Immunometabolic regulation of CD8+ T cell mediated intestinal epithelial cell death in people with HIV (PWH)

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A hallmark of human immunodeficiency virus (HIV) infection is intestinal inflammation and impairment of gut epithelial barrier function. These defects are thought to drive HIV disease progression by allowing translocation of luminal microbial products into the circulation, which triggers chronic systemic immune activation and disease progression. Although antiretroviral therapy (ART) effectively suppresses viral replication in the blood, it does not restore homeostasis in the intestine, even after years of treatment. This contributes to increased morbidity and mortality due to inflammatory non-communicable diseases (NCDs) such as heart disease and stroke in people with HIV (PWH). Despite the central role of intestinal barrier function in HIV disease pathogenesis, little is known about the specific mechanisms by which HIV results in epithelial damage. Studies of intestinal epithelial cell (IEC) dysfunction in HIV have relied primarily on correlative observations based on histology or peripheral biomarkers. Our proposal addresses critical gaps in knowledge by utilizing intestinal tissue samples from well-characterize cohorts of PWH and HIV-uninfected individuals, along with novel in vivo mouse and ex vivo human cell models and state-of-the-art technologies to explore specific mechanisms by which HIV contributes to IEC death in PWH. We hypothesize that HIV- associated defects in CD8+ T cell fatty acid (FA) metabolism cause them to scavenge lipids from nearby IEC, which leads to IEC death. This IEC death then results in intestinal barrier disruption. To address these hypotheses, we are proposing two complementary aims. In Aim 1 we will characterize the in vivo and ex vivo impact of HIV infection on IEC death in PWH using colon tissue samples obtained by endoscopy to characterize IEC death and CD8+ T cell phenotypes. We will also utilize novel mini-gut organoid models that incorporate autologous tissue resident immune cells and in-depth single cell sequencing analysis leveraging a platform optimized for small sample sizes developed by collaborators at MIT. In Aim 2, we will determine the mechanisms by which HIV-associated dysregulation of FA metabolism in intestinal CD8+ T cells disrupts the colonic epithelial barrier. In this aim we will utilize ex vivo human organoid and in vivo murine models to test the mechanistic role of impaired FA metabolism in CD8+ T cell mediated IEC death and intestinal barrier dysfunction. This approach will identify specific cellular and molecular mechanisms underlying the impact of HIV infection on intestinal barrier function and systemic immune activation. To carry out these Aims we have assembled a team with combined expertise in HIV disease, mucosal immunology, and GI pathology, who are well positioned to uncover specific mechanisms that underlie intestinal epithelial dysfunction in HIV infection. This proposal will address important unknown mechanisms of IEC biology that may help in the development of new strategies to reverse gut barrier defects in HIV infection.