Antiviral activity of trappin-2 and elafin in vitro and in vivo against genital herpes

J Virol. 2013 Jul;87(13):7526-38. doi: 10.1128/JVI.02243-12. Epub 2013 May 1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae
  • Analysis of Variance
  • Animals
  • Blotting, Western
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • DNA Primers / genetics
  • Elafin / genetics
  • Elafin / pharmacology*
  • Enzyme-Linked Immunosorbent Assay
  • Epithelial Cells / virology*
  • Female
  • Fluorescent Antibody Technique
  • Gene Knockdown Techniques
  • Genetic Vectors / genetics
  • Herpes Genitalis / prevention & control*
  • Herpesvirus 2, Human / drug effects*
  • Humans
  • Interferon Regulatory Factor-3 / metabolism
  • Interleukin-8 / metabolism
  • Mice
  • Mice, Transgenic
  • NF-kappa B / metabolism
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Tetrazolium Salts
  • Thiazoles
  • Tumor Necrosis Factor-alpha / metabolism
  • Vero Cells
  • Viral Load / drug effects*
  • Virus Attachment / drug effects
  • Virus Replication / drug effects


  • DNA Primers
  • Elafin
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Interleukin-8
  • NF-kappa B
  • PI3 protein, human
  • RNA, Small Interfering
  • Tetrazolium Salts
  • Thiazoles
  • Tumor Necrosis Factor-alpha
  • thiazolyl blue