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Abstract
Human Immunodeficiency Virus type 1 (HIV-1) infection remains one of the foremost global health challenges of the modern era, with approximately 39.9 million people living with HIV worldwide as of 2023 and 1.3 million new infections occurring annually. Despite four decades of intensive biomedical research, a definitive cure remains elusive.
This narrative review comprehensively addresses the molecular virology and replication cycle of HIV-1, the immunopathogenic mechanisms underlying progressive CD4⁺ T-cell depletion and immune dysfunction, contemporary global epidemiology, antiretroviral pharmacology and preferred treatment regimens, drug resistance mechanisms and surveillance, viral latency and reservoir biology, and the current landscape of curative strategies. Evidence was synthesised from primary research articles, systematic reviews, meta-analyses, landmark clinical trials, and international guidelines published between 2000 and 2024 (with select seminal/foundational studies from the late 1990s retained for historical context), retrieved from PubMed/MEDLINE, Embase, and the Cochrane Library.
Modern integrase strand-transfer inhibitor (INSTI)-based regimens achieve virological suppression exceeding 95% in treatment-naive adults. However, the transcriptionally silent proviral reservoir in resting CD4⁺ T cells persists lifelong, necessitating novel combinatorial interventions. Emerging curative approachesincluding shock-and-kill latency reversal, block-and-lock epigenetic silencing, CRISPR-Cas9-mediated proviral excision, broadly neutralising antibodies, and allogeneic stem cell transplantation represent credible scientific pathways toward functional or sterilising cure.
Equitable global access to antiretroviral therapy and sustained investment in cure research are indispensable to achieving the UNAIDS 95–95–95 targets and ending the HIV pandemic.
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Copyright (c) 2026 Ruqayah Taher Habash*, Fatemeh Roodbari (Author)
This work is licensed under a Creative Commons Attribution 4.0 International License.
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References
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- Lewin SR, Rouzioux C. HIV cure and eradication: how will we get from the laboratory to effective clinical trials? AIDS. 2011;25(7):885-97. https://doi.org/10.1097/QAD.0b013e3283467041
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- Volberding PA, Deeks SG. Antiretroviral therapy and management of HIV infection. Lancet. 2010;376(9734):49-62. https://doi.org/10.1016/S0140-6736(10)60676-9
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- Fauci AS, Redfield RR, Sigounas G, Weahkee MD, Giroir BP. Ending the HIV epidemic: a plan for the United States. JAMA. 2019;321(9):844-5. https://doi.org/10.1001/jama.2019.1343
References
UNAIDS. Global HIV & AIDS statistics Fact sheet 2023. Geneva: UNAIDS; 2023. https://www.unaids.org/en/resources/fact-sheet
Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med. 1998;338(13):853-60. https://doi.org/10.1056/NEJM199803263381301
Coffin JM, Hughes SH, Varmus HE. Retroviruses. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 1997.
Frankel AD, Young JA. HIV-1: fifteen proteins and an RNA. Annu Rev Biochem. 1998;67:1-25. https://doi.org/10.1146/annurev.biochem.67.1.1
Deeks SG, Overbaugh J, Phillips A, Buchbinder S. HIV infection. Nat Rev Dis Primers. 2015;1:15035. https://doi.org/10.1038/nrdp.2015.35
Sundquist WI, Krausslich HG. HIV-1 assembly, budding, and maturation. Cold Spring Harb Perspect Med. 2012;2(7):a006924. https://doi.org/10.1101/cshperspect.a006924
Arts EJ, Hazuda DJ. HIV-1 antiretroviral drug therapy. Cold Spring Harb Perspect Med. 2012;2(4):a007161. https://doi.org/10.1101/cshperspect.a007161
Siliciano JM, Siliciano RF. Recent developments in the search for a cure for HIV-1 infection. J Allergy Clin Immunol. 2014;134(1):12-9. https://doi.org/10.1016/j.jaci.2014.05.026
Barre-Sinoussi F, Ross AL, Delfraissy JF. Past, present and future: 30 years of HIV research. Nat Rev Microbiol. 2013;11(12):877-83. https://doi.org/10.1038/nrmicro3132
Klatt NR, Chomont N, Douek DC, Deeks SG. Immune activation and HIV persistence: implications for curative approaches. Immunol Rev. 2013;254(1):326-42. https://doi.org/10.1111/imr.12065
Altfeld M, Gale M Jr. Innate immunity against HIV-1 infection. Nat Immunol. 2015;16(6):554-62. https://doi.org/10.1038/ni.3157
World Health Organization. Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach. Geneva: World Health Organization; 2021. ISBN 978-92-4-003159-3.
