HIV-1 Tat and gp120 as key drivers of neurodegeneration in the central nervous system
TL;DR
Converging data achieved from in vitro models, Tat and gp120-transgenic mice, post-mortem tissue, and cerebrospinal fluid biomarkers indicate that these viral proteins contribute to frontostriatal atrophy and hybrid HAND-AD phenotypes increasingly observed in aging HIV patients.
Abstract
Combined antiretroviral therapy (cART) has deeply changed the approach to HIV disease treatment. cART tackles HIV replication and improves the life expectancy of HIV-infected people. Notwithstanding the effectiveness of cART in HIV infection control, several observations have determined that 15–50% of HIV-infected people display HIV-associated neurocognitive disorders (HAND) even under long-term viral suppression. Persistent production of the viral proteins Tat and gp120 by central nervous system reservoirs drives chronic neurotoxicity due to their remarkable extracellular stability and efficient uptake by neurons and glial cells. In this review, we will discuss current evidence on the molecular mechanisms by which extracellular Tat and gp120 orchestrate neurodegeneration. Four principal interconnected pathways emerge: (i) mitochondrial dysfunction; (ii) synaptodendritic injury; (iii) chronic neuroinflammation; and (iv) crosstalk with Alzheimer’s disease (AD) pathways. Converging data achieved from in vitro models, Tat and gp120-transgenic mice, post-mortem tissue, and cerebrospinal fluid (CSF) biomarkers indicate that these viral proteins contribute to frontostriatal atrophy and hybrid HAND-AD phenotypes increasingly observed in aging HIV patients. Understanding these mechanisms highlights the need for adjunctive neuroprotective strategies targeting CXCR4/CCR5 signaling, mitochondrial quality control, inflammatory pathways, and Aβ/Tau homeostasis derangement and supports the integration of multimodal neuroimaging and CSF proteomics in future longitudinal studies aimed at improving diagnosis and therapeutic development.