Abstract
HIV-Associated neurocognitive disorder (HAND) is one of the major concerns since it persists in 40% of this population. Nowadays, HAND neuropathogenesis is considered to be caused by the infected cells that cross the brain–blood barrier and produce viral proteins that can be secreted and internalized into neurons leading to disruption of cellular processes. The evidence points to viral proteins such as Tat as the causal agent for neuronal alteration and thus HAND. The hallmarks in Tat-induced neurodegeneration are endoplasmic reticulum stress and mitochondrial dysfunction. Sirtuins (SIRTs) are NAD+-dependent deacetylases involved in mitochondria biogenesis, unfolded protein response, and intrinsic apoptosis pathway. Tat interaction with these deacetylases causes inhibition of SIRT1 and SIRT3. Studies revealed that SIRTs activation promotes neuroprotection in neurodegenerative diseases such Alzheimer’s and Parkinson’s disease. Therefore, this review focuses on Tat-induced neurotoxicity mechanisms that involve SIRTs as key regulators and their modulation as a therapeutic strategy for tackling HAND and thereby improving the quality of life of people living with HIV.
Highlights
Introduction iationsIn 2020, the human immunodeficiency virus (HIV) infected more than 37 million people around the world, and 73% of this population was under antiretroviral therapy [1].This combined antiretroviral treatment has expanded their life span
Ghosh et al [100] reported that even without endoplasmic reticulum (ER) stress stimulus, SIRT1 depletion is involved in PERK unfolded protein response (UPR) branch activation by regulating levels of phosphorylated eIF-2α; in addition, they found evidence of physical interaction between SIRT1, CCAAT/enhancer-binding protein homologous protein (CHOP), and GADD34 [100] that was later confirmed by evidence showing formation of an arsenite-induced Sirt1/GADD34/PP1/eIF-2α complex and nuclear SIRT1 translocation to cytoplasm, which leads to GADD34-mediated dephosphorylation/deacetylation of eIF-2α and dephosphorylation of SIRT1 [101]
Later works indicated that viral protein Tat reduces deacetylation activity of SIRT1, its gene expression, and protein levels in vitro [131] and induces SIRT1 post-transcriptional silencing mediated by miRNA-34a and miRNA-138 [132]. These findings propose a particular requirement at different stages of infection, and because of the combined antiretroviral treatment (cART), viral transcription is controlled, so inhibition of SIRTs could lead to concomitant neurodegeneration
Summary
SIRT1SIRT1 and SIRT3 inhibition lead to lead endoplasmic reticulumreticulum (ER) stress(ER). 1. Tat-mediated and SIRT3 inhibition to endoplasmic mitochondrial dysfunction. Tat-mediated and SIRT3 inhibition to endoplasmic mitochondrial dysfunction These cellular events induce activation of the intrinsic pathway that mitochondrial dysfunction. These cellular events induce activation of the intrinsic pathway that causes causes cell death, a hallmark in HAND. In the case of SIRT2, the effect of Tat interaction remains unknown (dotted line). SIRTs modulators have been used in other neurodegenerative disorders. They could contribute to Tat-induced neurotoxicity mitigation
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