Current Knowledge on the Role of Monocytes and Macrophages in the Pathogenesis of Non-AIDS Defining Events: Mechanisms, Host Factors, and Therapeutic Implications

Monocytes and macrophages play a crucial role in the development 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 serve as long-lived viral reservoirs, driving chronic inflammation through persistent immune activation, oxidative stress, and tissue-specific damage. HIV-infected monocytes infiltrate tissues such as 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 like atherosclerosis, neurocognitive disorders, and hepatorenal disease. Emerging evidence highlights the importance of macrophage polarisation (M1/M2 imbalance) and epigenetic modifications in sustaining inflammation, even during antiretroviral therapy (ART). Besides persistent immune activation, the ability of these cells to cause tissue-specific damage is significantly influenced by host genetic factors, such as polymorphisms in the APOL1 and CCL2 genes, which can determine the severity of end-organ diseases like HIV-associated nephropathy. Additionally, epigenetic reprogramming of monocytes and macrophages—triggered by HIV proteins and the inflammatory environment—establishes a lasting pro-inflammatory state that remains despite ART. This reprogramming, marked by changes in histone modifications and DNA methylation, sustains mechanisms of tissue damage. Understanding these processes and their interaction with host factors provides critical insights for developing targeted treatments, including immunomodulators, antioxidants, and strategies for reservoir elimination. This review summarises current knowledge on how monocytes and macrophages contribute to the pathogenesis of nADEs. It explores potential new therapeutic approaches to reduce chronic inflammation and enhance clinical outcomes in PLWH.