title: HIV-1 gp120 induces TLR2- and TLR4-mediated innate immune activation in human female genital epithelium.
abstract: Although women constitute half of all HIV-1-infected people worldwide (UNAIDS World AIDS Day Report, 2011), the earliest events in the female reproductive tract (FRT) during heterosexual HIV-1 transmission are poorly understood. Recently, we demonstrated that HIV-1 could directly impair the mucosal epithelial barrier in the FRT. This suggested that the HIV-1 envelope glycoprotein gp120 was being recognized by a membrane receptor on genital epithelial cells, leading to innate immune activation. In this study, we report that pattern-recognition receptors TLR2 and -4 bind to HIV-1 gp120 and trigger proinflammatory cytokine production via activation of NF-κB. The gp120-TLR interaction also required the presence of heparan sulfate (HS). Bead-binding assays showed that gp120 can bind to HS, TLR2, and TLR4, and studies in transfected HEK293 cells demonstrated that HS and TLR2 and -4 were necessary to mediate downstream signaling. Exposure to seminal plasma from HIV-1-infected and uninfected men with gp120 added to it induced a significant proinflammatory cytokine response from genital epithelial cells and disruption of tight junctions, indicating a role for gp120 in mucosal barrier disruption during HIV-1 heterosexual transmission. These studies provide, for the first time to our knowledge, a possible mechanism by which HIV-1 gp120 could directly initiate innate immune activation in the FRT during heterosexual transmission.
authors.affiliation: McMaster Immunology Research Centre, Michael G. DeGroote Centre for Learning and Discovery, McMaster University, Hamilton, Ontario L8S 4K1, Canada;
authors.forename: Aisha
authors.initials: A
authors.lastname: Nazli
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Kafka
authors.forename: Victor H
authors.initials: VH
authors.lastname: Ferreira
authors.forename: Varun
authors.initials: V
authors.lastname: Anipindi
authors.forename: Kristen
authors.initials: K
authors.lastname: Mueller
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Osborne
authors.forename: Sara
authors.initials: S
authors.lastname: Dizzell
authors.forename: Sarah
authors.initials: S
authors.lastname: Chauvin
authors.forename: M Firoz
authors.initials: MF
authors.lastname: Mian
authors.forename: Michel
authors.initials: M
authors.lastname: Ouellet
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Tremblay
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mossman
authors.forename: Ali A
authors.initials: AA
authors.lastname: Ashkar
authors.forename: Colin
authors.initials: C
authors.lastname: Kovacs
authors.forename: Dawn M E
authors.initials: DM
authors.lastname: Bowdish
authors.forename: Denis P
authors.initials: DP
authors.lastname: Snider
authors.forename: Rupert
authors.initials: R
authors.lastname: Kaul
authors.forename: Charu
authors.initials: C
authors.lastname: Kaushic
mesh_terms: D000328:Adult; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation; D004848:Epithelium / Q000276:immunology / Q000821:virology; D005260:Female; D005836:Genitalia, Female / Q000276:immunology* / Q000821:virology; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000276:immunology* / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology* / Q000635:transmission; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism; D006497:Heparan Sulfate; D006801:Humans; D007113:Immunity, Innate; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane / Q000276:immunology / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D012661:Semen / Q000378:metabolism / Q000821:virology; D015398:Signal Transduction / Q000276:immunology; D019108:Tight Junctions / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; D015699:HIV Envelope Protein gp120; D006497:Heparan Sulfate; D016328:NF-kappa B; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C514793:gp120 protein, Human immunodeficiency virus 1