Mechanisms of change in a community-based alcohol prevention framework among adolescents.

More than 4 decades since its discovery, HIV continues to pose a significant global health burden. Despite the success of antiretroviral therapy (ART) in achieving durable suppression of plasma viremia, people with HIV (PWH) continue to remain at risk for developing non-AIDS–related comorbidities such as cognitive impairment, cardiovascular disease (CVD), and liver disease (, ). A hallmark of these conditions is chronic immune activation and inflammation, which persist even under long-term ART and predict adverse clinical outcomes (). The precise drivers of this immune dysfunction are not yet fully understood, with a potential contributor being the HIV reservoir, a pool of latently infected cells that evades immune clearance and persists with an exceptionally long half-life (–). Historically, reservoir measurements have focused on total HIV DNA within peripheral blood mononuclear cells (PBMCs), which is cost effective and only requires small amounts of blood (). However, a major limitation of such bulk measurements is that it does not delineate the quality of the integrated HIV genomes. The development of the Intact Proviral DNA Assay (IPDA) and related droplet digital PCR (ddPCR) approaches has resulted in the ability distinguish intact from defective proviruses with a greater sensitivity, allowing for precise quantification of low levels of proviral DNA in a high-throughput fashion (). This approach has been used to study multiple cellular reservoirs, and previous work has demonstrated that both myeloid (monocytes and macrophages) and CD4 T cells comprise the latent HIV reservoir (–). Despite the flexibility of the IPDA approach, most studies only focus on the HIV reservoir in CD4 T cells or monocytes in isolation. However, there is a strong likelihood that both cellular reservoirs are interdependent and influence chronic inflammation throughout ART in a concurrent fashion. The CD4 T cell reservoir, and its corresponding associations with chronic inflammation, have been extensively characterized. Increased immune exhaustion (PD-1, LAG-3) and activation (CD38, HLA-DR) on CD4s are associated with larger reservoirs (, ) as well as lower CD4 T cell nadir, CD4/CD8 ratio, and CD4 T cell counts (). However, the role of the monocyte reservoir in shaping immune activation and HIV-associated comorbidities remains poorly understood. The monocyte reservoir, like CD4 T cells, can be measured in the blood and provides insights into myeloid reservoir dynamics. Monocytes, short-lived circulating cells that migrate into tissues and differentiate into long-lived macrophages, contribute to chronic inflammation via the release of proinflammatory cytokines and chemokines (). HIV infection results in increased proportions of CD16 monocyte subsets, including intermediate and nonclassical monocytes, which are associated with disease progression and highly susceptible to HIV infection (–). CD16 monocytes remain elevated despite effective ART; they are associated with aberrant inflammation and immune dysfunction and reported to house the majority of the monocyte reservoir (–). In addition, plasma levels of soluble CD163 (sCD163), sCD14, TNF, C-reactive protein (CRP), and IL-6, immune analytes secreted by inflammatory monocytes or known to activate these cells, remain elevated despite long-term ART, suggesting persistent monocyte activation (–).