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Persons with human immunodeficiency virus (PWH) have subcutaneous adipose tissue (SAT) dysfunction related to antiretroviral therapy and direct viral effects, which may contribute to a higher risk of nonalcoholic fatty liver disease compared with human immunodeficiency virus–negative individuals. We assessed relationships between SAT expression of major adipocyte regulatory and lipid storage genes with hepatic and other ectopic lipid deposits in PWH. We enrolled 97 PWH on long‐term antiretroviral therapy with suppressed plasma viremia and performed computed tomography measurements of liver attenuation, a measure of hepatic steatosis, skeletal muscle (SM) attenuation, and the volume of abdominal subcutaneous, visceral, and pericardial adipose tissue. Whole SAT gene expression was measured using the Nanostring platform, and relationships with computed tomography imaging and fasting lipids were assessed using multivariable linear regression and network mapping. The cohort had a mean age of 47 years, body mass index of 33.4 kg/m2, and CD4 count of 492 cells/mm3. Lower liver attenuation, a marker of greater steatosis, was associated with differences in SAT gene expression, including lower lipoprotein lipase and acyl‐CoA dehydrogenase, and higher phospholipid transfer protein. Lower liver attenuation clustered with lower visceral adipose tissue (VAT) attenuation and greater VAT volume, pericardial fat volume and triglycerides, but no relationship was observed between liver attenuation and SAT volume, SM attenuation, or low‐density lipoprotein. Conclusion: Liver attenuation was associated with altered SAT expression of genes regulating lipid metabolism and storage, suggesting that SAT dysfunction may contribute to nonalcoholic fatty liver disease in PWH. SAT gene‐expression relationships were similar for VAT volume and attenuation, but not SM, indicating that ectopic lipid deposition may involve multiple pathways.

Persons with HIV (PWH) are at high risk for diabetes mellitus. Adipose tissue T cells are a central regulator of inflammation and adipocyte function, and the known establishment of a HIV reservoir in adipose could contribute to metabolic dysregulation. Here, we show that CD4+ T cell subsets increased in the adipose of diabetic PWH, specifically CD69+ and CD69lo CD57+ GPR56+ CX3CR1+, are clonally expanded with shared T cell receptors, suggesting a common lineage. We observed that both CD69+ and CX3CR1+ CD4+ T cells have transcriptomes consistent with a TH1 profile in diabetics versus TH2 in non-diabetics. CX3CR1+ CD4+ T cells from diabetic PWH also have increased expression of genes in innate immune pathways, not present in CD69+ cells, suggesting functional differences. This study sets the stage for future investigations to determine whether viral antigens in adipose tissue may promote clonal expansion of pro-inflammatory CX3CR1+ and CD69+ CD4+ T cells.

Summary Persons with HIV are at increased risk for diabetes mellitus compared with individuals without HIV. Adipose tissue is an important regulator of glucose and lipid metabolism, and adipose tissue T cells modulate local inflammatory responses and, by extension, adipocyte function. Persons with HIV and diabetes have a high proportion of CX3CR1+ GPR56+ CD57+ (C-G-C+) CD4+ T cells in adipose tissue, a subset of which are cytomegalovirus specific, whereas individuals with diabetes but without HIV have predominantly CD69+ CD4+ T cells. Adipose tissue CD69+ and C-G-C+ CD4+ T cell subsets demonstrate higher receptor clonality compared with the same cells in blood, potentially reflecting antigen-driven expansion, but C-G-C+ CD4+ T cells have a more inflammatory and cytotoxic RNA transcriptome. Future studies will explore whether viral antigens have a role in recruitment and proliferation of pro-inflammatory C-G-C+ CD4+ T cells in adipose tissue of persons with HIV., Graphical Abstract, Highlights Adipose tissue memory CD4+ T cells are frequently CD69+ in persons with diabetes Persons with HIV and diabetes have more CX3CR1+ GPR56+ CD57+ (C-G-C+) CD4+ T cells Adipose tissue C-G-C+ CD4+ T cells and CD69+ CD4+ T cells are clonally expanded C-G-C+ CD4+ T cells are often CMV specific and have more inflammatory transcriptomes, Wanjalla et al. demonstrate that adipose tissue in persons with HIV and diabetes includes a large proportion of clonally expanded, inflammatory, and frequently CMV-specific CX3CR1+ GPR56+ CD57+ (C-G-C+) CD4+ T cells. These cells may contribute to the altered adipocyte function and elevated risk of metabolic disease observed among persons with HIV.

Chronic T cell activation and accelerated immune senescence are hallmarks of HIV infection, which may contribute to the increased risk of cardiometabolic diseases in people living with HIV (PLWH). T lymphocytes play a central role in modulating adipose tissue inflammation and, by extension, adipocyte energy storage and release. Here, we assessed the CD4+ and CD8+ T cell profiles in the subcutaneous adipose tissue (SAT) and blood of non-diabetic (n = 9; fasting blood glucose [FBG] < 100 mg/dL), pre-diabetic (n = 8; FBG = 100–125 mg/dL) and diabetic (n = 9; FBG ≥ 126 mg/dL) PLWH, in addition to non- and pre-diabetic, HIV-negative controls (n = 8). SAT was collected by liposuction and T cells were extracted by collagenase digestion. The proportion of naïve (TNai) CD45RO−CCR7+, effector memory (TEM) CD45RO+CCR7−, central memory (TCM) CD45RO+CCR7+, and effector memory revertant RA+(TEMRA) CD45RO−CCR7− CD4+ and CD8+ T cells were measured by flow cytometry. CD4+ and CD8+ TEM and TEMRA were significantly enriched in SAT of PLWH compared to blood. The proportions of SAT CD4+ and CD8+ memory subsets were similar across metabolic status categories in the PLWH, but CD4+ T cell expression of the CD69 early-activation and tissue residence marker, particularly on TEM cells, increased with progressive glucose intolerance. Use of t-distributed Stochastic Neighbor Embedding (t-SNE) identified a separate group of predominantly CD69lo TEM and TEMRA cells co-expressing CD57, CX3CR1, and GPR56, which were significantly greater in diabetics compared to non-diabetics. Expression of the CX3CR1 and GPR56 markers indicate these TEM and TEMRA cells may have anti-viral specificity. Compared to HIV-negative controls, SAT from PLWH had an increased CD8:CD4 ratio, but the distribution of CD4+ and CD8+ memory subsets was similar irrespective of HIV status. Finally, whole adipose tissue from PLWH had significantly higher expression of TLR2, TLR8, and multiple chemokines potentially relevant to immune cell homing compared to HIV-negative controls with similar glucose tolerance.