In women with HIV and diabetes mellitus (DM), CD4+ lymphocytes may contribute to the development of DM, according to study results presented at the 10th IAS (International AIDS Society) Conference on HIV Science, held July 21 to24 in Mexico City, Mexico.

Chronic inflammation and an increased prevalence of DM are seen in people living with HIV. Chronic CD4+ T lymphocyte activation is central to HIV pathogenesis and combination antiretroviral therapy (cART)-treated people living with HIV exhibit residual CD4+ T lymphocyte activation that could contribute to age-related disease, like DM. Previous studies have suggested that activated CD4+ T lymphocytes have a reliance on glycolytic metabolism and an increased expression of glucose transporter-1 (GLUT1) in order to achieve efficient function. So, CD4+ T lymphocyte activation may be a link between inflammation and DM in people living with HIV. However, this immune activation remains largely unexplored. Therefore, this study explored the relationship between CD4+ T lymphocyte immunometabolism and DM in people living with HIV.

In total, peripheral blood mononuclear cells from 36 treated mostly virally suppressed women with HIV in the Women’s Interagency HIV Study (WIHS) without DM (n=18) and those with untreated DM (n=18) were identified and matched for race/ethnicity, smoking status, age, and CD4 count. DM was defined by either self-reported use of DM medications, hemoglobin A1c (HbA1c) ³6.5% or fasting glucose ³126 mg/dL confirmed by other clinical or laboratory parameters. Using flow cytometry, CD4+ T lymphocyte GLUT1 surface expression was examined from the peripheral blood mononuclear cells. Using a Seahorse XF96 analyzer (Agilent, Santa Rosa, California), the extracellular acidification rate (glycolysis) and the oxygen consumption rate (oxidative phosphorylation) was examined from purified CD4+ T lymphocytes. Using Fluidigm HD Biomark RT-PCR for all gene isoforms of the pentose phosphate pathway, glycolysis pathway, and the tricarboxylic acid (TCA) cycle a gene expression analysis was performed on CD4+ T lymphocytes. Using the Wilcoxon signed-rank test, comparisons of groups were calculated.

Results showed that women with HIV and untreated DM have evidence of increased CD4+ T lymphocyte metabolism and inflammation. Compared with the group of women with HIV but without DM, the group with both HIV and DM demonstrated an increased percentage of CD4+ T lymphocytes expressing GLUT1 via flow cytometric analysis. Further, the percentage of GLUT1-expressing cells correlated with CD38+HLA-DR+CD4+ T lymphocytes, suggesting that these cells were activated (P =.0016). When stimulated CD4+ T lymphocytes were assessed via Seahorse XF96, the group with both HIV and DM showed a 2.1-fold increase in oxidative phosphorylation and a 1.9-fold increase in glycolytic metabolism when compared with the group with HIV but not DM. Gene analysis of the CD4+ T lymphocytes from the group with HIV and DM showed an increased gene expression for rate-limiting enzymes in the glycolysis and pentose phosphate pathway and intermediary enzymes in the TCA cycle.

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Overall, the presenter concluded, “CD4+ T lymphocytes from women with HIV with [diabetes mellitus] display immunometabolic dysfunction that may contribute to [diabetes mellitus] development and associated complications.”

Reference

Butterfield TR, Hanna DB, Kaplan RC, et al. HIV+ women with diabetes mellitus exhibit CD4+ T lymphocyte immunometabolic dysfunction. Presented at: 10th IAS Conference on HIV Science; July 21-24, 2019; Mexico City, MX. Abstract 3512.