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J Neuroimmune Pharmacol. 2017 Jun;12(2):233-248. doi: 10.1007/s11481-016-9708-3. Epub 2016 Oct 10.

HIV-1 Viral Protein R Activates NLRP3 Inflammasome in Microglia: implications for HIV-1 Associated Neuroinflammation.

Author information

1
Department of Medicine, University of Alberta, T6G 2S2, Edmonton, AB, Canada.
2
Institut de recherches cliniques de Montréal (IRCM) and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada.
3
Department of Medicine, University of Alberta, T6G 2S2, Edmonton, AB, Canada. chris.power@ualberta.ca.

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.

KEYWORDS:

HIV-1; Inflammasomes; Interleukin-1 beta; NLRP3; Neuroinflammation; Viral protein R

PMID:
27726055
DOI:
10.1007/s11481-016-9708-3
[Indexed for MEDLINE]

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