Carpenter, C. C. et al. Antiretroviral therapy for HIV infection in 1996. Recommendations of an international panel. Int. AIDS Soc.-USA. JAMA 276, 146–154 (1996).
Gulick, R. M. et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N. Engl. J. Med. 337, 734–739 (1997).
Schapiro, J. M. et al. The effect of high-dose saquinavir on viral load and CD4+ T-cell counts in HIV-infected patients. Ann. Intern Med. 124, 1039–1050 (1996).
García, F. et al. Dynamics of viral load rebound and immunological changes after stopping effective antiretroviral therapy. AIDS 13, F79–F86 (1999).
Finzi, D. 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. 5, 512–517 (1999).
Finzi, D. et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278, 1295–1300 (1997).
Chun, T.-W., Moir, S. & Fauci, A. S. HIV reservoirs as obstacles and opportunities for an HIV cure. Nat. Immunol. 16, 584–589 (2015).
Halvas, E. K. et al. HIV-1 viremia not suppressible by antiretroviral therapy can originate from large T cell clones producing infectious virus. J. Clin. Invest 130, 5847–5857 (2020).
Mohammadi, A. et al. Viral and host mediators of non-suppressible HIV-1 viremia. Nat. Med. 29, 3212–3223 (2023).
Palmer, S. 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 41, 4531–4536 (2003).
Wiegand, A. et al. Single-cell analysis of HIV-1 transcriptional activity reveals expression of proviruses in expanded clones during ART. Proc. Natl. Acad. Sci. USA 114, E3659–E3668 (2017).
McManus, W. R. et al. HIV-1 in lymph nodes is maintained by cellular proliferation during antiretroviral therapy. J. Clin. Invest 129, 4629–4642 (2019).
Maldarelli, F. et al. ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. PLoS Pathog. 3, e46 (2007).
Palmer, S. et al. Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc. Natl. Acad. Sci. USA 105, 3879–3884 (2008).
Hatano, H. et al. Prospective antiretroviral treatment of asymptomatic, HIV-1 infected controllers. PLoS Pathog. 9, e1003691 (2013).
Martinez-Picado, J. & Deeks, S. G. Persistent HIV-1 replication during antiretroviral therapy. Curr. Opin. HIV AIDS 11, 417–423 (2016).
Imamichi, H. et al. Defective HIV-1 proviruses produce viral proteins. Proc. Natl. Acad. Sci. USA 117, 3704–3710 (2020).
Deeks, S. G. et al. Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood 104, 942–947 (2004).
Giorgi, J. V. et al. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J. Infect. Dis. 179, 859–870 (1999).
Liu, Z. et al. CD8+ T-lymphocyte activation in HIV-1 disease reflects an aspect of pathogenesis distinct from viral burden and immunodeficiency. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 18, 332–340 (1998).
López, M. et al. Elite controllers display higher activation on central memory CD8 T cells than HIV patients successfully on HAART. AIDS Res Hum. Retroviruses 27, 157–165 (2011).
Desai, S. & Landay, A. Early immune senescence in HIV disease. Curr. HIV/AIDS Rep. 7, 4–10 (2010).
Hua, S. et al. Potential role for HIV-specific CD38-/HLA-DR+ CD8+ T cells in viral suppression and cytotoxicity in HIV controllers. PLoS One 9, e101920 (2014).
Gandhi, R. T. et al. Effect of baseline- and treatment-related factors on immunologic recovery after initiation of antiretroviral therapy in HIV-1-positive subjects: results from ACTG 384. J. Acquir Immune Defic. Syndr. 42, 426–434 (2006).
Helleberg, M. et al. Course and Clinical Significance of CD8+ T-Cell Counts in a Large Cohort of HIV-Infected Individuals. J. Infect. Dis. 211, 1726–1734 (2015).
Tanko, R. F. et al. Residual T cell activation and skewed CD8+ T cell memory differentiation despite antiretroviral therapy-induced HIV suppression. Clin. Immunol. 195, 127–138 (2018).
Takata, H. et al. 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 31, 1494–1506.e4 (2023).
Trautmann, L. et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat. Med. 12, 1198–1202 (2006).
Perdomo-Celis, F., Feria, M. G., Taborda, N. A. & Rugeles, M. T. A Low Frequency of IL-17-Producing CD8+ T-Cells Is Associated With Persistent Immune Activation in People Living With HIV Despite HAART-Induced Viral Suppression. Front Immunol. 9, 2502 (2018).
Migueles, S. A. et al. Defective human immunodeficiency virus-specific CD8+ T-cell polyfunctionality, proliferation, and cytotoxicity are not restored by antiretroviral therapy. J. Virol. 83, 11876–11889 (2009).
Dubé, M. et al. Spontaneous HIV expression during suppressive ART is associated with the magnitude and function of HIV-specific CD4+ and CD8+ T cells. Cell Host Microbe 31, 1507–1522.e5 (2023).
Kelleher, A. D., Sewell, W. A. & Cooper, D. A. Effect of protease therapy on cytokine secretion by peripheral blood mononuclear cells (PBMC) from HIV-infected subjects. Clin. Exp. Immunol. 115, 147–152 (1999).
