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CD38 is a potential therapeutic target for mitigating chronic inflammation that likely drives cellular aging, comorbidities, and end organ disease in PWH
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Persistent CD38 expression on CD8+ T lymphocytes contributes to altered mitochondrial function and chronic inflammation in people with HIV, despite ART
JAIDS August 24, 2022 Mathur, Poonam DO, MPH1; Kottilil, Shyamasundaran MD, PhD1; Pallikkuth, Suresh PhD2; Frasca, Daniela PhD3; Ghosh, Alip PhD, MSc1
Abstract
Background.
Age-associated comorbidities are higher in people with HIV (PWH) than HIV-negative individuals. This is partially attributed to immune activation and CD38 expression on T cells driving chronic inflammation. However, the exact contribution of CD38-expressing T cells on the proinflammatory response is not completely understood.
Methods.
CD38-expressing CD8+ T lymphocytes were measured from PWH and HIV-negative individuals. Mitochondrial mass, superoxide content, membrane depolarization of CD4+ and CD8+ T lymphocytes, and cytokine production after HIV(gag) specific-peptide stimulation from CD38+CD8+ T lymphocytes of PWH was measured to link biological effects of CD38 expression on cellular metabolism.
Results. The frequency of activated CD8+CD38+ T cells persists in PWH on ART as compared to HIV-negative individuals. Higher CD38 expression is associated with mitochondrial biogenesis and HIV(gag)-specific proinflammatory cytokine production in PWH. Blockade of CD38 results in lower Gag-specific cytokine production.
Conclusions.
ART only partially reduced HIV-induced CD38 expression on CD8+ T cells. CD8+ CD38+ T cells are highly activated in vivo and HIV-specific stimulation in vitro augments CD38 expression, contributing to a proinflammatory response despite virologic control with ART. Therefore, CD38 is a potential therapeutic target for mitigating chronic inflammation that likely drives cellular aging, comorbidities, and end organ disease in PWH.
"Our findings show increased mitochondrial mass in PWH, which may indicate an increase in biogenesis of the lymphocytes in a given condition or an improper destruction and/or clearance of unhealthy mitochondria by mitophagy. However, the second scenario would also lead to mitochondrial membrane depolarization with increased mitochondrial mass32. Superoxide products are produced in large amounts during oxidative phosphorylation, but they are quickly neutralized by the superoxide dismutase present in the mitochondria. Impaired oxidative phosphorylation or superoxide dismutase may lead to increases in amount of superoxide content in the mitochondria, ultimately leading to redox imbalance in the lymphocytes33. Thus, the
increased mitochondrial mass and decreased superoxide content without accompanying significant change in mitochondria membrane polarization in PWH suggests that there may be increased biogenesis in the mitochondria of CD4+ and CD8+ T lymphocytes in PWH, linked to their over-activated state.
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