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.
