HIV-1 gp120 drives neurocognitive decline by inducing synaptic dysfunction and neuronal damage, even with cART

Despite effective combination antiretroviral therapy (cART), many individuals with HIV experience HIV-associated neurocognitive disorders (HAND), ranging from mild impairment to dementia. This persistent challenge highlights that cART alone doesn't fully prevent neurocognitive decline, which involves accelerated biological aging and neurodegenerative-like changes. Structural brain changes, such as cortical thinning and synaptic dysfunction, suggest that functional impairment precedes neuronal death, pointing to a need for targeted interventions beyond viral suppression.

This review synthesizes current understanding of how the HIV-1 envelope glycoprotein, gp120, contributes to neurocognitive decline. It explores the mechanisms by which gp120, released by infected cells in the central nervous system (CNS), induces neuronal damage and synaptic dysfunction. The review aims to consolidate evidence on gp120's role in neuroinflammation, oxidative stress, and excitotoxicity, providing a comprehensive overview of its pathogenic contributions to HAND in the cART era.

The review highlights that HIV-1 establishes CNS infection early, with infected monocytes and T-cells crossing the blood-brain barrier via a 'Trojan horse' mechanism. Once in the brain, HIV-1 infects perivascular macrophages, microglia, and astrocytes, which then release viral proteins like gp120. This gp120 is a critical factor in driving neurocognitive impairment, even in virally suppressed individuals. It contributes to dendritic simplification, spine loss, and synaptic dysfunction, which are hallmarks of HAND. These changes are distinct from overt neuronal death, suggesting a more subtle, functional impairment that may be reversible. The review posits that gp120's interaction with host receptors triggers a cascade of events leading to neuroinflammation and neuronal injury. While specific numerical findings are not provided in this introductory section, the overarching finding is the persistent and direct neurotoxic role of gp120.

gp120-induced synaptic dysfunction and dendritic simplification are central to HAND pathology, occurring independently of active viral replication.