title: Anti-HIV-1 activity of elafin is more potent than its precursor's, trappin-2, in genital epithelial cells.
abstract: Cervicovaginal lavage fluid (CVL) is a natural source of anti-HIV-1 factors; however, molecular characterization of the anti-HIV-1 activity of CVL remains elusive. In this study, we confirmed that CVLs from HIV-1-resistant (HIV-R) compared to HIV-1-susceptible (HIV-S) commercial sex workers (CSWs) contain significantly larger amounts of serine antiprotease trappin-2 (Tr) and its processed form, elafin (E). We assessed anti-HIV-1 activity of CVLs of CSWs and recombinant E and Tr on genital epithelial cells (ECs) that possess (TZM-bl) or lack (HEC-1A) canonical HIV-1 receptors. Our results showed that immunodepletion of 30% of Tr/E from CVL accounted for up to 60% of total anti-HIV-1 activity of CVL. Knockdown of endogenous Tr/E in HEC-1A cells resulted in significantly increased shedding of infectious R5 and X4 HIV-1. Pretreatment of R5, but not X4 HIV-1, with either Tr or E led to inhibition of HIV-1 infection of TZM-bl cells. Interestingly, when either HIV-1 or cells lacking canonical HIV-1 receptors were pretreated with Tr or E, HIV-1 attachment and transcytosis were significantly reduced, and decreased attachment was not associated with altered expression of syndecan-1 or CXCR4. Determination of 50% inhibitory concentrations (IC(50)) of Tr and E anti-HIV-1 activity indicated that E is ∼130 times more potent than its precursor, Tr, despite their equipotent antiprotease activities. This study provides the first experimental evidence that (i) Tr and E are among the principal anti-HIV-1 molecules of CVL; (ii) Tr and E affect cell attachment and transcytosis of HIV-1; (iii) E is more efficient than Tr regarding anti-HIV-1 activity; and (iv) the anti-HIV-1 effect of Tr and E is contextual.
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Anna G
authors.initials: AG
authors.lastname: Drannik
authors.forename: Kakon
authors.initials: K
authors.lastname: Nag
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Yao
authors.forename: Bethany M
authors.initials: BM
authors.lastname: Henrick
authors.forename: Sumiti
authors.initials: S
authors.lastname: Jain
authors.forename: T Blake
authors.initials: TB
authors.lastname: Ball
authors.forename: Francis A
authors.initials: FA
authors.lastname: Plummer
authors.forename: Charles
authors.initials: C
authors.lastname: Wachihi
authors.forename: Joshua
authors.initials: J
authors.lastname: Kimani
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Rosenthal
mesh_terms: D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology*; D015704:CD4 Antigens / Q000378:metabolism; D002460:Cell Line; D053492:Elafin / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D004847:Epithelial Cells / Q000276:immunology; D005260:Female; D020868:Gene Silencing; D005836:Genitalia, Female / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D018928:Immunity, Mucosal; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000378:metabolism; D054380:Receptors, CXCR5 / Q000378:metabolism; D057900:Transcytosis / Q000187:drug effects; D053585:Virus Attachment / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D015704:CD4 Antigens; C095085:CXCR5 protein, human; D053492:Elafin; C506806:PI3 protein, human; D034741:RNA, Small Interfering; D054380:Receptors, CXCR5; D019272:Leukocyte Elastase