Mapping HIV reservoir geography: lessons for cure from the Last Gift rapid autopsy cohort

PURPOSE OF REVIEW: Deep tissue reservoirs remain a major barrier to HIV cure. Their anatomical distribution and connectivity are difficult to study in living people. We examine how the Last Gift rapid-autopsy cohort clarifies reservoir connectivity, persistence behind anatomical barriers, and variation within organs, and consider the implications for cure. RECENT FINDINGS: Tissue studies reveal HIV reservoirs that are interconnected across yet differ between and within anatomical sites. Viral sequence analyses suggest that blood links tissue reservoirs, with gut and lymphoid tissues acting as hubs of viral dispersal. Recovery of replication-competent HIV from brain microglia during suppressive antiretroviral therapy (ART) provides direct evidence of a resident brain reservoir. Even within the gastrointestinal tract, HIV DNA burden and transcriptions vary by region, with different microbiome associations in the small and large bowel. SUMMARY: HIV reservoir geography supports durable ART-free remission as a practical goal. Achieving this goal will likely require combination therapies with complementary functions and tissue access. Because tissue heterogeneity limits what negative biopsies can establish, remission should be assessed through carefully monitored analytical treatment interruption and long-term follow up.