Akondy, R. S. et al. Origin and differentiation of human memory CD8 T cells after vaccination. Nature 552, 362–367 (2017).
Bruner, K. M. et al. A quantitative approach for measuring the reservoir of latent HIV-1 proviruses. Nature 566, 120–125 (2019).
Gaebler, C. et al. Combination of quadruplex qPCR and next-generation sequencing for qualitative and quantitative analysis of the HIV-1 latent reservoir. J. Exp. Med. 216, 2253–2264 (2019).
Abdel-Mohsen, M. et al. Recommendations for measuring HIV reservoir size in cure-directed clinical trials. Nat. Med. 26, 1339–1350 (2020).
Kinloch, N. N. et al. HIV-1 diversity considerations in the application of the Intact Proviral DNA Assay (IPDA). Nat. Commun. 12, 165 (2021).
Pollack, R. A. et al. Defective HIV-1 Proviruses Are Expressed and Can Be Recognized by Cytotoxic T Lymphocytes, which Shape the Proviral Landscape. Cell Host Microbe 21, 494–506.e4 (2017).
Kuniholm, J., Coote, C. & Henderson, A. J. Defective HIV-1 genomes and their potential impact on HIV pathogenesis. Retrovirology 19, 13 (2022).
Martin, H. A. et al. New Assay Reveals Vast Excess of Defective over Intact HIV-1 Transcripts in Antiretroviral Therapy-Suppressed Individuals. J. Virol. 96, e01605-22 (2022).
Reeves, D. B. et al. Impact of misclassified defective proviruses on HIV reservoir measurements. Nat. Commun. 14, 4186 (2023).
Gray, E. R. et al. p24 revisited: a landscape review of antigen detection for early HIV diagnosis. AIDS 32, 2089–2102 (2018).
Wu, G. et al. Gag p24 Is a Marker of Human Immunodeficiency Virus Expression in Tissues and Correlates With Immune Response. J. Infect. Dis. 224, 1593–1598 (2021).
Miedouge, M., Grèze, M., Bailly, A. & Izopet, J. Analytical sensitivity of four HIV combined antigen/antibody assays using the p24 WHO standard. J. Clin. Virol. 50, 57–60 (2011).
Passaes, C. P. B. et al. Ultrasensitive HIV-1 p24 Assay Detects Single Infected Cells and Differences in Reservoir Induction by Latency Reversal Agents. J. Virol. 91, e02296–16 (2017).
Levinger, C. et al. An ultrasensitive planar array p24 Gag ELISA to detect HIV-1 in diverse biological matrixes. Sci. Rep. 11, 23682 (2021).
Kuzmichev, Y. V. et al. Application of ultrasensitive digital ELISA for p24 enables improved evaluation of HIV-1 reservoir diversity and growth kinetics in viral outgrowth assays. Sci. Rep. 13, 10958 (2023).
Streeck, H. et al. Recognition of a defined region within p24 gag by CD8+ T cells during primary human immunodeficiency virus type 1 infection in individuals expressing protective HLA class I alleles. J. Virol. 81, 7725–7731 (2007).
Steiger, J. H. Testing Pattern Hypotheses On Correlation Matrices: Alternative Statistics And Some Empirical Results. Multivar. Behav. Res. 15, 335–352 (1980).
Hiener, B. et al. Identification of Genetically Intact HIV-1 Proviruses in Specific CD4+ T Cells from Effectively Treated Participants. Cell Rep. 21, 813–822 (2017).
Sun, W. et al. Persistence of intact HIV-1 proviruses in the brain during antiretroviral therapy. Elife 12, RP89837 (2023).
Bourgeois, C. et al. Contribution of Adipose Tissue to the Chronic Immune Activation and Inflammation Associated With HIV Infection and Its Treatment. Front Immunol. 12, 670566 (2021).
Osborne, O., Peyravian, N., Nair, M., Daunert, S. & Toborek, M. The Paradox of HIV Blood-Brain Barrier Penetrance and Antiretroviral Drug Delivery Deficiencies. Trends Neurosci. 43, 695–708 (2020).
Richter, E. et al. Reduction of CD8 T Cell Functionality but Not Inhibitory Capacity by Integrase Inhibitors. J. Virol. 96, e0173021 (2022).
Bronnimann, M. P., Skinner, P. J. & Connick, E. The B-Cell Follicle in HIV Infection: Barrier to a Cure. Front Immunol. 9, 20 (2018).
Moar, P., Premeaux, T. A., Atkins, A. & Ndhlovu, L. C. The latent HIV reservoir: current advances in genetic sequencing approaches. mBio 14, e0134423 (2023).
Teixeira, A. R. et al. Transcription of HIV-1 at sites of intact latent provirus integration. J. Exp. Med. 221, e20240391 (2024).
Falcinelli, S. D., Ceriani, C., Margolis, D. M. & Archin, N. M. New Frontiers in Measuring and Characterizing the HIV Reservoir. Front. Microbiol. 10, 2878 (2019).
