HIV-1 Vpr-Induced Proinflammatory Response and Apoptosis Are Mediated through the Sur1-Trpm4 Channel in Astrocytes.

Autor:	Li G; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA., Makar T; Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA., Gerzanich V; Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA., Kalakonda S; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA., Ivanova S; Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA., Pereira EFR; Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA., Andharvarapu S; Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA., Zhang J; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA., Simard JM; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA msimard@som.umaryland.edu rzhao@som.umaryland.edu.; Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA., Zhao RY; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA msimard@som.umaryland.edu rzhao@som.umaryland.edu.; Department of Microbiology-Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.; Institute of Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.; Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Jazyk:	angličtina
Zdroj:	MBio [mBio] 2020 Dec 08; Vol. 11 (6). Date of Electronic Publication: 2020 Dec 08.
DOI:	10.1128/mBio.02939-20
Abstrakt:	Successful treatment of HIV-infected patients with combinational antiretroviral therapies (cART) can now prolong patients' lives to nearly normal life spans. However, the new challenge faced by many of those HIV-infected patients is chronic neuroinflammation and neurotoxicity that often leads to HIV-associated neurocognitive disorders (HAND). However, the mechanism of neuropathogenesis underlying HAND, especially in those who are under cART, is not well understood. HAND is typically characterized by HIV-mediated glial neuroinflammation and neurotoxicity. However, the severity of HAND does not always correlate with HIV-1 viral load but, rather, with the extent of glial activation, suggesting that other HIV-associated factors might contribute to HAND. HIV-1 viral protein R (Vpr) could be one of those viral factors because of its association with neuroinflammation and neurotoxicity. The objective of this study was to delineate the specific roles of HIV-1 infection and Vpr in the activation of neuroinflammation and neurotoxicity, and the possible relationships with the Sur1-Trpm4 channel that contributes to neuroinflammation and neuronal death. Here, we show that HIV-1 expression correlates with activation of proinflammatory markers (TLR4, TNF-α, and NF-κB) and the Sur1-Trpm4 channel in astrocytes of HIV-infected postmortem human and transgenic Tg26 mouse brain tissues. We further show that Vpr alone activates the same set of proinflammatory markers and Sur1 in a glioblastoma SNB19 cell line that is accompanied by apoptosis. The Sur1 inhibitor glibenclamide significantly reduced Vpr-induced apoptosis. Together, our data suggest that HIV-1 Vpr-induced proinflammatory response and apoptosis are mediated at least in part through the Sur1-Trpm4 channel in astrocytes. IMPORTANCE Effective antiretroviral therapies can now prolong patients' lives to nearly normal life span. The current challenge faced by many HIV-infected patients is chronic neuroinflammation and neurotoxicity that contributes to HIV-associated neurocognitive disorders (HAND). We show here that the expression of HIV-1 infection and Vpr correlates with the activation of proinflammatory markers (Toll-like receptor 4 [TLR4], tumor necrosis factor alpha [TNF-α], and NF-κB) and the sulfonylurea receptor 1 (Sur1)-transient receptor potential melastatin 4 (Trpm4) channel in astrocytes of brain tissues. We further show that an FDA-approved Sur1 inhibitory drug called glibenclamide significantly ameliorates apoptotic astrocytic cell death caused by HIV-1 Vpr, which could potentially open the possibility of repurposing glibenclamide for treating HAND. (Copyright © 2020 Li et al.)
Databáze:	MEDLINE
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