Cervicovaginal Secretions Contribute to Innate Resistance to Herpes Simplex Virus Infection

Abstract

Defining and preserving the innate antiviral activity found in cervicovaginal secretions is critical. Cervicovaginal lavage (CVL) samples were obtained from 20 healthy women and evaluated for anti-herpes simplex virus (HSV) activity. CVL samples reduced HSV-2 yields by 23-fold (median), and the anti-HSV activity of CVL samples correlated with the concentration of human neutrophil peptides (HNP)-1-3. Both CVL samples and HNP-1-3 interacted with virus and prevented entry after binding. Substantially less protective activity was observed in CVL samples obtained from 20 human immunodeficiency virus--infected subjects, but the addition of CVL samples from healthy subjects enhanced the antiviral activity. The significance of the innate activity was further demonstrated by showing that CVL samples prevented murine genital herpes. Fourteen of 15 mice were protected from genital herpes if they were challenged with HSV-2 pretreated with CVL samples from healthy subjects. In contrast, all 15 mice challenged with untreated HSV-2 died. These findings are evidence that cervicovaginal secretions contribute to innate resistance to HSV-2 and identify defensins as contributors to this activity.

Herpes Simplex Virus Downregulates Secretory Leukocyte Protease Inhibitor: a Novel Immune Evasion Mechanism

“…First, we previously demonstrated that recombinant SLPI interacts with human epithelial cells to inhibit HSV infection in vitro (25). Downregulation could overcome the antiviral activity of SLPI in mucosal secretions, thus providing a mechanism for immune evasion.…”

“…Cervicovaginal secretions provide intrinsic protection and inhibit HSV infection in vitro by as much as 90% (25,27). Multiple factors may contribute to this activity, including the acidic pH of the healthy female genital tract and antimicrobial proteins such as mucins, defensins, lactoferrin, lysozyme, and secretory leukocyte protease inhibitor (SLPI) (21,32,47).…”

“…We recently demonstrated that SLPI also inhibits HSV infection in vitro by binding to epithelial cell surfaces and preventing viral infection, although the precise mechanisms have not yet been elucidated (25). While no epidemiological studies have evaluated the role played by SLPI in protecting against HSV, several studies demonstrate a protective role for SLPI in preventing HIV infection.…”

Innate Immunity in the Female Reproductive Tract: Role of Sex Hormones in Regulating Uterine Epithelial Cell Protection Against Pathogens

“…In other studies, John et al have tested cervico-vaginal lavage (CVL) from healthy women and found that they have an intrinsic ability to inhibit HSV-2. Anti-HSV-2 activity correlated with the concentrations of α-defensins in CVL [207]. CVL has also been shown to contain antimicrobials SLPI, lactoferrin and gp340 that are inhibitory to HIV replication in vitro and therefore might potentially inhibit viral entry in vivo [209].…”

“…In addition, the envelope glycoprotein gp120 from X4/T-Tropic HIV-1 induces the mRNA expression of HBD2, SLPI, and IL-8 by uterine and Fallopian tube epithelial cells (Ghosh et al, unpublished observations). Several of the antimicrobials described above are effective in killing gram-positive and gramnegative bacteria, fungi, and viruses including N. gonorrhoeae, C. trachomatis, C. albicans, herpes simplex virus-2 (HSV-2), and HIV-1, all of which are important reproductive tract pathogens [202,[204][205][206][207]. Other factors found in FRT secretions exhibiting antiviral activity, notably against HIV-1, are the chemokines MIP-1α, MIP-1β, regulated upon activation, normal T-cell expressed and secreted (RANTES), and stromal derived factor 1 alpha (SDF-1α) which inhibit HIV-1 infection of target host cells by interfering with the ability of HIV-1 to bind coreceptors CCR5 and CXCR4 found on host cells [208].…”