Altered adipose tissue macrophage populations in people with HIV on integrase inhibitor-containing antiretroviral therapy

Antiretroviral therapy (ART) extends the life of people with HIV (PWH), but these individuals are at increased risk for obesity, dyslipidemia, diabetes, and cardiovascular disease. These comorbidities may be a consequence of HIV-related chronic inflammation and/or adverse effects of ART on tissue regulatory adipose tissue macrophages (ATMs). We sought to determine the effects of HIV/ART on metabolically beneficial ATM populations and functions. DESIGN: We examined subcutaneous ATMs from PWH on integrase inhibitor-containing ART (n = 5) and uninfected persons (n = 9). We complemented these studies with ex vivo and in vitro analyses of peripheral blood mononuclear cell (PBMC) and murine macrophage lipid metabolism and fatty acid oxidation gene expression. METHODS: ATM populations were examined by flow cytometry. Macrophage lipid metabolism and fatty acid oxidation gene expression were examined by Seahorse assay and quantitative PCR. RESULTS: Adipose tissue from PWH had reduced populations of metabolically activated CD9(+) ATMs compared to that of uninfected controls (P < 0.001). PBMCs of PWH had lower fatty acid metabolism compared to those of uninfected controls (P < 0.01). Analysis of murine macrophages revealed that dolutegravir reduced lipid metabolism (P < 0.001) and increased expression of the fatty acid beta-oxidation enzyme enoyl-CoA hydratase, short chain 1 (P < 0.05). CONCLUSIONS: We report the loss of metabolically beneficial ATM populations in PWH on ART, altered fatty acid metabolism of blood immune cells, and evidence that dolutegravir alters macrophage fatty acid metabolism. Future studies should examine direct or indirect effects and mechanisms of dolutegravir, and other integrase inhibitors and ART classes, on fatty acid beta-oxidation.