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

PURPOSE OF REVIEW: Antiretroviral 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 FINDINGS: Initiating 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.