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

• Published in: Journal of neuroimmune pharmacology 2017-06, Vol.12 (2), p.233-248
• Main Authors: Mamik, Manmeet K., Hui, Elizabeth, Branton, William G., McKenzie, Brienne A., Chisholm, Jesse, Cohen, Eric A., Power, Christopher
• Format: Article
• Language: English
• Subjects: Adult; Aged, 80 and over; Animals; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell Survival - physiology; Cells, Cultured; Female; Fetus; HIV; HIV-1 - immunology; HIV-1 - metabolism; Human immunodeficiency virus; Humans; Immunology; Inflammasomes - immunology; Inflammasomes - metabolism; Inflammation - immunology; Inflammation - metabolism; Inflammation Mediators - immunology; Inflammation Mediators - metabolism; Male; Mice; Mice, Transgenic; Microglia - immunology; Microglia - metabolism; Middle Aged; Neurosciences; NLR Family, Pyrin Domain-Containing 3 Protein - immunology; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Original Article; Pharmacology/Toxicology; Proteins; Rodents; Virology; vpr Gene Products, Human Immunodeficiency Virus - immunology; vpr Gene Products, Human Immunodeficiency Virus - metabolism
• ISSN: 1557-1890; 1557-1904
• DOI: 10.1007/s11481-016-9708-3

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.