Gunthard HF, Saag MS, Benson CA, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults. JAMA. 2016;316(2):191-210. https://doi.org/10.1001/jama.2016.8900
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Washington DC: DHHS; 2023.
Landovitz RJ, Donnell D, Clement ME, et al. Cabotegravir for HIV prevention in cisgender men and transgender women. N Engl J Med. 2021;385(7):595-608. https://doi.org/10.1056/NEJMoa2101016
Gunthard HF, Calvez V, Paredes R, et al. European recommendations for the clinical use of HIV drug resistance testing: 2019 Update. HIV Med. 2019;20(2):73-8. https://doi.org/10.1111/hiv.12614
Chun TW, Davey RT, Ostrowski M, Justement JS, Engel D, Mullins JI, et al. Relationship between pre-existing viral reservoirs and the re-emergence of plasma viremia after discontinuation of HAART. Nat Med. 2000;6(7):757-61. https://doi.org/10.1038/77481
Lewin SR, Rouzioux C. HIV cure and eradication: how will we get from the laboratory to effective clinical trials? AIDS. 2011;25(7):885-97. https://doi.org/10.1097/QAD.0b013e3283467041
Archin NM, Liberty AL, Kashuba AD, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012;487(7408):482-5. https://doi.org/10.1038/nature11286
Gupta RK, Abdul-Jawad S, McCoy LE, et al. HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation. Nature. 2019;568(7751):244-8. https://doi.org/10.1038/s41586-019-1027-4
Caskey M, Klein F, Nussenzweig MC. Broadly neutralizing anti-HIV-1 antibodies: new insights and opportunities. Nat Med. 2019;25(10):1468-78. https://doi.org/10.1038/s41591-019-0601-5
Cohen MS, Chen YQ, McCauley M, et al. Antiretroviral therapy for the prevention of HIV-1 transmission. N Engl J Med. 2016;375(9):830-9. https://doi.org/10.1056/NEJMoa1600693
Buchbinder SP, Liu A. Pre-exposure prophylaxis and the promise of combination prevention approaches. AIDS Behav. 2011;15(Suppl 1):S72-9. https://doi.org/10.1007/s10461-011-9894-1
Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367(5):411-22. https://doi.org/10.1056/NEJMoa1202614
Molina JM, Capitant C, Spire B, et al. On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. N Engl J Med. 2015;373(23):2237-46. https://doi.org/10.1056/NEJMoa1506273
Volberding PA, Deeks SG. Antiretroviral therapy and management of HIV infection. Lancet. 2010;376(9734):49-62. https://doi.org/10.1016/S0140-6736(10)60676-9
Havlir DV, Currier JS. Complications of HIV infection and antiretroviral therapy. Top Antivir Med. 2009;17(2):63-7.
Dalmau J, Vidal N, Clotet B, et al. HIV-1 tropism and neurocognitive disorders: a review. Rev Med Virol. 2011;21(5):282-93. https://doi.org/10.1002/rmv.695
Fauci AS, Redfield RR, Sigounas G, Weahkee MD, Giroir BP. Ending the HIV epidemic: a plan for the United States. JAMA. 2019;321(9):844-5. https://doi.org/10.1001/jama.2019.1343