HIV Infection, Neurotoxicity, Inflammation, Premature Aging, and Therapeutic Challenges to PLWH: An Overview

HIV infection remains a major global health challenge due to its complex pathogenesis and lifelong persistence in people living with HIV (PLWH). A central barrier to eradication is the virus’s ability to establish long-lived latent reservoirs in different tissues, including the central nervous system (CNS), where it evades immune clearance and antiretroviral therapy (ART). These reservoirs, seeded early during infection, fuel viral rebound if ART is interrupted, requiring lifelong treatment. In the CNS, HIV persists despite systemic viral suppression because of limited ART penetration across the blood–brain barrier (BBB), and infection of long-lived cells such as microglia and perivascular macrophages. Although modern ART regimens significantly reduce viral burden and HIV-related morbidity, they do not eliminate neurocognitive complications. Suboptimal CNS drug penetration and certain ART-associated toxicities contribute to CNS dysfunction, persistent neuroinflammation, and accelerated aging of the brain. As PLWH now experience increased life expectancy, prolonged exposure to ART and persistent low-level viral activity exacerbate chronic inflammation, immune activation, and metabolic dysregulation, collectively accelerating neurobiological aging. These pathological processes contribute to the development of HIV-associated neurocognitive disorders (HAND), which affect nearly half of virally suppressed PLWH. This review examines HIV-associated inflammation, neurotoxic pathways, and accelerated aging in PLWH in the modern ART era.