1 provirus activates type I interferon and inflammatory cytokines. Nat Commun 2018; 9: 5305.
Cartwright EK, Spicer L, Smith SA,. CD8(+) lymphocytes are required for maintaining viral suppression in SIV-infected macaques treated with short-term antiretroviral therapy. Immunity 2016; 45: 656-668.
McBrien JB, Mavigner M, Franchitti L,. Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells. Nature 2020; 578: 154-159.
Kahan SM, Wherry EJ, Zajac AJ,. T cell exhaustion during persistent viral infections. Virology 2015; 479-480: 180-193.
Abdel-Mohsen M, Richman D, Siliciano RF,. Recommendations for measuring HIV reservoir size in cure-directed clinical trials. Nat Med 2020; 26: 1339-1350.
Moranguinho I, Valente ST,. Block-and-lock: new horizons for a cure for HIV-1. Viruses 2020; 12: 1443.
Vansant G, Bruggemans A, Janssens J, Debyser Z,. Block-and-lock strategies to cure HIV infection. Viruses 2020; 12: E84.
Moron-Lopez S, Bernal S, Wong JK,. ABX464 decreases the total human immunodeficiency virus (HIV) reservoir and HIV transcription initiation in CD4+ T cells from antiretroviral therapy-suppressed individuals living with HIV. Clin Infect Dis 2022; 74: 2044-2049.
Bernal S, Puertas MC, Morón-López S,. Impact of obefazimod on viral persistence, inflammation, and immune activation in people with human immunodeficiency virus on suppressive antiretroviral therapy. J Infect Dis 2023; 228: 1280-1291.
Yeh YJ, Jenike KM, Calvi RM,. Filgotinib suppresses HIV-1-driven gene transcription by inhibiting HIV-1 splicing and T cell activation. J Clin Invest 2020; 130: 4969-4984.
Mousseau G, Clementz MA, Bakeman WN,. An analog of the natural steroidal alkaloid cortistatin A potently suppresses Tat-dependent HIV transcription. Cell Host Microbe 2012; 12: 97-108.
