Preferential Exhaustion and Loss of Predominant Reservoir in Gut-Associated Lymph Nodes of a SIVmac239-Infected...

Gut-associated lymph nodes (GALNs) constitute an important anatomical reservoir during early and chronic human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection, but the fate of this compartment during terminal AIDS remains unclear. This study investigated viral persistence and lymph node injury in a rhesus macaque with long-term SIVmac239 infection and end-stage AIDS, characterized by profound CD4+ T cell depletion (30 cells/μL) and persistent viremia (1192 copies/mL). At necropsy, GALNs, including mesenteric, paracolic, and ileocecal lymph nodes, and non-gut-associated lymph nodes (NGALNs), including hepatic hilar, common iliac, and inguinal lymph nodes, were collected for viral RNA/DNA quantification, histopathology, immunofluorescence, and transcriptomics. SIV DNA was markedly lower in GALNs than in NGALNs, whereas SIV RNA was detectable only in NGALNs. GALNs exhibited extensive fibrotic remodeling, paracortical collapse, severe CD4+ T cell loss across B cell and paracortical regions, and pronounced CD8+ T cell accumulation within B cell zones. Transcriptomic profiling further revealed an exhaustion signature in GALNs, with reduced DNA replication and repair, impaired cell-cycle activity, and suppressed RNA processing, accompanied by activation of innate immune programs and attenuation of adaptive immune responses. These findings indicate that, during terminal AIDS, GALNs no longer serve as the predominant viral reservoir but instead undergo preferential and severe structural and functional exhaustion. This case highlights marked anatomical heterogeneity in lymph node vulnerability during advanced disease and supports a model in which collapse of the gut-associated immune barrier contributes to disease progression toward terminal AIDS.