The HIV, Adipose Tissue Immunology, and Metabolism Study

Study Overview
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Brief Summary
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With the introduction of effective anti-retroviral therapy (ART), HIV-infected persons can now survive for decades, but this success has been accompanied by an increased risk of developing metabolic disease and diabetes in HIV-infected persons compared to the general population. Recent studies from HIV-negative subjects have identified several associations between circulating immune cell populations and impaired glucose tolerance, including increased activated CD4+ and CD8+ T cells, and reduced regulatory T cells. Of note, these same changes in peripheral T cell subsets are frequently observed in patients with chronic HIV infection. The goal of this study is to assess whether the circulating T cell distribution is reflective of the adipose tissue T cell distribution, and to understand whether chronic adipose tissue T cell activation may impair adipocyte (i.e., fat cell) function and insulin sensitivity. If the investigators' hypotheses are correct, this will demonstrate that chronic peripheral immune activation (i.e., high memory T cells, low naïve cells, and increased expression of activation surface markers) is associated with greater adipose-resident CD4+ and CD8+ T cell expression of activation markers, adipose tissue inflammation, and insulin resistance.

Detailed Description
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With the introduction of effective antiretroviral therapy (ART), HIV-infected persons can now survive for decades, but this success has been accompanied by an increased risk of developing metabolic disease compared HIV-negative persons. In the Multicenter AIDS Cohort Study, HIV-infected men had a greater than 4-fold increased incidence of a new diabetes diagnosis compared to HIV-negative men after adjusting for age and body mass index (BMI). Prevalence studies of diabetes in HIV-infected individuals on ART have reported incidence rates of 3.1 to 14 per 1000 patient-years. Furthermore, treated HIV infection appears to act synergistically with other risk factors, and diabetes prevalence is especially high among HIV-infected individuals with high BMI and advanced age. Recent studies from HIV-negative subjects identified several associations between adaptive immune cell populations and impaired glucose tolerance. Peripheral T regulatory (Treg) cells are significantly lower in patients with type-2 diabetes , while the numbers activated T cells, CD4+ TH1 (pro-inflammatory) cells, and memory CD4+ T cells are higher in diabetics. Immune cells translocate from the circulation into adipose tissue in a dynamic process, and T cells are present in the stromal fraction of adipose tissue and affect adipocyte function. The striking increase in adipose tissue CD4+ TH1 cells and CD8+ T cells, and a decrease in Treg cells, observed in obesity may have an important role in the development of insulin resistance. Secretion of the proinflammatory cytokines interferon-γ and interleukin (IL)-17 by TH1 and TH17 cells are implicated in the induction of proinflammatory M1 macrophages, which express IL-6 and tumor necrosis factor alpha, and inhibit adipocyte insulin signaling by promoting phosphorylation of insulin receptor substrate 1. The investigators hypothesize that the chronic, HIV-related activation of circulating CD4+ and CD8+ T cells may be accompanied by the accumulation of activated T cells in adipose tissue with adverse effects on metabolic activity. In this study, the investigators will test the hypothesis that the oligoclonal expansion of chronically activated peripheral T cells in adipose tissue is a primary driver of macrophage inflammation and reduced adipocyte insulin sensitivity. Furthermore, the investigators propose that this represents a central mechanistic linkage underlying the association between circulating T cell activation and incident diabetes risk observed in HIV-infected and HIV-negative individuals.

Official Title
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The HIV, Adipose Tissue Immunology, and Metabolism Study

Conditions
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Hiv, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Procedure: Subcutaneous adipose tissue biopsy
* Radiation: CT scan
* Diagnostic Test: Oral glucose tolerance test
* Diagnostic Test: Blood collection


Participation Criteria
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Eligibility Criteria
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HIV+ Participants: Inclusion Criteria: On antiretroviral therapy for at least 18 months HIV-1 RNA <400 copies/ml for the prior 12 months CD4+ count >350 cells/µl in the prior 12 months HbA1c in prior 6 months within specified limits (See Figure) Pre-menopausal by self-report or post-menopausal but not on hormone replacement therapy (HRT) Exclusion Criteria: Known inflammatory or rheumatologic conditions Heavy alcohol (>11 drinks per week) or cocaine, amphetamine, or illicit (non-prescribed) opiate abuse by self-report Current use of DPP-4 inhibitors. HIV-negative Participants: Inclusion Criteria: A HbA1c >6.5% or a fasting glucose >126mg/dl, or on anti-diabetic medications for at least 6 months Pre-menopausal by self-report or post-menopausal but not on hormone replacement therapy (HRT) Exclusion criteria: Known inflammatory or rheumatologic conditions Heavy alcohol (>11 drinks per week) or cocaine, amphetamine, or illicit (non-prescribed) opiate abuse by self-report Current use of DPP-4 inhibitors.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| HIV+ non-diabetics<br>HIV-infected participants with hemoglobin A1c (HbA1c) <5.7% or fasting glucose <100 mg/dl. | Procedure: Subcutaneous adipose tissue biopsy<br>* Percutaneous adipose tissue biopsy<br>Radiation: CT scan<br>* CT scan of chest and abdomen without contrast<br>Diagnostic Test: Oral glucose tolerance test<br>* Ingestion of 75g of oral glucose syrup and measurement of blood glucose and insulin at time 0, 15 min, 30 min, 60 min, 90 min, and 120 min.<br>Diagnostic Test: Blood collection<br>* Fasting blood collection for plasma cytokines and T cell phenotypes.<br>|
| HIV+ pre-diabetics<br>HIV-infected participants with HbA1c 5.7-6.4% or fasting glucose 100-125 mg/dl. | Procedure: Subcutaneous adipose tissue biopsy<br>* Percutaneous adipose tissue biopsy<br>Radiation: CT scan<br>* CT scan of chest and abdomen without contrast<br>Diagnostic Test: Oral glucose tolerance test<br>* Ingestion of 75g of oral glucose syrup and measurement of blood glucose and insulin at time 0, 15 min, 30 min, 60 min, 90 min, and 120 min.<br>Diagnostic Test: Blood collection<br>* Fasting blood collection for plasma cytokines and T cell phenotypes.<br>|
| HIV+ diabetics<br>HIV-infected participants with HbA1c >=6.5% or fasting glucose >=126 mg/dl or on anti-diabetic medications. | Procedure: Subcutaneous adipose tissue biopsy<br>* Percutaneous adipose tissue biopsy<br>Radiation: CT scan<br>* CT scan of chest and abdomen without contrast<br>Diagnostic Test: Blood collection<br>* Fasting blood collection for plasma cytokines and T cell phenotypes.<br>|
| HIV-negative diabetics<br>HIV-negative participants with HbA1c >=6.5% or fasting glucose >=126 mg/dl or on anti-diabetic medications. | Procedure: Subcutaneous adipose tissue biopsy<br>* Percutaneous adipose tissue biopsy<br>Radiation: CT scan<br>* CT scan of chest and abdomen without contrast<br>Diagnostic Test: Blood collection<br>* Fasting blood collection for plasma cytokines and T cell phenotypes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adipose tissue T cell surface marker phenotype and antigen receptor sequence | Flow cytometry measurement of adipose tissue T cell surface marker phenotypes and sequencing of T cell receptors, compared by HIV and diabetes status | At study enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CT measurements of visceral, hepatic, and pericardial fat content | Quantification of visceral, hepatic, and pericardial adipose tissue content, compared by HIV and diabetes status | At study enrollment | 
| Circulating T cell surface marker phenotype | Flow cytometry measurement of circulating T cell surface marker phenotypes, compared by HIV and diabetes status | At study enrollment |