Adipose Tissue T Cell Polarization and Metabolic Health in Persons Living with HIV

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Project Summary Persons with HIV (PWH) on antiretroviral therapy (ART) suffer from higher rates of cardiometabolic diseases compared with the general population, which contributes to poor health outcomes. Adipose tissue is a critical regulator of systemic metabolic processes, and changes in adipose tissue immune cell populations that modulate adipose tissue function, may in part, contribute to the risk of metabolic disease in PWH. Prior studies have shown striking changes in adipose tissue CD4+ and CD8+ T cell profile in PWH. Yet the current understanding of the role of adipose tissue immune cells in metabolic disease is limited by few studies to date evaluating PWH on contemporary ART, limited studies using single cell technologies to characterize specific cell populations, and finally limited understanding of the relationship of adipose tissue T cell populations with adipose tissue viral reservoir. Defining the mechanisms through which adipose tissue innate and adaptive immune cells contribute to metabolic diseases is critical for identifying preventative and therapeutic strategies that reduce morbidity and mortality in PWH. I leveraged single-cell RNA sequencing (scRNA-seq) to define adipose tissue compositional and transcriptional changes that occur with glucose intolerance in PWH using cross-sectional data, and compared these changes to diabetic HIV-negative adipose tissue. I found that higher proportion of CD4+ and CD8+ T effector memory (TEM) cells and lipid-associated macrophages (LAMs) was associated with glucose intolerance in PWH and higher CD4+ and CD8+ TEM proportion were associated with greater fibroblastic cells in PWH only. Our overall hypothesis is that proinflammatory TEM cells expressing interferon-g and tumor necrosis factor a are increased in PWH on ART, infiltrate adipose tissue and promote macrophage polarization, are associated with the adipose tissue viral reservoir, and contribute to the development of metabolic disease. Building upon my computational analysis skills, my career development plan will enhance my skills and knowledge in: 1) T cell immunology and analyses; 2) conducting clinical and translational research; and 3) application of multi-omic analysis to address critical research gaps. In Aim 1, I will define the cell-type specific transcriptional pattern and adipose tissue composition that are associated with progressive insulin resistance in PWH on long-term ART. In Aim 2, I will investigate the adipose tissue T cell transcriptional and compositional pattern pre-treatment and at one year of integrase strand transferase inhibitor-based regimen in those who develop progressive insulin resistance compared with those who do not. In Aim 3, I will determine the relationship between anti-viral T cells, the adipose tissue viral reservoir, and adipose tissue inflammation. Completion of these aims will greatly increase the understanding of specific immune cells contributing to inflammation and the potential factors that drive inflammation. Additionally, the training and data from the K23 award will allow me to transition to research independence in the HIV co- morbidities field with a concentration on immune cell response.