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bioRxiv · 10.1101/2020.03.19.999268

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

Li, G.·Makar, T. K.·Gerzanich, V.·Kalakonda, S.·Ivanova, S.·Pereira, E. F. R.·Simard, J. M.·ZHAO, R. Y.
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Abstract

There are about 38 million people currently living with HIV/AIDS worldwide. Successful treatment with combinational antiretroviral therapies (cART) can eliminate active replicating viruses and prolong lives to nearly normal lifespans. However, the new challenge faced by more than half of those HIV-infected and aging patients is chronic CNS neuroinflammation, which leads to HIV-associated neurocognitive disorders (HAND). While severe and progressive HAND has decreased significantly due to cART, chronic HAND often persists, resulting in high rates of delirium, dementia and depression that could lead to suicide. Indeed, the risk of suicide mortality in HIV-infected persons is significantly higher than in HIV-uninfected counterparts. Nevertheless, the mechanism of neuropathogenesis underlying HAND is not well understood. HAND is typically characterized by HIV-mediated glial neuroinflammation and neurotoxicity. Interestingly, the severity of some HAND does not always correlate with the levels of HIV, but rather with glial activation, suggesting other HIV-associated factors, not the whole virus per se, contribute to those HAND. HIV-1 viral protein R (Vpr) might be one of those viral factors, because Vpr induces neuroinflammation and causes neuronal apoptosis. The objective of this study was to delineate the specific role(s) of Vpr in activation of host neuroinflammation and neurotoxicity, as well as its contribution to HAND. In this report, we show correlations between HIV expression and activation of proinflammatory markers (TLR4, TNF, and NF{kappa}B) and the Sur1-Trpm4 channel in astrocytes of HIV-infected postmortem human and transgenic mouse brain tissues. We further show that Vpr alone activate the same set of proinflammatory markers in an astrocytic cell line SNB19. Vpr-induced host cell proinflammatory responses result in apoptotic cell death. Together, our data suggest that HIV-1 Vpr-induced proinflammatory response and apoptotic cell death are mediated through the Sur1-Trpm4 channel in astrocytes.

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Li, G., Makar, T. K., Gerzanich, V., Kalakonda, S., Ivanova, S., Pereira, E. F. R., Simard, J. M., ZHAO, R. Y.. 2020-03-20. HIV-1 Vpr-induced Proinflammatory Response and Apoptosis are Mediated through the Sur1-Trpm4 Channel in Astrocytes. https://doi.org/10.1101/2020.03.19.999268

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