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 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.

7,8-Dihydroxyflavone improves neuropathological changes in the brain of Tg26 mice, a model for HIV-associated neurocognitive disorder

“…Inhibition of NF-κB activity can reverse neuronal autophagy induced by Tat 91 . We recently reported that HIV-1 Vpr-induced proinflammatory response and apoptotic cell death are mediated through the NF-kB activation in astrocytes 92 . Targeting NFkB may ameliorate HIV-associated neuroinflammation.…”

Sulfonylurea Receptor 1 in Central Nervous System Injury: An Updated Review

“…HIV-associated neurocognitive disorders (HAND) are characterized by glial activation, cytokine/chemokine dysregulation, and neuronal damage, thought to be a result of chronic neuroinflammation and neurotoxicity [ 201 ]. It has been speculated that HIV-1 viral protein R (Vpr), may contribute to HAND.…”

“…It has been speculated that HIV-1 viral protein R (Vpr), may contribute to HAND. A recently published single study has evaluated the role of SUR1-TRPM4 expression patterns and inhibition in a preclinical mouse models of HIV (Tg26) as well as postmortem human tissue [ 201 ].…”

“…In Tg26 mouse brain, HIV-1 infection increased several inflammatory markers in the hippocampus vs. wildtype controls [ 201 ]; these markers are known to upregulate SUR1 including TLR4, TNFa, and NF-κB ( Section 2.4 ). This was also associated with upregulated expression of astrocytic SUR1-TRPM4 in the hippocampus of infected mice ( p < 0.001 vs. wildtype controls).…”

“…The benefits of glibenclamide in terms of blocking Vpr-induced apoptosis have been demonstrated in vitro, using cells from the human glioblastoma SNB19 cell line (of glial cell origin) [ 201 ]. In this study, a concentration-dependent inhibition of Vpr-induced apoptosis was observed at 2, 4 and 6 h post-infection using glibenclamide at increasing concentrations of 10, 30 and 90 mM.…”