title: HIV-1 infection induces interleukin-1β production via TLR8 protein-dependent and NLRP3 inflammasome mechanisms in human monocytes.
abstract: The induction of inflammatory cytokines such as IL-1β is associated with the progression of human immunodeficiency virus, type 1 (HIV-1) disease or AIDS. Unlike most inflammatory cytokines that are regulated by NF-κB at the transcriptional level, production of mature IL-1β also depends on inflammasome activation. The mechanism by which HIV-1 induces pro-IL-1β expression and activates inflammasomes to cleave pro-IL-1β into its bioactive form is not clearly defined. We report here that HIV-1 infection in human monocytes efficiently induced IL-1β expression and inflammasome activation. Toll-like receptor 8 (TLR8) was required for inducing pro-IL-1β expression, whereas the NLRP3 inflammasome was required for IL-1β maturation and release. Furthermore, the lysosomal protease cathepsin B and HIV-1 induced production of reactive oxygen species were critical for HIV-induced inflammasome activation and IL-1β production. HIV-1 entry, reverse transcription, and integration were all required for both pro-IL-1β expression and inflammasome activation. Finally, we show that HIV-1-derived RNA was sufficient to induce both pro-IL-1β expression and inflammasome activation. We conclude that HIV-1 infection induced the expression of pro-IL-1β via TLR8-mediated mechanisms and activated caspase-1 through the NLRP3 inflammasome to cleave pro-IL-1β into bioactive IL-1β. These findings help to elucidate mechanisms of HIV-1 disease progression and identify novel targets for treating HIV-1 induced inflammation and immune activation.
authors.affiliation: From the Lineberger Comprehensive Cancer Center and.
authors.forename: Haitao
authors.initials: H
authors.lastname: Guo
authors.affiliation: From the Lineberger Comprehensive Cancer Center and.
authors.forename: Jianmei
authors.initials: J
authors.lastname: Gao
authors.affiliation: From the Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Taxman
authors.affiliation: From the Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.
authors.forename: Jenny P Y
authors.initials: JP
authors.lastname: Ting
authors.affiliation: From the Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 lsu@med.unc.edu.
authors.forename: Lishan
authors.initials: L
authors.lastname: Su
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D002401:Cathepsin B / Q000096:biosynthesis; D055785:Gene Knockdown Techniques; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis*; D009000:Monocytes / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012367:RNA, Viral / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000235:genetics / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D012367:RNA, Viral; D017382:Reactive Oxygen Species; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; D002401:Cathepsin B
keywords: AIDS; HIV-1 Protease; Host-Pathogen Interaction; Infectious Disease; Inflammation; Innate Immunity; Macrophage; Monocyte; Toll-like Receptor (TLR); Viral Replication