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

ABSTRACT 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 lea...

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Autores principales:	Ge Li, Tapas Makar, Volodymyr Gerzanich, Sudhakar Kalakonda, Svetlana Ivanova, Edna F. R. Pereira, Sanketh Andharvarapu, Jiantao Zhang, J. Marc Simard, Richard Y. Zhao
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Human immunodeficiency virus type 1 (HIV-1) HIV-associated neurocognitive disorders (HAND) viral protein R (Vpr) neuroinflammation neurotoxicity TLR4 Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ea8b4ab945e34b9381587cff74289f97
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spelling	oai:doaj.org-article:ea8b4ab945e34b9381587cff74289f972021-11-15T15:55:43ZHIV-1 Vpr-Induced Proinflammatory Response and Apoptosis Are Mediated through the Sur1-Trpm4 Channel in Astrocytes10.1128/mBio.02939-202150-7511https://doaj.org/article/ea8b4ab945e34b9381587cff74289f972020-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02939-20https://doaj.org/toc/2150-7511ABSTRACT 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.Ge LiTapas MakarVolodymyr GerzanichSudhakar KalakondaSvetlana IvanovaEdna F. R. PereiraSanketh AndharvarapuJiantao ZhangJ. Marc SimardRichard Y. ZhaoAmerican Society for MicrobiologyarticleHuman immunodeficiency virus type 1 (HIV-1)HIV-associated neurocognitive disorders (HAND)viral protein R (Vpr)neuroinflammationneurotoxicityTLR4MicrobiologyQR1-502ENmBio, Vol 11, Iss 6 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Human immunodeficiency virus type 1 (HIV-1) HIV-associated neurocognitive disorders (HAND) viral protein R (Vpr) neuroinflammation neurotoxicity TLR4 Microbiology QR1-502
spellingShingle	Human immunodeficiency virus type 1 (HIV-1) HIV-associated neurocognitive disorders (HAND) viral protein R (Vpr) neuroinflammation neurotoxicity TLR4 Microbiology QR1-502 Ge Li Tapas Makar Volodymyr Gerzanich Sudhakar Kalakonda Svetlana Ivanova Edna F. R. Pereira Sanketh Andharvarapu Jiantao Zhang J. Marc Simard Richard Y. Zhao HIV-1 Vpr-Induced Proinflammatory Response and Apoptosis Are Mediated through the Sur1-Trpm4 Channel in Astrocytes
description	ABSTRACT 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.
format	article
author	Ge Li Tapas Makar Volodymyr Gerzanich Sudhakar Kalakonda Svetlana Ivanova Edna F. R. Pereira Sanketh Andharvarapu Jiantao Zhang J. Marc Simard Richard Y. Zhao
author_facet	Ge Li Tapas Makar Volodymyr Gerzanich Sudhakar Kalakonda Svetlana Ivanova Edna F. R. Pereira Sanketh Andharvarapu Jiantao Zhang J. Marc Simard Richard Y. Zhao
author_sort	Ge Li
title	HIV-1 Vpr-Induced Proinflammatory Response and Apoptosis Are Mediated through the Sur1-Trpm4 Channel in Astrocytes
title_short	HIV-1 Vpr-Induced Proinflammatory Response and Apoptosis Are Mediated through the Sur1-Trpm4 Channel in Astrocytes
title_full	HIV-1 Vpr-Induced Proinflammatory Response and Apoptosis Are Mediated through the Sur1-Trpm4 Channel in Astrocytes
title_fullStr	HIV-1 Vpr-Induced Proinflammatory Response and Apoptosis Are Mediated through the Sur1-Trpm4 Channel in Astrocytes
title_full_unstemmed	HIV-1 Vpr-Induced Proinflammatory Response and Apoptosis Are Mediated through the Sur1-Trpm4 Channel in Astrocytes
title_sort	hiv-1 vpr-induced proinflammatory response and apoptosis are mediated through the sur1-trpm4 channel in astrocytes
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/ea8b4ab945e34b9381587cff74289f97
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HIV-1 Vpr-Induced Proinflammatory Response and Apoptosis Are Mediated through the Sur1-Trpm4 Channel in Astrocytes

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