Mechanisms of HIV-1 Tat neurotoxicity via CDK5 translocation and hyper-activation: role in HIV-associated neurocognitive disorders

Current HIV Research
Jerel FieldsEliezer Masliah

Abstract

The advent of more effective antiretroviral therapies has reduced the frequency of HIV dementia, however the prevalence of milder HIV associated neurocognitive disorders [HAND] is actually rising. Neurodegenerative mechanisms in HAND might include toxicity by secreted HIV-1 proteins such as Tat, gp120 and Nef that could activate neuro-inflammatory pathways, block autophagy, promote excitotoxicity, oxidative stress, mitochondrial dysfunction and dysregulation of signaling pathways. Recent studies have shown that Tat could interfere with several signal transduction mechanisms involved in cytoskeletal regulation, cell survival and cell cycle re-entry. Among them, Tat has been shown to hyper-activate cyclin-dependent kinase [CDK] 5, a member of the Ser/Thr CDKs involved in cell migration, angiogenesis, neurogenesis and synaptic plasticity. CDK5 is activated by binding to its regulatory subunit, p35 or p39. For this manuscript we review evidence showing that Tat, via calcium dysregulation, promotes calpain-1 cleavage of p35 to p25, which in turn hyper-activates CDK5 resulting in abnormal phosphorylation of downstream targets such as Tau, collapsin response mediator protein-2 [CRMP2], doublecortin [DCX] and MEF2. We also present new ...Continue Reading

Citations

Jul 11, 2018·Journal of Neurovirology·Rebeca Geffin, Micheline McCarthy
Mar 12, 2020·Frontiers in Cellular and Infection Microbiology·David Ajasin, Eliseo A Eugenin
Aug 5, 2020·Translational Neurodegeneration·Kalimuthusamy NatarajaseenivasanDianne Langford
Sep 16, 2016·Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology·Mahmoud L SolimanXuesong Chen
Feb 22, 2017·Nature Structural & Molecular Biology·Alina HateganAvindra Nath
Feb 23, 2019·Journal of Neurovirology·Miroslaw Mack MackiewiczEliezer Masliah
Dec 13, 2018·Virusdisease·Sayed Sartaj SohrabNigel H Greig
Apr 9, 2020·Frontiers in Microbiology·Anthony R MeleMichael R Nonnemacher
Aug 23, 2019·Virus Research·Robert W LinkMichael R Nonnemacher
Oct 27, 2020·Epigenetics : Official Journal of the DNA Methylation Society·Mayur DokeThangavel Samikkannu
Apr 2, 2021·Neuroscience Letters·Susmita SilShilpa Buch
Apr 13, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Hao Yu, Jie Wu
Jul 3, 2021·International Journal of Molecular Sciences·Jarosław MazurykPiotr Mucha

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