HIV-1 VPR-induced proinflammatory response and apoptosis are mediated through the SUR1-TRPM4 channel in astrocytes
PublisherAmerican Society for Microbiology
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AbstractSuccessful 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.
SponsorsThis research was supported in part by intramural support from the University of Maryland Medical Center and a VA merit-based award (I01 BX004652 to R.Y.Z.). V.G. is supported by grants from NINDS (R01NS061934 and R01NS107262), and J.M.S. is supported by grants from the NHLBI (R01HL082517) and NINDS (R01NS060801, R01NS102589, and R01NS105633).
HIV-associated neurocognitive disorders (HAND)
Human immunodeficiency virus
Human immunodeficiency virus type 1 (HIV-1)
Viral protein R (Vpr)
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/14581
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