HIV-1 Tat-Mediated Calcium Dysregulation and Neuronal Dysfunction in Vulnerable Brain Regions

Author(s): Xiu-Ti Hu

Journal Name: Current Drug Targets

Volume 17 , Issue 1 , 2016


  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Despite the success of combined antiretroviral therapy, more than half of HIV-1-infected patients in the USA show HIV-associated neurological and neuropsychiatric deficits. This is accompanied by anatomical and functional alterations in vulnerable brain regions of the mesocorticolimbic and nigrostriatal systems that regulate cognition, mood and motivation-driven behaviors, and could occur at early stages of infection. Neurons are not infected by HIV, but HIV-1 proteins (including but not limited to the HIV-1 trans-activator of transcription, Tat) induce Ca2+ dysregulation, indicated by abnormal and excessive Ca2+ influx and increased intracellular Ca2+ release that consequentially elevate cytosolic free Ca2+ levels ([Ca2+]in). Such alterations in intracellular Ca2+ homeostasis significantly disturb normal functioning of neurons, and induce dysregulation, injury, and death of neurons or non-neuronal cells, and associated tissue loss in HIV-vulnerable brain regions. This review discusses certain unique mechanisms, particularly the over-activation and/or upregulation of the ligand-gated ionotropic glutamatergic NMDA receptor (NMDAR), the voltage-gated L-type Ca2+ channel (L-channel) and the transient receptor potential canonical (TRPC) channel (a non-selective cation channel that is also permeable for Ca2+), which may underlie the deleterious effects of Tat on intracellular Ca2+ homeostasis and neuronal hyper-excitation that could ultimately result in excitotoxicity. This review also seeks to provide summarized information for future studies focusing on comprehensive elucidation of molecular mechanisms underlying the pathophysiological effects of Tat (as well as some other HIV-1 proteins and immunoinflammatory molecules) on neuronal function, particularly in HIV-vulnerable brain regions.

Keywords: Cognition, electrophysiology, medial prefrontal cortex, neuroAIDS, neurotoxicity, over-excitation, pyramidal neuron.

Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 17
ISSUE: 1
Year: 2016
Published on: 31 May, 2015
Page: [4 - 14]
Pages: 11
DOI: 10.2174/1389450116666150531162212

Article Metrics

PDF: 48
HTML: 5
EPUB: 1