The Role of Monocytes and Macrophages in the Pathogenesis of Non-AIDS Defining Events: Mechanisms and Therapeutic Implications

Abstract

Monocytes and macrophages play a pivotal role in the pathogenesis of HIV infection, contributing not only to viral persistence but also to the development of non-AIDS-defining events (nADEs) in People Living with HIV (PLWH). These innate immune cells act as long-lived viral reservoirs, driving chronic inflammation through persistent immune activation, oxidative stress, and tissue-specific damage. HIV-infected monocytes infiltrate tissues, including the cardiovascular system, liver, kidneys, and central nervous system, where they differentiate into macrophages and release pro-inflammatory cytokines (e.g., TNF-α, IL-6), reactive oxygen species (ROS), and matrix metalloproteinases (MMPs). These mediators promote endothelial dysfunction, fibrosis, and organ damage, underpinning conditions such as atherosclerosis, neurocognitive disorders, and hepatorenal disorder. Emerging evidence highlights the role of macrophage polarization (M1/M2 imbalance) and epigenetic modifications in sustaining inflammation despite antiretroviral therapy (ART). Understanding these mechanisms provides critical insights for developing targeted therapies, including immunomodulators (e.g., IL-6 inhibitors), antioxidant agents, and reservoir-elimination strategies. This review synthesizes current knowledge on monocyte/macrophage-driven pathogenesis in HIV-associated nADEs. It explores plausible novel therapeutic approaches to mitigate chronic inflammation and improve clinical outcomes in PLWH.