interleukin-8 and Herpes-Genitalis

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.

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

Cervical shedding of HIV-1 DNA may influence HIV-1 sexual transmission. HIV-1 DNA was detected in 250 (80%) of 316 and 207 (79%) of 259 cervical cytobrush specimens from 56 US and 80 Kenyan women, respectively. Plasma HIV-1 RNA concentration was associated with increased HIV-1 DNA shedding among US and Kenyan women. Kenyan women had higher cervicovaginal concentrations of proinflammatory interleukins (IL)-1β, IL-6, IL-8, and anti-inflammatory secretory leukocyte protease inhibitor compared with US women (all P < 0.01). HIV-1 DNA shedding was associated with increased concentrations of IL-1β and IL-6 and lower secretory leukocyte protease inhibitor among US women but not Kenyan women.

Topics: Adult; Anti-Retroviral Agents; CD4 Lymphocyte Count; Cervix Uteri; Cytomegalovirus Infections; DNA, Viral; Female; Herpes Genitalis; HIV Infections; HIV-1; Humans; Interleukin-1; Interleukin-1beta; Interleukin-8; Kenya; Middle Aged; Prospective Studies; Reproductive Tract Infections; RNA, Viral; United States; Uterine Cervicitis; Vagina; Vaginitis; Viral Load