Unraveling the root causes of HIV-1 persistence

PURPOSE OF REVIEW: Although ART suppresses HIV-1 viral loads to undetectable levels and frequently enables a near-normal life expectancy for persons living with HIV, a reservoir of infected cells persists lifelong and cannot be eliminated with currently available therapeutic strategies. This review summarizes recent discoveries to elucidate the underlying causes of HIV-1 persistence despite antiretroviral therapy and offers insights for future interventions. RECENT FINDINGS: Recent advances in proviral sequencing, chromosomal integration site mapping, clonal cell tracking, single-cell multiomics, and spatial transcriptomic profiling reveal that HIV-1 persistence is not merely due to viral latency. Instead, it is also sustained by clonal expansion, cell-intrinsic survival programs, and immune-evasion properties of reservoir cells, as well as by the protective microenvironments found in specific tissue sanctuaries. While no single factor is identified as the sole driver of persistence, these findings collectively reshape and expand our understanding of HIV-1 reservoirs and the mechanisms underlying viral persistence. SUMMARY: HIV-1 persists through a multilayered network in which viral latency, clonal proliferation, cell-intrinsic survival and immune-evasion programs, and the biology of tissue sanctuaries act in concert to sustain the viral reservoir. This interconnected architecture-rather than any single mechanism-constitutes the fundamental basis of HIV-1 persistence.