Changes in the soluble mucosal immune environment during genital herpes outbreaks

Abstract

Background: Genital tract secretions provide variable inhibitory activity against herpes simplex virus (HSV) ex vivo. We hypothesize that the anti-HSV activity may prevent the spread of virus from the more commonly affected sites, such as the external genitalia, to the upper genital tract.

Methods: The antimicrobial activity of cervicovaginal lavage (CVL) and concentrations of mucosal immune mediators were measured in 10 HIV-seronegative women with an active external herpetic lesion and compared with 10 HIV-seronegative women who were HSV-1 and HSV-2 seronegative. Samples were obtained at the time of a symptomatic external lesion (day 0), after 1 week of oral acyclovir (day 7), and 1 week after completing treatment (day 14). Controls were evaluated at parallel intervals.

Results: The anti-HSV activity was higher in CVL obtained from cases compared to controls at presentation (day 0) (54.3% vs. 28%), fell to similar levels on day 7, and then rebounded on day 14 (69% vs. 25%). The anti-HSV activity correlated positively and significantly with the concentrations of several inflammatory proteins; the concentrations of these proteins tended to be higher in cases compared with controls and followed a similar temporal pattern.

Conclusions: Increases in inflammatory immune mediators and anti-HSV activity were detected in CVL at the time of clinical outbreaks and after completion of a short course of acyclovir. These mucosal responses may protect against HSV spread but could facilitate HIV infection and contribute to the clinical observation that, independent of clinical lesions, HSV-2 is a risk factor for HIV acquisition.

Figure 1. HSV recurrences are associated with an increase in HSV inhibitory activity, increased pro-inflammatory cytokines, decreased anti-inflammatory mediators and reduced E. coli bactericidal activity in genital tract secretions collected by lavage

Box-and- whisker plots showing the percent inhibition of HSV-2 plaque formation (a); the log-transformed concentrations of IL-1α (b), IL-1β (c), and SLPI (d) and percentage inhibition of E. coli (e) in CVL samples for controls (white) and cases (grey) at enrollment (Day 0), Day 7 and Day 14. The line indicates the median values and the circles are outliers. The asterisks denote significant differences between cases and controls.

Figure 2. CVL exhibit variable HIV inhibitory or enhancing activity

Individual CVL samples or control buffer were mixed with HIV-1_BaL prior to infecting TZM-bl cells and infection monitored by luciferase activity. Results are presented as histograms of the percentage inhibition (positive values) or enhancement (negative values) of HIV infection relative to control buffer.