HIV Reservoirs Across Multiple Tissues: From Heterogeneous Mechanisms to Therapeutic Targeting.

Despite effective antiretroviral therapy, HIV persists in diverse tissue reservoirs that pose major barriers to a cure. This review examines the heterogeneous maintenance mechanisms of HIV reservoirs in lymph nodes, intestinal mucosa, and the central nervous system (CNS). It analyzes how distinct tissue microenvironments-including immune-privileged niches, specialized cellular subsets, and local signaling networks-govern viral persistence and latency. Lymph nodes function as a dynamic hub interconnected with systemic reservoirs; the intestinal mucosa represents a site shaped by barrier integrity, microbial translocation, and mucosal immunity; the CNS constitutes a compartmentalized sanctuary protected by the blood-brain barrier. The review further discusses tissue-specific antiretroviral drug penetration and targeted clearance strategies, providing a foundation for developing multi-site intervention approaches toward HIV cure.