HIV-infected (HIV+) persons can survive decades on antiretroviral therapy, but this success is accompanied by a disproportionate burden of metabolic disease, including type 2 diabetes, in the HIV population. We hypothesize that the accumulation of chronically activated T cells in the adipose tissue of HIV+ persons is a central mechanism promoting local macrophage activation, impaired adipocyte function, and the development of HIV-associated glucose intolerance. This hypothesis is supported by our preliminary data showing 1.) a higher percentage of circulating memory CD4+ T cells in HIV+ persons is associated with insulin resistance and incident diabetes. 2.) Adipose tissue biopsies from HIV+ persons are enriched for activated CD8+ T cells compared to blood, and there is a strong correlation between the percentage of adipose-resident and circulating memory CD4+ T cells. 3.) In our murine model of obesity and insulin resistance, we found an association between adipose-resident CD8+ T cell density and T cell receptor oligoclonality, suggesting the expansion of CD8+ T cells in adipose tissue may represent an antigen-driven process Prior studies of immune activation and HIV-associated metabolic disease have only measured circulating T cell subsets. In contrast, our study will recruit a longitudinal cohort of HIV+ patients on antiretroviral therapy ranging from insulin sensitive to overtly diabetic, in addition to HIV-negative diabetic controls, to identify potential mechanistic linkages between adipose-resident T cell cytokine signaling, adipose tissue inflammation, and glucose intolerance in HIV+ persons. Our three aims will determine whether circulating blood T cell subsets are reflective of adipose-resident subsets in HIV+ persons (Aim 1), whether activated adipose-resident T cells contribute to macrophage activation, adipocyte dysfunction, and glucose intolerance (Aim 2), and whether greater adipose-resident CD8+ T cell receptor oligoclonality is correlated with metabolic dysfunction (Aim 3), which may indicate the development of HIV-associated diabetes has an antigen-driven component. This study will: 1.) clarify the role of chronic, HIV-related T cell activation in the development of glucose intolerance, 2.) assess whether the cytokine signaling profiles of adipose-resident activated, memory, and other T cell types differ from what is already known about circulating T cells, 3.) clarify the metabolic consequences of adipose tissue as a reservoir for latently HIV-infected CD4+ T cells, 4.) identify potential immunologic therapeutics targets for metabolic disease and HIV cure research, and 5.) assess whether adipose-resident CD8+ T cell oligoclonal expansion accompanies adipocyte dysfunction and glucose intolerance, and should be explored further to identify epitopes potentially contributing to HIV-associated metabolic disease. This study may also provide further insight into the role of T cells in the development of glucose intolerance in HIV-negative patients.

Public Health Relevance

/ Public Health Relevance Statement HIV-infected individuals can now survive decades on antiretroviral therapy, but this success has been accompanied by an increasing burden of metabolic disease, including diabetes, in the HIV patient population. HIV infection causes changes in the immune system, some of which may impair the health of adipose (fat) tissue and contribute to the development of diabetes. The goal of this study is to improve our understanding of how immune cells in adipose tissue affect glucose metabolism, and help design future therapies to reduce the prevalence of diabetes in both HIV-infected persons and the general population.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Malozowski, Saul N
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Vanderbilt University Medical Center
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Koethe, John R; Jenkins, Cathy A; Furch, Briana D et al. (2018) Brief Report: Circulating Markers of Immunologic Activity Reflect Adiposity in Persons With HIV on Antiretroviral Therapy. J Acquir Immune Defic Syndr 79:135-140
Koethe, John R; McDonnell, Wyatt; Kennedy, Arion et al. (2018) Adipose Tissue is Enriched for Activated and Late-Differentiated CD8+ T Cells and Shows Distinct CD8+ Receptor Usage, Compared With Blood in HIV-Infected Persons. J Acquir Immune Defic Syndr 77:e14-e21
McDonnell, Wyatt J; Koethe, John R; Mallal, Simon A et al. (2018) High CD8 T-Cell Receptor Clonality and Altered CDR3 Properties Are Associated With Elevated Isolevuglandins in Adipose Tissue During Diet-Induced Obesity. Diabetes 67:2361-2376
Wanjalla, Celestine N; McDonnell, Wyatt J; Koethe, John R (2018) Adipose Tissue T Cells in HIV/SIV Infection. Front Immunol 9:2730