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Context Cardiometabolic diseases are common in persons with HIV (PWH) on antiretroviral therapy (ART), which has been attributed to preferential lipid storage in visceral adipose tissue (VAT) compared with subcutaneous adipose tissue (SAT). However, the relationship of SAT-specific cellular and molecular programs with VAT volume is poorly understood in PWH. Objective We characterized SAT cell-type specific composition and transcriptional programs that are associated with greater VAT volume in PWH on contemporary ART. Methods We enrolled PWH on long-term ART with a spectrum of metabolic health. Ninety-two participants underwent SAT biopsy for bulk RNA sequencing and 43 had single-cell RNA sequencing. Computed tomography quantified VAT volume and insulin resistance was calculated using the Homeostasis Model Assessment 2 Insulin Resistance (HOMA2-IR). Results VAT volume was associated with HOMA2-IR (P <.001). Higher proportions of SAT intermediate macrophages (IMs), myofibroblasts, and MYOC+ fibroblasts were associated with greater VAT volume using partial Spearman's correlation adjusting for age, sex, and body mass index (r = 0.34-0.49, P <.05 for all). Whole SAT transcriptomics showed PWH with greater VAT volume have increased expression of extracellular matrix (ECM)– and inflammation-associated genes, and reduced expression of lipolysis- and fatty acid metabolism–associated genes. Conclusion In PWH, greater VAT volume is associated with a higher proportion of SAT IMs and fibroblasts, and a SAT ECM and inflammatory transcriptome, which is similar to findings in HIV-negative persons with obesity. These data identify SAT cell-type specific changes associated with VAT volume in PWH that could underlie the high rates of cardiometabolic diseases in PWH, though additional longitudinal studies are needed to define directionality and mechanisms. [ABSTRACT FROM AUTHOR]

Introduction: Subcutaneous adipose tissue (SAT) is a critical regulator of systemic metabolic homeostasis. Persons with HIV (PWH) have an increased risk of metabolic diseases and significant alterations in the SAT immune environment compared with the general population. Methods: We generated a comprehensive single-cell multi-omic SAT atlas to characterize cellular compositional and transcriptional changes in 59 PWH across a spectrum of metabolic health. Results: Glucose intolerance was associated with increased lipid-associated macrophages, CD4+ and CD8+ T effector memory cells, and decreased perivascular macrophages. We observed a coordinated intercellular regulatory program which enriched for genes related to inflammation and lipid-processing across multiple cell types as glucose intolerance increased. Increased CD4+ effector memory tissue-resident cells most strongly associated with altered expression of adipocyte genes critical for lipid metabolism and cellular regulation. Intercellular communication analysis demonstrated enhanced proinflammatory and pro-fibrotic signaling between immune cells and stromal cells in PWH with glucose intolerance compared with non-diabetic PWH. Lastly, while cell type-specific gene expression among PWH with diabetes was globally similar to HIV-negative individuals with diabetes, we observed substantially divergent intercellular communication pathways. Discussion: These findings suggest a central role of tissue-resident immune cells in regulating SAT inflammation among PWH with metabolic disease, and underscore unique mechanisms that may converge to promote metabolic disease. [ABSTRACT FROM AUTHOR]

[Figure: see text]. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Context: Cardiometabolic diseases are common in persons with HIV (PWH) on antiretroviral therapy (ART), which has been attributed to preferential lipid storage in visceral adipose tissue (VAT) compared with subcutaneous adipose tissue (SAT). However, the relationship of SAT-specific cellular and molecular programs with VAT volume is poorly understood in PWH., Objective: We characterized SAT cell-type specific composition and transcriptional programs that are associated with greater VAT volume in PWH on contemporary ART., Methods: We enrolled PWH on long-term ART with a spectrum of metabolic health. Ninety-two participants underwent SAT biopsy for bulk RNA sequencing and 43 had single-cell RNA sequencing. Computed tomography quantified VAT volume and insulin resistance was calculated using the Homeostasis Model Assessment 2 Insulin Resistance (HOMA2-IR)., Results: VAT volume was associated with HOMA2-IR (P < .001). Higher proportions of SAT intermediate macrophages (IMs), myofibroblasts, and MYOC+ fibroblasts were associated with greater VAT volume using partial Spearman's correlation adjusting for age, sex, and body mass index (r = 0.34-0.49, P < .05 for all). Whole SAT transcriptomics showed PWH with greater VAT volume have increased expression of extracellular matrix (ECM)- and inflammation-associated genes, and reduced expression of lipolysis- and fatty acid metabolism-associated genes., Conclusion: In PWH, greater VAT volume is associated with a higher proportion of SAT IMs and fibroblasts, and a SAT ECM and inflammatory transcriptome, which is similar to findings in HIV-negative persons with obesity. These data identify SAT cell-type specific changes associated with VAT volume in PWH that could underlie the high rates of cardiometabolic diseases in PWH, though additional longitudinal studies are needed to define directionality and mechanisms., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

While antiretroviral therapy (ART) has proven effective in suppressing viremia and disease progression among people living with human immunodeficiency virus (HIV; PLWH), suboptimal CD4 + T cell reconstitution remains a major obstacle in nearly 30% of ART-treated individuals. Epidemiological studies demonstrate that obesity, or a body mass index (BMI) ≥ 30 kg/m 2 , is positively correlated with greater CD4 + T cell recovery in PLWH on ART. Leptin is a known immunomodulator that is produced in proportion to fat mass and is increased in obese individuals, including PLWH. We hypothesized that CD4 + T cells from obese PLWH have increased cell proliferation and cytokine production compared to cells from lean PLWH, potentially modulated by differential effects of leptin signaling. To test this hypothesis, peripheral blood mononuclear cells from obese and lean PLWH with long-term virologic suppression on the same ART regimen were pretreated with recombinant leptin and then stimulated with anti-CD3/CD28 or PMA/ionomycin to measure Ki67 expression, leptin receptor (LepR) surface expression and cytokine production. In the absence of leptin, Ki67 expression and IL-17A production were significantly higher in CD4 + T cells from obese compared to lean PLWH. However, LepR expression was significantly lower on CD4 + T cells from obese compared to lean PLWH. After leptin treatment, Ki67 expression was significantly increased in CD4 + T cells from obese PLWH compared to the lean participants. Leptin also increased IL-17A production in CD4 + T cells from obese healthy controls. In contrast, leptin decreased IL-17A production in CD4 + T cells from both obese and lean PLWH. Combined, these results demonstrate that obesity is associated with greater CD4 + T cell proliferation among PLWH, and that higher circulating leptin levels in obesity may contribute to improved CD4 + T reconstitution in PLWH initiating ART., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fuseini, Smith, Nochowicz, Simmons, Hannah, Wanjalla, Gabriel, Mashayekhi, Bailin, Castilho, Hasty, Koethe and Kalams.)