Neuroimmune crosstalk in HIV-associated neurocognitive disorders and the impact of antiretroviral therapy.

HIV-associated neurocognitive disorders (HAND) remain prevalent among people living with HIV (PLWH) despite effective combination antiretroviral therapy (cART) and durable systemic viral suppression. The central nervous system (CNS) represents a unique immunological and pharmacological compartment in which HIV persists within long-lived reservoirs, particularly microglia and perivascular macrophages, thereby sustaining chronic neuroimmune activation. Current evidence indicates that HAND is driven primarily by indirect mechanisms rather than direct neuronal infection. Persistent viral transcription, ongoing expression of neurotoxic viral proteins, chronic glial activation, oxidative stress, mitochondrial dysfunction, excitotoxicity, and disruption of glial-neuronal communication collectively contribute to neuronal injury and cognitive decline. Microglia play a central role in these processes through the release of inflammatory mediators, reactive oxygen species (ROS), and viral proteins that propagate astrocyte dysfunction, disrupt glutamate homeostasis, and promote synaptic degeneration. Although cART has substantially reduced the incidence of HIV-associated dementia (HAD), milder forms of HAND remain common. Emerging preclinical and observational evidence suggests that certain antiretroviral agents may contribute to mitochondrial dysfunction, altered glial metabolism, and neurocognitive vulnerability in susceptible individuals. However, definitive clinical evidence linking long-term antiretroviral exposure to progressive HAND remains limited and is frequently confounded by aging, comorbidities, and historical disease severity. This review examines the neuroimmune crosstalk underlying HAND, with particular emphasis on microglial and astrocytic dysfunction, persistent CNS viral reservoirs, and the potential impact of antiretroviral therapy on CNS homeostasis, while highlighting key mechanistic gaps and potential therapeutic targets and intervention strategies.