The delicate balance between neurotoxicity and neuroprotection in the context of HIV‐1 infection

Abstract

Human immunodeficiency virus type-1 (HIV-1) causes a spectrum of neurological impairments, termed HIV-associated neurocognitive disorder (HAND), following the infiltration of infected cells into the brain. Even though the implementation of antiretroviral therapy reduced the systemic viral load, the prevalence of HAND remains unchanged and infected patients develop persisting neurological disturbances affecting their quality of life. As a result, HAND have gained importance in basic and clinical researches, warranting the need of developing new adjunctive treatments. Nonetheless, a better understanding of the molecular and cellular mechanisms remains necessary. Several studies consolidated their efforts into elucidating the neurotoxic signaling leading to HAND including the deleterious actions of HIV-1 viral proteins and inflammatory mediators. However, the scope of these studies is not sufficient to address all the complexity related to HAND development. Fewer studies focused on an altered neuroprotective capacity of the brain to respond to HIV-1 infection. Neurotrophic factors are endogenous polyproteins involved in neuronal survival, synaptic plasticity, and neurogenesis. Any defects in the processing or production of these crucial factors might compose a risk factor rendering the brain more vulnerable to neuronal damages. Due to their essential roles, they have been investigated for their diverse interplays with HIV-1 infection. In this review, we present a complete description of the neurotrophic factors involved in HAND. We discuss emerging concepts for their therapeutic applications and summarize the complex mechanisms that down-regulate their production in favor of a neurotoxic environment. For certain factors, we finally address opposing roles that rather lead to increased inflammation.

Gliotoxicity and Glioprotection: the Dual Role of Glial Cells

“…With regard to viral infections, glial cells can be primary targets of neurotropic viruses, such as the human immunodeficiency virus type 1 (HIV-1) and zika virus (ZIKV). Microglia and astrocytes constitute CNS reservoirs of HIV-1 [ 93 , 94 ], promoting neuroinflammation, which can explain neuronal damage and neurocognitive disorders in a number of patients, considering the relative incapacity of HIV-1 to directly infect neurons [ 95 ]. Due to the presence of AXL receptor, astrocytes and microglia are potentially the primary cells targeted by ZIKV in the CNS [ 96 ].…”

Role of cyclin‑dependent kinase 5 in early brain injury following experimental subarachnoid hemorrhage

“…A previous study suggested that Cdk5 is a regulator of various neuronal cell death cascades (37). However, some studies have provided contradictory evidence indicating that Cdk5 provides neuroprotection in some conditions (38,39). Several studies have revealed that the influence of Cdk5 on cell death depended on its subcellular localization as opposed to its activity.…”

Microglia: The Real Foe in HIV-1-Associated Neurocognitive Disorders?

“…As previously mentioned, transmigration of this macrophage population—which is highly susceptible to HIV infection—across the BBB into the CNS is critical to the pathogenesis of HAND. Work analyzing some of the mechanisms contributing to the entry of this mature monocyte subset into the brain has shown the presence of extremely increased sensitivity to CCL2 upon CC-chemokine receptor 2 (CCR2)-mediated HIV infection [ 54 , 55 ].…”

“…The HIV-1 Tat protein can activate the NLR and increase caspase-1 and IL-1β levels in microglia, which, in turn, generates TNF-α and IL-6 and intensifies the proinflammation response [ 16 ] ( Table 1 ). HIV-1 infection in microglial cells can also produce reactive oxygen species (ROS) and reactive nitrogen species (RNS), such as quinolinic acid, arachidonic acid, and nitric oxide [ 55 ]. Moreover, the presence of HIV-1 in the brain can cause the expression of inducible hypoxia factor (HIF)-1, leading to the generation of mitochondrial dysfunction and oxidative stress [ 52 , 74 ].…”

“…As previously mentioned, transmigration of this macrophage population-which is highly susceptible to HIV infection-across the BBB into the CNS is critical to the pathogenesis of HAND. Work analyzing some of the mechanisms contributing to the entry of this mature monocyte subset into the brain has shown the presence of extremely increased sensitivity to CCL2 upon CC-chemokine receptor 2 (CCR2)-mediated HIV infection [54,55]. Not only is the presence of CD4 required for HIV-1 to enter a CNS cell, but the CXCR4 or CC-chemokine receptor 5 (CCR5) co-receptors and CC-chemokine receptor 3 (CCR3) receptors are also required to produce effective infection.…”