Persistent CD38 Expression on CD8+T Lymphocytes Contributes to Altered Mitochondrial Function and Chronic Inflammation in People With HIV, Despite ART

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 were 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 compared with 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.