title: Trappin-2/Elafin: a novel innate anti-human immunodeficiency virus-1 molecule of the human female reproductive tract.
abstract: Trappin-2/Elafin is a serine protease inhibitor that plays a major role as an anti-inflammatory mediator at mucosal surfaces. In addition, Trappin-2/Elafin has antibacterial activity against Gram-positive and Gram-negative bacterial and fungal pathogens. In this study we examined the production of Trappin-2/Elafin by epithelial cells from the human upper and lower female reproductive tract as well as its activity as an anti-human immunodeficiency virus (HIV)-1 molecule. We found that primary uterine, Fallopian tube, cervical and ectocervical epithelial cells produce Trappin-2/Elafin constitutively and that production of Trappin-2/Elafin is enhanced following stimulation with Poly(I:C), especially by the uterine cells. Given the presence of Trappin-2/Elafin in the reproductive tract, we tested the ability of recombinant Trappin-2/Elafin to inhibit HIV-1, an important sexually transmitted pathogen. We found that recombinant Trappin-2/Elafin was able to inhibit both T-cell-tropic X4/IIIB and macrophage-tropic R5/BaL HIV-1 in a dose-dependent manner. The inhibitory activity was observed when virus was incubated with Trappin-2/Elafin but not when Trappin-2/Elafin was added to cells either before infection or after infection. This suggests that the mechanism of inhibition is likely to be a direct interaction between HIV-1 and Trappin-2/Elafin. Additionally, we measured the levels of secreted Trappin-2/Elafin in cervico-vaginal lavages (CVL) from both HIV-positive and HIV-negative women and found that average levels of secreted Trappin-2/Elafin were higher in the CVL from HIV-negative women, although the values did not reach statistical significance. We also found that women at the secretory phase of the menstrual cycle produced more Trappin-2/Elafin in CVL relative to women at the proliferative phase of the menstrual cycle. Our data suggest that Trappin-2/Elafin might be an important endogenous microbicide of the female reproductive tract that is protective against HIV-1.
authors.affiliation: Department of Physiology, Dartmouth Medical School, Lebanon, NH 03756, USA. Mimi.Ghosh@dartmouth.edu
authors.forename: Mimi
authors.initials: M
authors.lastname: Ghosh
authors.forename: Zheng
authors.initials: Z
authors.lastname: Shen
authors.forename: John V
authors.initials: JV
authors.lastname: Fahey
authors.forename: Susan
authors.initials: S
authors.lastname: Cu-Uvin
authors.forename: Kenneth
authors.initials: K
authors.lastname: Mayer
authors.forename: Charles R
authors.initials: CR
authors.lastname: Wira
mesh_terms: D002584:Cervix Uteri / Q000276:immunology / Q000473:pathology; D053492:Elafin / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005187:Fallopian Tubes / Q000473:pathology; D005260:Female; D005498:Follicular Phase / Q000276:immunology / Q000378:metabolism; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity; D006367:HeLa Cells; D006801:Humans; D008183:Luteal Phase / Q000276:immunology / Q000378:metabolism; D011070:Poly I-C / Q000276:immunology; D012098:Reproduction; D014599:Uterus / Q000276:immunology / Q000473:pathology*; D014774:Virulence
chemical_list: D053492:Elafin; D011070:Poly I-C