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

mBio. 2020 Dec 8;11(6):e02939-20. doi: 10.1128/mBio.02939-20.

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.

Keywords: HIV-associated neurocognitive disorders (HAND); Human immunodeficiency virus type 1 (HIV-1); NF-κB; Sur1-Trpm4 channel; TLR4; TNF-α; astrocytes; brain tissues; glibenclamide; host-pathogen interactions; human immunodeficiency virus; neuroinflammation; neurotoxicity; viral protein R (Vpr).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis*
  • Astrocytes / metabolism*
  • Biomarkers
  • Brain / metabolism
  • Brain / pathology
  • Brain / virology
  • Cell Line, Tumor
  • Cytokines / metabolism
  • Fluorescent Antibody Technique
  • HIV Infections / metabolism*
  • HIV Infections / virology*
  • HIV-1 / physiology*
  • Host-Pathogen Interactions / genetics
  • Humans
  • Immunity, Innate
  • Immunohistochemistry
  • Inflammation Mediators / metabolism
  • Mice
  • Protein Binding
  • Sulfonylurea Receptors / metabolism*
  • TRPM Cation Channels / metabolism*
  • vpr Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • Biomarkers
  • Cytokines
  • Inflammation Mediators
  • Sulfonylurea Receptors
  • TRPM Cation Channels
  • TRPM4 protein, mouse
  • vpr Gene Products, Human Immunodeficiency Virus