Sex-Specific Differences in Subcutaneous Adipose Tissue in Persons with HIV May Contribute to Diabetes Risk

Background: Men with HIV have greater visceral adipose tissue (VAT) accumulation compared to women, which contributes to insulin resistance and derives, in part, from a failure to sequester lipids in subcutaneous adipose tissue (SAT). We assessed whether sex-specific differences in SAT composition are associated with measures of VAT volume and insulin resistance. Methods: Adults with HIV and consistent viral suppression on antiretroviral therapy had SAT and VAT measured by CT imaging, HOMA2-IR using fasting plasma glucose and insulin, and a subset had abdominal SAT lipoaspirates for single-cell RNA-sequencing to define proportions of CD4 and CD8 T effector memory cells (TEM), perivascular (PVM) and intermediate (IM) macrophages, and fibroblasts. Adjusted ordinal regression models and partial Spearman’s assessed the interaction between sex and cell proportions. Results: We enrolled 111 participants (24% female) with a median age of 48 years, BMI of 31.5 kg/m2, and HOMA2-IR of 3.0. VAT volume was significantly associated with HOMA2-IR. Women had lower VAT volumes and higher proportions of SAT PVMs and lower IMs, as well as fewer cytotoxic CD4 and CD8 T cells compared with men (p ≤ 0.05 for all). The proportions of SAT CD4 TEM, CD8 TEM, myofibroblasts, MYOC fibroblasts, and IMs were associated with VAT volume (p ≤ 0.05 for all), but an interaction by sex was not observed. The proportions of CD4 and CD8 TEM cells were significantly associated with HOMA2-IR and there was evidence of an interaction by sex status (interaction term p = 0.09 & p = 0.06, respectively). Conclusions: Women with HIV have a greater adjusted proportion of PVMs and lower cytotoxic CD4 and CD8 T cells in SAT. While the relationship between immune cell proportions and HOMA-IR only appeared to differ for CD4 and CD8 TEM cells, lower ectopic fat deposition in the context of reduced SAT inflammatory cells in women suggests the sex difference in diabetes risk among persons with HIV may relate to adipose tissue cellular composition. Disclosure S.Bailin: None. M.Mashayekhi: None. C.L.Gabriel: None. L.Hannah: None. S.Kalams: None. S.A.Mallal: None. J.A.Kropski: Advisory Panel; APIE Therapeutics, Research Support; Boehringer Ingelheim Inc., Bristol-Myers Squibb Company, Genentech, Inc. C.N.Wanjalla: None. J.Koethe: Advisory Panel; Merck Sharp & Dohme Corp., Janssen Pharmaceuticals, Inc., Gilead Sciences, Inc., Theratechnologies, Research Support; Merck Sharp & Dohme Corp. Funding National Institutes of Health (R01DK112262, UL1RR024975, T32AI007474, P30AI110527)