title: HIV-1 Viral Protein R Activates NLRP3 Inflammasome in Microglia: implications for HIV-1 Associated Neuroinflammation.
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.
authors.affiliation: Department of Medicine, University of Alberta, T6G 2S2, Edmonton, AB, Canada.
authors.forename: Manmeet K
authors.initials: MK
authors.lastname: Mamik
authors.affiliation: Department of Medicine, University of Alberta, T6G 2S2, Edmonton, AB, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hui
authors.affiliation: Department of Medicine, University of Alberta, T6G 2S2, Edmonton, AB, Canada.
authors.forename: William G
authors.initials: WG
authors.lastname: Branton
authors.affiliation: Department of Medicine, University of Alberta, T6G 2S2, Edmonton, AB, Canada.
authors.forename: Brienne A
authors.initials: BA
authors.lastname: McKenzie
authors.affiliation: Department of Medicine, University of Alberta, T6G 2S2, Edmonton, AB, Canada.
authors.forename: Jesse
authors.initials: J
authors.lastname: Chisholm
authors.affiliation: Institut de recherches cliniques de Montréal (IRCM) and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Cohen
authors.affiliation: Department of Medicine, University of Alberta, T6G 2S2, Edmonton, AB, Canada. chris.power@ualberta.ca.
authors.forename: Christopher
authors.initials: C
authors.lastname: Power
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D005333:Fetus; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000276:immunology / Q000378:metabolism*; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000276:immunology / Q000378:metabolism*
chemical_list: D058847:Inflammasomes; D018836:Inflammation Mediators; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D054325:vpr Gene Products, Human Immunodeficiency Virus
keywords: HIV-1; Inflammasomes; Interleukin-1 beta; NLRP3; Neuroinflammation; Viral protein R