the hiv, adipose tissue immunology, and metabolism study

Conditions: Hiv; Diabetes Mellitus, Type 2

Summary: 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.

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.

Eligibility criteria:
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.