Human Immunodeficiency Virus: A Comprehensive Review of Virology, Immunopathogenesis, Antiretroviral Pharmacology, Drug Resistance, and Emerging Curative Strategies
TL;DR
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.
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.