Effect of Timing and Duration of ART on the Composition of HIV Reservoirs: Implications for HIV Cure Strategies.

purpose of reviewAntiretroviral therapy (ART) has transformed HIV from a fatal disease into a manageable condition by effectively suppressing viral replication. However, ART does not eradicate HIV due to the persistence of latent reservoirs-mainly replication-competent proviruses in resting CD4⁺ T cells and tissue sanctuaries-that reignite infection upon treatment interruption. This review examines how ART timing and duration influence the size, composition, and stability of the HIV reservoir. RECENT

findingsInitiating ART during acute infection limits reservoir seeding, reduces genetic diversity, and promotes faster decay of intact proviruses compared to delayed ART, which permits widespread viral integration into long-lived memory T cells and clonal expansion of replication-competent viruses. Anatomical sites such as lymph nodes, gut-associated lymphoid tissue, and the central nervous system act as critical reservoir niches. These insights are central to current HIV cure efforts, which aim for either a sterilizing cure (complete eradication of the virus) or a functional cure (durable remission without ART). Cure strategies-such as "shock-and-kill,""block-and-lock," gene editing, and immunotherapy-are being optimized based on reservoir dynamics. Evidence suggests that early-treated individuals, with smaller and more homogeneous reservoirs, are better candidates for these interventions. Although no strategy has yet achieved a cure, combining early ART with targeted interventions may improve outcomes. Understanding how ART influences reservoir dynamics is essential for developing effective HIV cure strategies. We emphasize the importance of prioritizing early-treated individuals in cure trials and advocate for integrated therapeutic approaches to achieve lasting viral remission or complete eradication.