Abstract
Human Immunodeficiency virus (HIV) enters the brain soon after seroconversion and induces chronic neuroinflammation by infecting and activating brain macrophages. Inflammasomes are cytosolic protein complexes that mediate caspase-1 activation and ensuing cleavage and release of IL-1β and −18 by macrophages. Our group recently showed that HIV-1 infection of human microglia induced inflammasome activation in NLRP3-dependent manner. The HIV-1 viral protein R (Vpr) is an accessory protein that is released from HIV-infected cells, although its effects on neuroinflammation are undefined. Infection of human microglia with Vpr-deficient HIV-1 resulted in reduced caspase-1 activation and IL-1β production, compared to cells infected with a Vpr-encoding HIV-1 virus. Vpr was detected at low nanomolar concentrations in cerebrospinal fluid from HIV-infected patients and in supernatants from HIV-infected primary human microglia. Exposure of human macrophages to Vpr caused caspase-1 cleavage and IL-1β release with reduced cell viability, which was dependent on NLRP3 expression. Increased NLRP3, caspase-1, and IL-1β expression was evident in HIV-1 Vpr transgenic mice compared to wild-type littermates, following systemic immune stimulation. Treatment with the caspase-1 inhibitor, VX-765, suppressed NLRP3 expression with reduced IL-1β expression and associated neuroinflammation. Neurobehavioral deficits showed improvement in Vpr transgenic animals treated with VX-765. Thus, Vpr-induced NLRP3 inflammasome activation, which contributed to neuroinflammation and was abrogated by caspase-1 inhibition. This study provides a new therapeutic perspective for HIV-associated neuropsychiatric disease.
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Acknowledgments
This work was supported by grants from the Canadian Institutes of Health Research (CP, EAC) and fellowships from the Alberta Innovates-Health Solutions (MM, EH) and Campus Alberta Neuroscience (MM). CP and EAC hold Canada Research Chairs (Tier 1) in Neurological Infection & Immunity and Human Retrovirology, respectively. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: pSVIII-92TH014.12 from Dr. Feng Gao and Dr. Beatrice Hahn.
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Mamik, M.K., Hui, E., Branton, W.G. et al. HIV-1 Viral Protein R Activates NLRP3 Inflammasome in Microglia: implications for HIV-1 Associated Neuroinflammation. J Neuroimmune Pharmacol 12, 233–248 (2017). https://doi.org/10.1007/s11481-016-9708-3
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DOI: https://doi.org/10.1007/s11481-016-9708-3