Estradiol Regulates Susceptibility following Primary Exposure to Genital Herpes Simplex Virus Type 2, while Progesterone Induces Inflammation

Abstract

ABSTRACT We report here that sex hormones modulate susceptibility to a sexually transmitted viral agent, herpes simplex virus type 2 (HSV-2), in a mouse model. Ovariectomized mice were administered either saline (control), estradiol (E 2 ), progesterone (P 4 ), or a combination of both estradiol and progesterone (E+P) and infected intravaginally with HSV-2. With an inoculation dose of 10 5 PFU, the saline- and P 4 -treated mice were found to be highly susceptible to genital HSV-2 infection. Both groups had extensive pathology and high viral titers in vaginal secretions, and 100% of mice succumbed by day 4 postinfection. E 2 -treated mice were protected from HSV-2 infection at the same dose and did not display any vaginal pathology or viral shedding. There was a slow progression of genital pathology in the combination hormone-treated group, along with prolonged viral shedding; 80% of animals succumbed by day 13. With lower inoculation doses of 10 3 and 10 2 PFU, 50 and 100%, respectively, of the combination hormone-treated mice survived. Localization of HSV-2 infection showed extensive infection in the vaginal epithelium of P 4 - and saline-treated animals within 24 h of inoculation. E 2 -treated animals were clear of infection, while the E+P-treated group had focal infection at 24 h that had progressed extensively by day 3. Infection was accompanied by persistent inflammation and infiltration of neutrophils in the P 4 -treated group. An analysis of the genes in the vaginal tissue showed that inflammation in the P 4 -treated group correlated with local induction of chemokines and chemokine receptors that were absent in the E 2 -treated mice and in uninfected P 4 -treated mice. The results show that sex hormones regulate initiation of infection and immune responses to genital HSV-2 infection.