المؤلفون: Ayoda T. Werede, James G. Terry, Sangeeta Nair, Tecla M. Temu, Bryan E. Shepherd, Samuel S. Bailin, Mona Mashayekhi, Curtis L. Gabriel, Morgan Lima, Beverly Owen Woodward, LaToya Hannah, Simon A. Mallal, Joshua A. Beckman, Jonathan Z. Li, Jesse Fajnzylber, David G. Harrison, John Jeffrey Carr, John R. Koethe, Celestine N. Wanjalla

المصدر: Journal of the American Heart Association. 11(23)

مصطلحات موضوعية: Virology, Infectious agents, Cardiology and Cardiovascular Medicine

الوصف: Background Persons with HIV have a higher prevalence of coronary artery disease compared with their HIV‐negative counterparts. Earlier identification of subclinical atherosclerosis may provide a greater opportunity for cardiovascular disease risk reduction. We investigated coronary cross‐sectional area (CorCSA) by noncontrasted computed tomography imaging as a noninvasive measure of arterial remodeling among virally suppressed persons with HIV. Methods and Results We assessed 105 persons with HIV with a spectrum of cardiometabolic health. All participants underwent computed tomography imaging to assess the mean corCSA of the proximal left anterior descending artery and 28 participants underwent additional coronary computed tomography angiography. Partial Spearman rank correlations adjusted for cardiovascular disease risk factors were used to assess relationships of corCSA with anthropometric measurements, HIV‐related factors, and plasma cytokines. Mean corCSA measured by noncontrast computed tomography and coronary computed tomography angiography were strongly correlated (ρ=0.91, P P =0.005) and it correlated with participants' atherosclerotic cardiovascular disease risk score (ρ=0.35, P =0.01). After adjusting for established cardiovascular disease risk factors, we observed an inverse relationship between corCSA and CD4 + T‐cell count (ρ=−0.2, P =0.047). Removal of age from the model strengthened the relationships between corCSA and antiretroviral therapy duration (from ρ=0.19, P =0.08 to ρ=0.3, P =0.01). CorCSA was also inversely correlated with plasma IL‐10 (ρ=−0.25, P =0.03) but had no relationship with IL‐6 (ρ=0.11, P =0.4) or IL‐1β (ρ=0.08, P =0.5). Conclusions Positive coronary arterial remodeling, an imaging marker of subclinical atherosclerosis, is associated with a lower CD4 T‐cell count, lower circulating IL‐10, and possibly a longer antiretroviral therapy duration in persons with HIV. Registration Clinicaltrials.gov; Unique identifier: NCT04451980.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9a2e53d616ed4a4fa6f1c7ced0c10282Test
https://pubmed.ncbi.nlm.nih.gov/36382956Test

المؤلفون: J. Jeffrey Carr, LaToya Hannah, Paxton Baker, James G. Terry, Morgan C. Lima, Beverly O. Woodward, Celestine N. Wanjalla, Fei Ye, Sangeeta Nair, Curtis L. Gabriel, Sam Bailin, Heidi J. Silver, Run Fan, Mona Mashayekhi, John R. Koethe, Manhal Izzy, Jane F. Ferguson

المصدر: Hepatology Communications, Vol 5, Iss 7, Pp 1224-1237 (2021)
Hepatology Communications

مصطلحات موضوعية: medicine.medical_specialty, Lipoprotein lipase, Hepatology, business.industry, Adipose tissue, Lipid metabolism, Original Articles, RC799-869, Diseases of the digestive system. Gastroenterology, medicine.disease, chemistry.chemical_compound, Endocrinology, chemistry, Phospholipid transfer protein, Internal medicine, Adipocyte, Nonalcoholic fatty liver disease, medicine, Original Article, Steatosis, business, Lipoprotein

الوصف: 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.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::446455649f837913c4f7a0ac24eb5b8cTest
https://doi.org/10.1002/hep4.1695Test

المؤلفون: Samuel S. Bailin, Jonathan A. Kropski, Rama D. Gangula, LaToya Hannah, Joshua D. Simmons, Mona Mashayekhi, Fei Ye, Run Fan, Simon Mallal, Christian M. Warren, Spyros A. Kalams, Curtis L. Gabriel, Celestine N. Wanjalla, John R. Koethe

الوصف: 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. We generated a comprehensive SAT atlas to characterize cellular compositional and transcriptional changes in 59 PWH with a spectrum of metabolic health. Glucose intolerance was associated with increased lipid-associated macrophages and 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. Many of these findings were present in a separate group of 32 diabetic HIV-negative persons, suggesting these changes are not specific to HIV.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::120178fc4b1a0afd802e321509fade84Test
https://doi.org/10.1101/2022.03.21.484794Test

