Impact of HIV on Neuronal Health in the Brains of People with HIV

Despite effective viral suppression with antiretroviral therapy (ART), people with HIV (PWH) remain at increased risk of neurocognitive impairment and persistent neuroinflammation. Although neurons are not infected by HIV, they remain susceptible to the indirect effects of chronic infection, including exposure to viral proteins, inflammatory mediators, and glial dysfunction. The resulting neuronal injury is thought to contribute to the development and persistence of HIV-associated neurocognitive disorders in the ART era. This review examines the impact of chronic HIV infection on neuronal function, highlighting mechanisms of neuronal dysfunction driven by both viral-dependent and viral-independent pathways. We discuss the role of central nervous system viral reservoirs, neuroimmune interactions, and the neurotoxic effects of HIV proteins including Tat, gp120, and Nef. We further explore how chronic HIV infection influences synaptic integrity, neuronal metabolism, and age-related neurodegeneration. Finally, we highlight emerging biomarkers and therapeutic strategies aimed at preserving neuronal function. By integrating current evidence on both viral-dependent and viral-independent mechanisms of neuronal dysfunction, this review identifies critical knowledge gaps and future research priorities aimed at preserving neuron function and improving neurological outcomes in PWH.