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Rapid inflammasome activation in microglia contributes to brain disease in HIV/AIDS.

ABSTRACT: BACKGROUND: Human immunodeficiency virus type 1(HIV-1) infects and activates innate immune cells in the brain resulting in inflammation and neuronal death with accompanying neurological deficits. Induction of inflammasomes causes cleavage and release of IL-1? and IL-18, representing pathogenic processes that underlie inflammatory diseases although their contribution HIV-associated brain disease is unknown. RESULTS: Investigation of inflammasome-associated genes revealed that IL-1?, IL-18 and caspase-1 were induced in brains of HIV-infected persons and detected in brain microglial cells. HIV-1 infection induced pro-IL-1? in human microglia at 4 hr post-infection with peak IL-1? release at 24 hr, which was accompanied by intracellular ASC translocation and caspase-1 activation. HIV-dependent release of IL-1? from a human macrophage cell line, THP-1, was inhibited by NLRP3 deficiency and high extracellular [K+]. Exposure of microglia to HIV-1 gp120 caused IL-1? production and similarly, HIV-1 envelope pseudotyped viral particles induced IL-1? release, unlike VSV-G pseudotyped particles. Infection of cultured feline macrophages by the related lentivirus, feline immunodeficiency virus (FIV), also resulted in the prompt induction of IL-1?. In vivo FIV infection activated multiple inflammasome-associated genes in microglia, which was accompanied by neuronal loss in cerebral cortex and neurological deficits. Multivariate analyses of data from FIV-infected and uninfected animals disclosed that IL-1?, NLRP3 and caspase-1 expression in cerebral cortex represented key molecular determinants of neurological deficits. CONCLUSIONS: NLRP3 inflammasome activation was an early and integral aspect of lentivirus infection of microglia, which was associated with lentivirus-induced brain disease. Inflammasome activation in the brain might represent a potential target for therapeutic interventions in HIV/AIDS.

SUBMITTER: Walsh JG

PROVIDER: S-EPMC4038111 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Rapid inflammasome activation in microglia contributes to brain disease in HIV/AIDS.

Walsh John G JG Reinke Stacey N SN Mamik Manmeet K MK McKenzie Brienne A BA Maingat Ferdinand F Branton William G WG Broadhurst David I DI Power Christopher C

Retrovirology 20140513

<h4>Background</h4>Human immunodeficiency virus type 1(HIV-1) infects and activates innate immune cells in the brain resulting in inflammation and neuronal death with accompanying neurological deficits. Induction of inflammasomes causes cleavage and release of IL-1β and IL-18, representing pathogenic processes that underlie inflammatory diseases although their contribution HIV-associated brain disease is unknown.<h4>Results</h4>Investigation of inflammasome-associated genes revealed that IL-1β, ...[more]

PMID: 24886384

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Rapid inflammasome activation in microglia contributes to brain disease in HIV/AIDS.

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Rapid inflammasome activation in microglia contributes to brain disease in HIV/AIDS.

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