The role of HIV-1 viral proteins in HIV-associated brain injury: emerging mechanisms and recent advances
Year: 2026
Type: article
Abstract: Despite effective combination antiretroviral therapy (cART), HIV-1 infection remains associated with chronic neurological complications and persistent central nervous system (CNS) dysfunction. HIV-associated brain injury (HABI) occurs primarily through indirect mechanisms mediated by viral proteins released from infected and reservoir cells within the CNS, rather than through direct neuronal infection. Over the past decade, NeuroHIV research has increasingly recognized Tat, gp120, Vpr, and Nef as persistent regulators of interconnected neuroimmune, neurovascular, metabolic, and synaptic pathways that collectively sustain CNS injury. Emerging evidence demonstrates that these viral proteins promote chronic microglial activation, mitochondrial dysfunction, inflammasome signalling, oxidative stress, ferroptosis, lysosomal dysfunction, extracellular-vesicle signalling, synaptic remodelling, and blood–brain barrier disruption through overlapping and convergent mechanisms that may persist independently of active viral replication. Recent advances in human-based models and systems-level approaches further support the concept that HABI reflects a chronic network of neuroimmune, neurovascular, and metabolic dysfunction rather than isolated neuronal toxicity. This review synthesizes recent mechanistic advances in HIV-1 viral protein-mediated neuropathogenesis, highlights emerging pathways with translational potential, and discusses future directions for developing targeted therapeutic strategies to preserve long-term neurological health in people living with HIV.
Authors: Monray Edward Williams, Eliseo Eugenin
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $1,695
OpenAlex ID: W7169658710