A Tissue Virus Microenvironment with Activated Stress Responses Underlies Durable SIV Persistence

Persistent SIV reservoirs in rhesus macaques are associated with a tissue microenvironment characterized by activated stress responses, metabolic rewiring, and immunosuppressive structures.

• Why it matters: HIV persistence during ART remains a major obstacle to cure, especially within gut-associated lymphoid tissues, but the tissue-specific microenvironment factors that sustain reservoirs are not fully understood.
• What they did: Using spatial transcriptomics and immunoPET/CT-guided sampling of SIV-infected macaques, the study compared early and late ART initiation, focusing on tissue sites of viral production during the eclipse phase after treatment interruption, and identified features of persistent reservoirs.
• The result: Persistent reservoirs are linked to increased proviral burden, stress-response activation, and immunosuppressive cellular architectures, with stress adaptation pathways predicting viral density, suggesting that targeting the VME may be essential for HIV cure strategies.