More than 40%of HIV infections occur via female reproductive tract(FRT)through heterosexual transmission.Epithelial cells that line the female genital mucosa are the first line of defense against HIV-1 and other sexua...More than 40%of HIV infections occur via female reproductive tract(FRT)through heterosexual transmission.Epithelial cells that line the female genital mucosa are the first line of defense against HIV-1 and other sexually transmitted pathogens.These sentient cells recognize and respond to external stimuli by induction of a range of carefully balanced innate immune responses.Previously,we have shown that in response to HIV-1 gp120,the genital epithelial cells(GECs)from upper reproductive tract induce an inflammatory response that may facilitate HIV-1 translocation and infection.In this study,we report that the endometrial and endocervical GECs simultaneously induce biologically active interferon-β(IFNβ)antiviral responses following exposure to HIV-1 that act to protect the epithelial tight junction barrier.The innate antiviral response was directly induced by HIV-1 envelope glycoprotein gp120 and addition of gp120 neutralizing antibody inhibited IFNβproduction.Interferon-βwas induced by gp120 in upper GECs through Toll-like receptor 2 signaling and required presence of heparan sulfate on epithelial cell surface.The induction of IFNβwas dependent upon activation of transcription factor IRF3(interferon regulatory factor 3).The IFNβwas biologically active,had a protective effect on epithelial tight junction barrier and was able to inhibit HIV-1 infection in TZM-bl indicator cells and HIV-1 replication in T cells.This is the first report that recognition of HIV-1 by upper GECs leads to induction of innate antiviral pathways.This could explain the overall low infectivity of HIV-1 in the FRT and could be exploited for HIV-1 prophylaxis.展开更多
基金by grants from the Canadian Institutes of Health Research(CIHR)Operating Grant FRN 126019(to CK)CIHR Team Grant on Mucosal Immunology of HIV Vaccine Development FRN 138657(to CK)+1 种基金the Ontario HIV Treatment Network(OHTN)Applied HIV Research Chair AHRC 779(to CK)VHF was supported by CIHR Banting Scholarship.
文摘More than 40%of HIV infections occur via female reproductive tract(FRT)through heterosexual transmission.Epithelial cells that line the female genital mucosa are the first line of defense against HIV-1 and other sexually transmitted pathogens.These sentient cells recognize and respond to external stimuli by induction of a range of carefully balanced innate immune responses.Previously,we have shown that in response to HIV-1 gp120,the genital epithelial cells(GECs)from upper reproductive tract induce an inflammatory response that may facilitate HIV-1 translocation and infection.In this study,we report that the endometrial and endocervical GECs simultaneously induce biologically active interferon-β(IFNβ)antiviral responses following exposure to HIV-1 that act to protect the epithelial tight junction barrier.The innate antiviral response was directly induced by HIV-1 envelope glycoprotein gp120 and addition of gp120 neutralizing antibody inhibited IFNβproduction.Interferon-βwas induced by gp120 in upper GECs through Toll-like receptor 2 signaling and required presence of heparan sulfate on epithelial cell surface.The induction of IFNβwas dependent upon activation of transcription factor IRF3(interferon regulatory factor 3).The IFNβwas biologically active,had a protective effect on epithelial tight junction barrier and was able to inhibit HIV-1 infection in TZM-bl indicator cells and HIV-1 replication in T cells.This is the first report that recognition of HIV-1 by upper GECs leads to induction of innate antiviral pathways.This could explain the overall low infectivity of HIV-1 in the FRT and could be exploited for HIV-1 prophylaxis.
