Circulating CD4+ TEMRA and CD4+ CD28- T cells and incident diabetes among persons with and without HIV

Abstract

Objective: A higher proportion of circulating memory CD4+ T cells is associated with prevalent diabetes mellitus in persons with HIV (PWH) and HIV-negative persons. We assessed whether circulating T-cell subsets could also identify individuals who will subsequently develop diabetes.

Design: This is a longitudinal follow-up study of PWH and similar HIV-negative individuals from the Veterans Aging Cohort Study who provided peripheral mononuclear blood cells between 2005 and 2007.

Methods: We quantified T-cell subsets using flow cytometry and functional assays to identify CD4+ and CD8+ naive, activated, senescent, memory (central, effector, and effector RA+), and TH1, TH2, and TH17-phenotype cells. The occurrence of an incident diabetes diagnosis (i.e. after baseline blood draw) was adjudicated by a two-physician chart review. Cox proportional hazards models adjusted for traditional risk factors, cytomegalovirus serostatus, and plasma inflammatory biomarkers assessed the relationship between T-cell subsets and incident diabetes.

Results: One thousand, eight hundred and thirty-seven participants (1259 PWH) without diabetes at baseline were included; 69% were black, 95% were men, and median follow-up was 8.6 years. Higher baseline frequencies of CD4+ T effector memory RA+ (TEMRA) cells defined as CD45RA+ CD27- (P = 0.04) and senescent T cells defined as CD4+ CD28- (P = 0.04) were associated with incident diabetes in PWH only.

Conclusions: Higher frequencies of CD4+ TEMRA and CD4+ CD28- T cells were associated with incident diabetes in PWH only after adjustment for other factors. Additional studies are necessary to assess whether these cells act in blood via inflammatory mediators or reflect T-cell populations in metabolically active tissues.

Figure 1.

Overview of study design and participant inclusion. Abbreviations: ART, antiretroviral therapy; HIV+, persons with HIV; HIV-, HIV-negative; VACS-BC, Veterans Aging Cohort Study Biomarker Cohort; VL, viral load.

Figure 2.

Unadjusted Cox proportional hazards model assessing the relationship between baseline clinical variables and incident diabetes in persons with HIV (black square) and HIV-negative individuals (open diamond). For linear variables, the hazard ratio is reported per kg/m² for body mass index, per year for age, and per standard deviation (SD) increment for T cell subsets with 95% confidence interval (95% CI).

Figure 3.

Cox proportional hazards model assessing the relationship of baseline T cell subsets and incident diabetes in persons with HIV (black square) and HIV-negative individuals (open diamond) adjusted for age, race, cytomegalovirus serostatus, plasma HIV-1 RNA copies/mL (persons with HIV only), high-density lipoprotein, low-density lipoprotein, total cholesterol, time-updated body mass index, hepatitis C virus serostatus, history of alcohol abuse, and circulating concentrations of interleukin-6, d-dimer, and soluble CD14. Hazard ratio is reported per standard deviation (SD) increment with 95% confidence interval (95% CI).

Figure 4.

Cox proportional hazards model assessing the relationship of baseline T cell subsets and incident diabetes in cytomegalovirus (CMV) seropositive (black square) with HIV adjusted for age, race, plasma HIV-1 RNA copies/mL, high-density lipoprotein, low-density lipoprotein, total cholesterol, time-updated body mass index (BMI), hepatitis C virus serostatus, history of alcohol abuse, and circulating concentrations of interleukin-6, d-dimer, and soluble CD14. The model for CMV seronegative PWH (open diamond) was only adjusted for age and time-updated BMI. Hazard ratio is reported per standard deviation (SD) increment with 95% confidence interval (95% CI).