HIV-1 Vpr-Induced Proinflammatory Response and Apoptosis Are Mediated through the Sur1-Trpm4 Channel in Astrocytes
Ge Li, Tapas K. Makar, Volodymyr Gerzanich, Sudhakar Kalakonda, Svetlana Ivanova, Edna F. R. Pereira, Sanketh Andharvarapu, Jiantao Zhang, J. Marc Simard, Yuqi Zhao
Abstract
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.