The selected few: Mechanisms of HIV-1 reservoir persistence

Combination antiretroviral therapy durably suppresses HIV-1 replication yet leaves untouched a small, highly specialized population of infected cells that sustains lifelong viral persistence and remains the principal obstacle to cure. In this review, we synthesize emerging insights into viral and host mechanisms that maintain this extremely durable cellular reservoir, with emphasis on proviral transcriptional regulation, interactions between immune effectors and infected cells, cell-intrinsic programs governing survival and proliferation, and microenvironmental cues that confer competitive fitness and long-term persistence to infected clones. We argue that viral reservoir cells are considerably more visible, and therefore more vulnerable, to host immune responses than the traditional latency-centered model of HIV-1 persistence has assumed and propose that a deeper mechanistic understanding of these immunological vulnerabilities, rather than latency reversal alone, provides the most rational foundation for designing combination strategies aimed at destabilizing infected cells and achieving durable virological remission or cure.