Sex difference in viral reservoir and intestinal immune responses during simian HIV infection and antiretroviral therapy in rhesus macaques 2308802

Abstract Introduction Despite effective viral suppression by antiretroviral therapy (ART), HIV persists in tissues, particularly in gut-associated lymphoid tissue (GALT). Previously, we showed sex difference in rectal immune responses and disease outcomes in rhesus macaques (RMs) following intrarectal SHIV-C109 challenge. Here, we examined viral burden and intestinal immune responses during infection and ART in RMs with intravenous (iv) SHIV infection. Methods Sixteen adult RMs (8 males, 8 females) were infected intravenously with SHIV-C109P4 (1 × 106 TCID50). Blood, rectal, and jejunal biopsies were collected before and during acute, chronic infection, and ART. Gene expression was assessed by RNA-seq. Viral RNA was detected by smFISH. Rectal T cells and neutrophils were quantified by immunofluorescence using anti-CD3 Ab and myeloperoxidase staining and analyzed with QuPath. Results Rectal viral RNA was higher in males during chronic infection on ART. Immune responses were tissue- and stage-specific: acute infection featured type I interferon signaling in the jejunum and combined type I/II interferon and remodeling pathways in the rectum, while chronic infection was marked by neutrophil-associated pathways in both tissues. ART revealed divergent responses, with wound healing and oxidative stress in rectal tissue and enhanced protein translation in the jejunum. Sex-specific mucosal responses were minimal during acute infection after iv challenge but emerged during chronic infection and ART. Rectal T cell loss was similar in both sexes, while neutrophil dynamics differed, higher in females during acute infection and in males during chronic infection on ART. Overall, sex differences were most pronounced during chronic infection with ART. Conclusion Our findings demonstrate sex-dependent regulation of intestinal immunity and viral persistence during chronic SHIV infection and ART, with potential implications for long-term disease outcomes. Funding Source NIH Topic Categories Viral Immunology (VIR)