Rapid NLRP3 inflammasome activation in microglia by lentivirus infection promotes neurovirulence

Background: Human immunodeficiency virus (HIV) infects and activates innate immune cells in the brain resulting in inflammation and neuronal death with neurological deficits, termed neurovirulence. Induction of inflammasomes causes cleavage and release of cytokines, representing pathogenic processes...

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Bibliographic Details
Published in:Canadian journal of neurological sciences 2014-05, Vol.41 (3), p.S56-S56
Main Authors: Walsh, J, Reinke, S, Maingat, F, Branton, W G, Broadhurst, D, Power, C
Format: Article
Language:English
Subjects:
Feline immunodeficiency virus
Human immunodeficiency virus
Lentivirus
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Summary:Background: Human immunodeficiency virus (HIV) infects and activates innate immune cells in the brain resulting in inflammation and neuronal death with neurological deficits, termed neurovirulence. Induction of inflammasomes causes cleavage and release of cytokines, representing pathogenic processes that underlie inflammatory diseases although their contribution HIV neurovirulence is unknown. Methods: Gene expression was examined in brain tissue from HIV/AIDS and control patients in cultured human microglia and macrophages and in brains from animals with or without feline immunodeficiency virus (FIV) infection. Results: Inflammasome-associated genes, IL-1 beta , IL-18 and caspase-1, were induced in brains of HIV-infected persons and detected in brain microglial cells. HIV infection induced pro-IL-1 beta in human microglia at 4 hr post-infection, which was prevented by the caspase inhibitor, YVAD-fmk. Exposure of microglia to HIV gp120 caused IL-1 beta production. HIV-dependent release of IL-1 beta from human macrophages was inhibited by NLRP3 deficiency and high extracellular [K+]. In vivo FIV infection activated multiple inflammasome-associated genes in microglia, which was accompanied by cortical neuronal loss and neurobehavioral deficits; multivariate analyses of FIV-infected and uninfected animals disclosed that IL-1 beta , NLRP3 and caspase-1 in the cerebral cortex represented key molecular determinants of neurovirulence. Conclusions: NLRP3 inflammasome activation was an early and integral aspect of HIV infection of microglia, leading to neurovirulence and might represent a potential target for therapeutic interventions.
ISSN:0317-1671