期刊
JOURNAL OF NEUROIMMUNE PHARMACOLOGY
卷 12, 期 2, 页码 233-248出版社
SPRINGER
DOI: 10.1007/s11481-016-9708-3
关键词
HIV-1; Neuroinflammation; Inflammasomes; NLRP3; Viral protein R; Interleukin-1 beta
资金
- Canadian Institutes of Health Research
- Alberta Innovates-Health Solutions
- Campus Alberta Neuroscience
- NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH [pSVIII-92TH014.12]
- Alberta Innovates [201400453, 201500153] Funding Source: researchfish
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-1 beta 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-1 beta 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-1 beta release with reduced cell viability, which was dependent on NLRP3 expression. Increased NLRP3, caspase-1, and IL-1 beta 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-1 beta 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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