Extracellular HIV-1 Tat Mediates Increased Glutamate in the CNS Leading to Onset of Senescence and Progression of HAND

Jamie Marino,Michael R Nonnemacher,Brian Wigdahl

doi:10.3389/fnagi.2020.00168

Abstract

Human immunodeficiency virus type 1 (HIV-1)- associated neurocognitive disorders (HAND) is a disease of neurologic impairment that involves mechanisms of damage similar to other degenerative neurologic diseases such as Alzheimer’s disease (AD). In the current era of antiretroviral therapy (ART), HIV-1 replication is well-suppressed, and yet, HIV-1-infected patients still have high levels of chronic inflammation, indicating that factors other than viral replication are contributing to the development of neurocognitive impairment in these patients. The underlying mechanisms of HAND are still unknown, but the HIV-1 protein, Tat, has been highlighted as a potential viral product that contributes to the development of cognitive impairment. In AD, the presence of senescent cells in the CNS has been discussed as a contributing factor to the progression of cognitive decline and may be a mechanism also involved in the development of HAND. This mini-review discusses the viral protein HIV-1 Tat, and its potential to induce senescence in the CNS, contributing to the development of HAND.

Highlights

Human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders (HAND) represents a range of neurologic impairments observed in HIV-1-infected patients who are well-suppressed on antiretroviral therapy (ART) (Dickens et al, 2017; Williams et al, 2020)
Due to the similarities between HAND and Alzheimer’s disease (AD), we propose a possible HIV-1-Tat-induced mechanism of senescence in the CNS of HIV patients that exhibit HAND
Decreased blood-brain barrier (BBB) integrity occurs in HIV-1 infection, where the loss of BBB integrity, potentially due to exposure to Tat and altered glutamate levels may induce the onset of senescence in astrocytes and brain microvascular endothelial cells (BMECs), the major cells of the BBB, culminating in the generation of neurocognitive disorders such as HAND (Beaupere et al, 2015; Yamazaki et al, 2016; Hijmans et al, 2018)

Summary

Introduction

Human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders (HAND) represents a range of neurologic impairments observed in HIV-1-infected patients who are well-suppressed on antiretroviral therapy (ART) (Dickens et al, 2017; Williams et al, 2020). Dysregulation of the BBB, caused by HIV-1 can exacerbate neurodegenerative disorders by allowing aberrant influx of cells into the CNS, leading to increased inflammation and neurotoxicity (Rao et al, 2014; Yamazaki et al, 2016; Baker and Petersen, 2018).

Results

Conclusion