title: Antiviral activity of trappin-2 and elafin in vitro and in vivo against genital herpes.
abstract: Serine protease inhibitor elafin (E) and its precursor, trappin-2 (Tr), have been associated with mucosal resistance to HIV-1 infection. We recently showed that Tr/E are among principal anti-HIV-1 molecules in cervicovaginal lavage (CVL) fluid, that E is ∼130 times more potent than Tr against HIV-1, and that Tr/E inhibited HIV-1 attachment and transcytosis across human genital epithelial cells (ECs). Since herpes simplex virus 2 (HSV-2) is a major sexually transmitted infection and risk factor for HIV-1 infection and transmission, we assessed Tr/E contribution to defense against HSV-2. Our in vitro studies demonstrated that pretreatment of endometrial (HEC-1A) and endocervical (End1/E6E7) ECs with human Tr-expressing adenovirus (Ad/Tr) or recombinant Tr/E proteins before or after HSV-2 infection resulted in significantly reduced virus titers compared to those of controls. Interestingly, E was ∼7 times more potent against HSV-2 infection than Tr. Conversely, knockdown of endogenous Tr/E by small interfering RNA (siRNA) significantly increased HSV-2 replication in genital ECs. Recombinant Tr and E reduced viral attachment to genital ECs by acting indirectly on cells. Further, lower viral replication was associated with reduced secretion of proinflammatory interleukin 8 (IL-8) and tumor necrosis factor alpha (TNF-α) and decreased NF-κB nuclear translocation. Additionally, protected Ad/Tr-treated ECs demonstrated enhanced interferon regulatory factor 3 (IRF3) nuclear translocation and increased antiviral IFN-β in response to HSV-2. Lastly, in vivo studies of intravaginal HSV-2 infection in Tr-transgenic mice (Etg) showed that despite similar virus replication in the genital tract, Etg mice had reduced viral load and TNF-α in the central nervous system compared to controls. Collectively, this is the first experimental evidence highlighting anti-HSV-2 activity of Tr/E in female genital mucosa.
authors: Department of Medicine, Neurology Division, McMaster University, Hamilton, Ontario, Canada.
authors: Anna G
authors: AG
authors: Drannik
authors: Kakon
authors: K
authors: Nag
authors: Jean-Michel
authors: JM
authors: Sallenave
authors: Kenneth L
authors: KL
authors: Rosenthal
mesh_terms: D000256:Adenoviridae; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D017931:DNA Primers / Q000235:genetics; D053492:Elafin / Q000235:genetics / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000821:virology*; D005260:Female; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors / Q000235:genetics; D006558:Herpes Genitalis / Q000517:prevention & control*; D018258:Herpesvirus 2, Human / Q000187:drug effects*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013778:Tetrazolium Salts; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014709:Vero Cells; D019562:Viral Load / Q000187:drug effects*; D053585:Virus Attachment / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D017931:DNA Primers; D053492:Elafin; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016209:Interleukin-8; D016328:NF-kappa B; C506806:PI3 protein, human; D034741:RNA, Small Interfering; D013778:Tetrazolium Salts; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C022616:thiazolyl blue
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