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

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 Ca(2+) dysregulation, indicated by abnormal and excessive Ca(2+) influx and increased intracellular Ca(2+) release that consequentially elevate cytosolic free Ca(2+) levels ([Ca(2+)]in). Such alterations in intracellular Ca(2+) 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 Ca(2+) channel (L-channel) and the transient receptor potential canonical (TRPC) channel (a non-selective cation channel that is also permeable for Ca(2+)), which may underlie the deleterious effects of Tat on intracellular Ca(2+) 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.

journal_name

Curr Drug Targets

journal_title

Current drug targets

authors

Hu XT

doi

10.2174/1389450116666150531162212

subject

Has Abstract

pub_date

2016-01-01 00:00:00

pages

4-14

issue

1

eissn

1389-4501

issn

1873-5592

pii

CDT-EPUB-67777

journal_volume

17

pub_type

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