المؤلفون: Hubaida Fuseini, Rita Smith, Cindy H. Nochowicz, Joshua D. Simmons, LaToya Hannah, Celestine N. Wanjalla, Curtis L. Gabriel, Mona Mashayekhi, Samuel S. Bailin, Jessica L. Castilho, Alyssa H. Hasty, John R. Koethe, Spyros A. Kalams

المصدر: Frontiers in Immunology, Vol 12 (2022)
Frontiers in Immunology

مصطلحات موضوعية: Adult, CD4-Positive T-Lymphocytes, Male, obesity, Immunology, Gene Expression, HIV Infections, body mass index, Lymphocyte Activation, leptin, CD4+ T cell, IL-17A, Humans, Immunology and Allergy, Lymphocyte Count, Original Research, HIV, Middle Aged, RC581-607, Flow Cytometry, Ki-67 Antigen, Leukocytes, Mononuclear, Cytokines, Female, Immunologic diseases. Allergy, Ki67, Biomarkers

الوصف: 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/m2, 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.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c2b7959e69e8e184fa4384e60dca7dcaTest
https://doi.org/10.3389/fimmu.2021.796898Test

المؤلفون: Samuel Bailin, Jonathan A. Kropski, Rama Gangula, LaToya Hannah, Joshua D. Simmons, Mona Mashayekhi, Fei Ye, Run Fan, Abha Chopra, Ramesh Ram, Simon A. Mallal, Christian M. Warren, Spyros A. Kalams, Curtis L. Gabriel, Celestine N. Wanjalla, John R. Koethe

المصدر: SSRN Electronic Journal.

مصطلحات موضوعية: History, Polymers and Plastics, Business and International Management, Industrial and Manufacturing Engineering

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::e4e9e306ab0943132ec0343eb77ce8a2Test
https://doi.org/10.2139/ssrn.4097122Test

المؤلفون: Robert Manning, John R. Koethe, Hui Nian, Chang Yu, Jorge L. Gamboa, Justina Ray, LaToya Hannah, Anthony DeMatteo, Mona Mashayekhi, Dawei Wei, James M. Luther, Dungeng Peng, Nancy J. Brown, Andrew S. Terker

المصدر: Hypertension

مصطلحات موضوعية: Adult, Male, medicine.medical_specialty, Soluble epoxide hydrolase activity, Adipose tissue, medicine.disease_cause, Article, Insulin resistance, Double-Blind Method, Internal medicine, Internal Medicine, medicine, Humans, Muscle, Skeletal, Epoxide Hydrolases, Cyclohexylamines, F2-Isoprostanes, Cross-Over Studies, Chemistry, Triazines, Insulin sensitivity, Middle Aged, medicine.disease, Endocrinology, Adipose Tissue, cardiovascular system, Female, Insulin Resistance, Oxidative stress

الوصف: Epoxyeicosatrienoic acids (EETs) reduce blood pressure by acting in the vasculature and kidney, and interventions to increase circulating EETs improve insulin sensitivity and prevent diabetes in animal models. Inhibition of EET hydrolysis with a sEH (soluble epoxide hydrolase) inhibitor is an attractive approach for hypertension and diabetes. We tested the hypothesis that sEH inhibition increases circulating EETs, reduces blood pressure, and improves insulin sensitivity, blood flow, and inflammation in a randomized, double-blind, placebo-controlled crossover study. Sixteen participants with obesity and prediabetes were randomized to GSK2256294 10 mg QD or placebo for 7 days, insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and adipose and muscle tissues biopsies were performed to assess insulin-stimulated Akt phosphorylation. We assessed tissue and plasma EETs and their respective diol concentrations and sEH activity within plasma, muscle, and adipose tissues. GSK2256294 reduced circulating and adipose tissue sEH activity, but blood pressure, circulating EET, and tissue EETs were unchanged. Plasma sEH activity correlated with muscle and adipose tissue sEH activity. Insulin sensitivity assessed during hyperinsulinemic clamps, as well as adipose and muscle phosphorylated-Akt/Akt expression were similar during GSK2256294 and placebo. sEH inhibition with GSK2256294 reduced plasma F2-isoprostanes (50.7±15.8 versus 37.2±17.3 pg/mL; P =0.03) but not IL (interleukin)-6. Resting blood pressure, forearm blood flow, and renal plasma flow were similar during GSK2256294 and placebo. We demonstrate that GSK2256294 administration for 7 days effectively inhibits sEH activity in plasma, muscle, and adipose tissue and reduces F2-isoprostanes—a marker of oxidative stress—but does not improve insulin sensitivity or blood pressure.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4291bee92ebfac0bf5f1745e49d6639dTest
https://pubmed.ncbi.nlm.nih.gov/34455816Test

