Ongoing lymphoid HIV production drives pyroptosis and GLP-1 counter-regulation in ART-suppressed infection

Despite effective antiretroviral therapy (ART), many people with HIV (PWH) exhibit persistent immune activation (IA) and suffer metabolic comorbidities. We investigated whether residual HIV production in lymphoid tissues drives IA. Among 20 ART-suppressed PWH, HIV RNA⁺ cells were detected in lymph nodes and correlated directly with markers of pyroptosis, assessed via cleaved gasdermin D positivity, but not with most plasma cytokines or IA markers. Notably, glucagon-like peptide 1 (GLP-1), an enteroendocrine hormone with anti-inflammatory roles, was upregulated in the ileum of PWH and correlated directly with systemic cytokines but inversely with lymph node pyroptosis. These findings suggest that chronic occult inflammation in people with successfully suppressed HIV infection is mediated by persistent virus production in lymph nodes leading to pyroptosis, which may trigger compensatory anti-inflammatory enteroendocrine activation that may dampen pyroptosis. Targeting pyroptosis or enhancing GLP-1 signaling represent potential therapeutic strategies for modulating IA and managing metabolic comorbidities in PWH.