Passaes, C. et al. Ultrasensitive Detection of p24 in Plasma Samples from People with Primary and Chronic HIV-1 Infection. J. Virol. 95, e0001621 (2021).
White, J. A. et al. Clonally expanded HIV-1 proviruses with 5’-leader defects can give rise to nonsuppressible residual viremia. J. Clin. Invest 133, e165245 (2023).
Petrara, M. R. et al. HIV reservoir and premature aging: risk factors for aging-associated illnesses in adolescents and young adults with perinatally acquired HIV. PLOS Pathog. 20, e1012547 (2024).
Imaz, A. et al. Dynamics of the Decay of Human Immunodeficiency Virus (HIV) RNA and Distribution of Bictegravir in the Genital Tract and Rectum in Antiretroviral-naive Adults Living With HIV-1 Treated With Bictegravir/Emtricitabine/Tenofovir Alafenamide (Spanish HIV/AIDS Research Network, PreEC/RIS 58). Clin. Infect. Dis. 73, e1991–e1999 (2021).
Armenia, D. et al. Very high pre-therapy viral load is a predictor of virological rebound in HIV-1-infected patients starting a modern first-line regimen. Antivir. Ther. 24, 321–331 (2019).
Brinkhof, M. W. G. et al. Evaluation of p24-based antiretroviral treatment monitoring in pediatric HIV-1 infection: prediction of the CD4+ T-cell changes between consecutive visits. J. Acquir. Immune Defic. Syndr. 41, 557–562 (2006).
Shahid, A. et al. The replication-competent HIV reservoir is a genetically restricted, younger subset of the overall pool of HIV proviruses persisting during therapy, which is highly genetically stable over time. J. Virol. 98, e0165523 (2024).
Sannier, G. et al. Combined single-cell transcriptional, translational, and genomic profiling reveals HIV-1 reservoir diversity. Cell Rep. 36, 109643 (2021).
Baxter, A. E., O’Doherty, U. & Kaufmann, D. E. Beyond the replication-competent HIV reservoir: transcription and translation-competent reservoirs. Retrovirology 15, 18 (2018).
Engelman, A. N. & Singh, P. K. Cellular and molecular mechanisms of HIV-1 integration targeting. Cell Mol. Life Sci. 75, 2491–2507 (2018).
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 13, e0000722 (2022).
Dwivedi, R., Prakash, P., Kumbhar, B. V., Balasubramaniam, M. & Dash, C. HIV-1 capsid and viral DNA integration. mBio 15, e0021222 (2024).
Zhang, X. & Chen, J. HIV Reservoir: How to Measure It? Curr. HIV/AIDS Rep. 20, 29–41 (2023).
Couturier, J. et al. Adipocytes impair efficacy of antiretroviral therapy. Antivir. Res. 154, 140–148 (2018).
Licht, A. & Alter, G. A Drug-Free Zone–Lymph Nodes as a Safe Haven for HIV. Cell Host Microbe 19, 275–276 (2016).
Davis, D. A. et al. Activity of human immunodeficiency virus type 1 protease inhibitors against the initial autocleavage in Gag-Pol polyprotein processing. Antimicrob. Agents Chemother. 56, 3620–3628 (2012).
Moore, M. D. et al. Suboptimal inhibition of protease activity in human immunodeficiency virus type 1: effects on virion morphogenesis and RNA maturation. Virology 379, 152–160 (2008).
Baird, H. A. et al. Monitoring processed, mature Human Immunodeficiency Virus type 1 particles immediately following treatment with a protease inhibitor-containing treatment regimen. AIDS Res. Ther. 2, 2 (2005).
Sacha, J. B. et al. Gag-specific CD8+ T lymphocytes recognize infected cells before AIDS-virus integration and viral protein expression. J. Immunol. 178, 2746–2754 (2007).
Julg, B. et al. Enhanced anti-HIV functional activity associated with Gag-specific CD8 T-cell responses. J. Virol. 84, 5540–5549 (2010).
Borrow, P., Lewicki, H., Hahn, B. H., Shaw, G. M. & Oldstone, M. B. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J. Virol. 68, 6103–6110 (1994).
Koup, R. A. et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J. Virol. 68, 4650–4655 (1994).
Jones, N. A. et al. Determinants of human immunodeficiency virus type 1 escape from the primary CD8+ cytotoxic T lymphocyte response. J. Exp. Med. 200, 1243–1256 (2004).
Ogg, G. S. et al. Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 279, 2103–2106 (1998).
Ndhlovu, Z. M. et al. Elite controllers with low to absent effector CD8+ T cell responses maintain highly functional, broadly directed central memory responses. J. Virol. 86, 6959–6969 (2012).
Cartwright, E. K. et al. CD8(+) Lymphocytes Are Required for Maintaining Viral Suppression in SIV-Infected Macaques Treated with Short-Term Antiretroviral Therapy. Immunity 45, 656–668 (2016).
Lembas, A., Załęski, A., Peller, M., Mikuła, T. & Wiercińska-Drapało, A. Human Immunodeficiency Virus as a Risk Factor for Cardiovascular Disease. Cardiovasc. Toxicol. 24, 1–14 (2024).