Friday, May 3, 2024
5/3/2024
Project Summary/Abstract Antiretroviral therapy (ART) has improved the lives of people living with HIV (PWH). However, the increased burden of HIV-associated non-communicable diseases (NCDs) such as diabetes, cardiovascular disease, and obesity is leading to higher morbidity and mortality among these individuals. The disruption of the intestinal barrier, resulting in microbial translocation and chronic systemic inflammation, has been linked to NCDs. However, the mechanism of intestinal barrier disruption in PWH on ART remains incompletely understood. Interactions between tissue resident CD8+ T cells and the intestinal epithelium are critical for maintaining barrier integrity. Colonic CD8+ T cells are dependent upon on lipid metabolism for energy production and PPARs (peroxisome proliferator-activated receptors) are a family of lipid-sensing receptors that critically regulate lipid metabolism in colon CD8+ T cells. Increases in PPAR-induced lipid metabolism have previously been shown to boost CD8+ T cell immune function in the tumor microenvironment and improve colitis in patients with inflammatory bowel disease. In PWH on ART, we show that PPARs are downregulated in colon CD8+ T cells, which results in impaired internal lipid storage. Moreover, PPAR deficiency in these cells is also associated with CD8+ T cell-mediated epithelial damage that disrupts intestinal barrier integrity. This has led us to hypothesize that in PWH on ART, downregulation of PPARs result in impaired lipid metabolism in colonic CD8+ T cells, which decrease effector functions and leads to impaired intestinal barrier integrity. During the K99 phase, this proposal aims to determine the effects of PPARs on CD8+ T cell effector function in PWH on ART. In Aim 1 we will use PPAR knock-out mice to determine the role of PPAR signaling in the CD8+ T cell subpopulations in the mouse colon (K99 phase). Aim 2 we will characterize the mechanism of how PPAR signaling impacts lipid metabolism in colonic CD8+ T cells (K99 to R00 transition). In Aim 3, we will determine how dysregulation of cellular metabolism in colonic CD8+ T cells impacts epithelial function in the intestine (R00 phase). This proposal will involve using ex vivo intestinal organoids that incorporate colonic CD8+ T cells from human subjects and genetically engineered mice with deficiencies in CD8+ T cell cellular energy production. To carry out these aims, the PI has assembled a team with combined expertise in HIV pathogenesis, mucosal immunology, immunometabolism, intestinal pathology, and single-cell transcriptomics who will collaborate and support the PI’s work and career development. This proposal seeks to identify novel therapeutic interventions that can restore tissue-resident CD8+ T cell function in PWH on ART (K99) and characterize the molecular mechanism of intestinal barrier damage associated with chronic immune activation to help ameliorate NCDs in ART-treated PWH (R00).
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