CD38 intensifies immune activation in women living with HIV (the CIGNAL study) - Project Summary/Abstract Worldwide, 52% of adults infected with HIV are women. Though access to effective antiretroviral therapy (ART) has increased, women living with HIV (WLWH) have higher rates of non-AIDS comorbidities, faster progression to AIDS, and mortality than men living with HIV(MLWH). One reason for this difference is HIV- induced immune activation, which persists despite viral suppression with ART. HIV-induced immune activation is critical to viral pathogenesis, a strong predictor of disease progression, and discordant by sex, even after viral suppression with ART. Prior studies suggest that WLWH experience less of an ART-associated reduction in immune activation and inflammation than men with HIV. The immunological basis for sex differences in HIV-induced immune activation likely account for the discordant morbidity and mortality in WLWH, however, sex- specific differences in HIV pathogenesis are poorly understood. Therefore, it is imperative to explore if HIV- associated cellular markers contribute to HIV pathogenesis and if they are targets for therapeutic intervention in WLWH. A hallmark of HIV infection is increased expression of CD38 on T cells. CD38 activates inflammatory cytokine production and is the main enzyme responsible for catalyzing intracellular nicotinamide adenine dinucleotide (NAD+). Ours and other published data show that increased CD38 expression on CD4+ and CD8+ T cells is not reversed with ART and viral suppression. In addition, in our lab, we have shown that CD38+CD8+ T cells in WLWH produce more inflammatory cytokine (IFN-γ) than CD38+CD8+ T cells of MLWH. Blocking CD38 may mitigate inflammatory cytokine production, however, counteracting CD38 has been shown to cause immunodeficiency. Since CD38+ is largely responsible for intracellular NAD+ decline, we developed a strategy to counteract CD38’s effects without directly targeting it. In vitro, we added the NAD+ precursor, nicotinamide riboside (NR), to peripheral blood mononuclear cells (PBMCs), and found that NR increased intracellular NAD+ levels in PBMCs and decreased cytokine production from CD38+ CD4+ and CD8+ T cells, without directly blocking CD38. Therefore, increasing intracellular NAD+ levels may be a therapeutic option to mitigate CD38-induced immune activation and inflammation in WLWH. It is well-established that CD38 expression increases on T cells after HIV infection. However, it is unknown if sex-based differences in CD38 expression account for increased inflammation in WLWH. Our central hypothesis is that CD38 expression is increased and intensifies immune activation and inflammatory cytokine in WLWH compared to MLWH. The overall goal of this project is to establish that increasing NAD+ levels can reduce CD38-induced immune activation and inflammation, leading to randomized-control trials using NR in WLWH.