المؤلفون: Samuel S. Bailin, Curtis L. Gabriel, Run Fan, Fei Ye, Sangeeta Nair, James G. Terry, John J. Carr, Heidi Silver, Celestine N. Wanjalla, Mona Mashayekhi, Morgan Lima, Beverly Woodward, LaToya Hannah, Hubaida Fuseini, Jane F. Ferguson, Jonathan A. Kropski, John R. Koethe

المصدر: J Acquir Immune Defic Syndr

مصطلحات موضوعية: Inflammation, Infectious Diseases, Adipose Tissue, Subcutaneous Fat, Gene Expression, Humans, Pharmacology (medical), HIV Infections, Intra-Abdominal Fat, Lipids, Subcutaneous Fat, Abdominal, Article

الوصف: OBJECTIVE: Fat redistribution from subcutaneous adipose tissue (SAT) to the abdominal viscera, pericardium, liver and skeletal muscle contributes to the rising burden of cardiometabolic disease among persons with HIV (PWH). Prior studies found SAT inflammation in PWH impairs lipid storage and persists despite plasma viral suppression on antiretroviral therapy (ART). In this study, we identify SAT immune-related genes associated with ectopic fat deposition in PWH on long-term ART. DESIGN AND METHODS: A total of 92 PWH with well-controlled viremia underwent computed tomography (CT) imaging and abdominal SAT biopsy for gene expression analysis. SAT gene expression was measured using a NanoString panel of 255 immune-related genes. Associations between gene expression and CT measurements of the volume and attenuation (radiodensity) of metabolically relevant ectopic fat depots were assessed using multivariable linear regression and network analysis. RESULTS: Greater SAT volume was associated with higher visceral and pericardial adipose tissue volume, but lower skeletal muscle attenuation. Lower SAT attenuation, a measure of lipid content, was associated with lower VAT attenuation. Hierarchical clustering identified a subset of macrophage-related genes in SAT, including CCL2, CCL22, CCL13, CCR1, CD86, CD163, IL-6, IL-10, MRC1, and TREM2, that were associated with increased lipid deposition in multiple ectopic depots. CONCLUSION: Altered expression of macrophage-related genes in SAT is associated with differences in ectopic fat depot morphometrics among PWH on long-term ART, including in the pericardial and visceral compartments. These findings provide basis for future studies to assess host, virus, and treatment factors shaping the SAT immune environment and its effects on morphometric changes and metabolic comorbidities in PWH.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aba4f2080da599e8dfc69370aeac1bd0Test
https://pubmed.ncbi.nlm.nih.gov/35125474Test

المؤلفون: Aloke V. Finn, Shay Leary, Samuel S Bailin, Abha Chopra, Daniela T. Fuller, Simon Mallal, Joshua D. Simmons, Christian M Warren, Curtis L. Gabriel, Alyssa H. Hasty, Mark A. Pilkinton, Celestine N. Wanjalla, LaToya Hannah, Wyatt J. McDonnell, Briana D. Furch, Mona Mashayekhi, Liang Guo, Kenji Kawai, Rama Gangula, Morgan C. Lima, Beverly O. Woodward, John R. Koethe, Renu Virmani, Spyros A. Kalams, Ramesh Ram

المصدر: Cell Reports Medicine

مصطلحات موضوعية: CD4-Positive T-Lymphocytes, T cell, Adipose tissue, HIV Infections, CD8-Positive T-Lymphocytes, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Transcriptome, CX3CR1, chemistry.chemical_compound, T-Lymphocyte Subsets, Adipocyte, Diabetes Mellitus, medicine, Humans, Cytotoxic T cell, CD69, Receptor, cytomegalovirus, diabetes, HIV, Lipid metabolism, adipose tissue, single cell, GPR56, medicine.anatomical_structure, chemistry, Cytomegalovirus Infections, Immunology, Single-Cell Analysis, CD57, CD4 T cell

الوصف: 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.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::235d3105800203184cad32145b73ceb7Test
https://doi.org/10.1016/j.xcrm.2021.100205Test

المؤلفون: Abha Chopra, Simon Mallal, Christian M. Warren, Morgan C. Lima, Celestine N. Wanjalla, Rama Gangula, Shay Leary, Alyssa M. Hasty, John R. Koethe, Spyros A. Kalams, Briana D. Furch, Curtis L. Gabriel, Joshua D. Simmons, Beverly O. Woodward, Mona Mashayekhi, Ramesh Ram, Wyatt J. McDonnell, Samuel Bailin, LaToya Hannah, Mark A. Pilkinton

المصدر: SSRN Electronic Journal.

مصطلحات موضوعية: Innate immune system, T cell, T-cell receptor, Adipose tissue, Inflammation, Biology, Transcriptome, chemistry.chemical_compound, medicine.anatomical_structure, Single-cell analysis, chemistry, Adipocyte, Immunology, medicine, medicine.symptom

الوصف: 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.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::2c5c52037b8484d2f3315435309caaa6Test
https://doi.org/10.2139/ssrn.3489447Test