Abstract
Introduction With the advent of antiretroviral therapy (ART), HIV has become a manageable chronic disease. Despite effective virologic suppression, approximately 30% of people living with HIV (PLWH) experience immunological failure, characterized by inadequate CD4+ T cell recovery. This study explores the hypothesis that overactivation of the CD38 receptor leads to NAD+ depletion and subsequent mitochondrial dysfunction, contributing to immunological failure in virologically suppressed HIV patients. Methods A comprehensive review of existing literature was conducted to investigate the roles of CD38, NAD+, and mitochondrial function in HIV pathogenesis. Data were collected from studies on CD38 expression, NAD+ metabolism, and mitochondrial dysfunction in the context of HIV and aging. The integrative approach included examining immune cell activation, metabolic pathways, and potential therapeutic interventions. Results CD38, a type II transmembrane glycoprotein, is overexpressed in PLWH and serves as a predictor of HIV progression. Its enzymatic activities deplete NAD+, a crucial coenzyme involved in energy metabolism, DNA repair, and cell signaling. NAD+ depletion impairs mitochondrial oxidative phosphorylation (OXPHOS), leading to reduced ATP production and increased reliance on glycolysis, which promotes inflammation. Overactivation of CD38 also activates the kynurenine pathway through IDO-1, further depleting NAD+ and generating toxic metabolites that damage mitochondria. This cascade results in persistent immune activation, immune exhaustion, and CD4+ T cell apoptosis. Conclusion The overactivation of CD38 and subsequent NAD+ depletion are central to the pathogenesis of immunological failure in virologically suppressed HIV patients. This mechanism links chronic immune activation, metabolic dysfunction, and accelerated aging. Therapeutic interventions targeting CD38 inhibition, NAD+ supplementation, and mitochondrial function enhancement could potentially reverse immunological failure and improve health outcomes in PLWH. Further experimental validation and clinical trials are necessary to confirm these findings and develop effective treatments.