This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Cervicovaginal secretions play a protective role in innate immunity to sexually transmitted infections (STI). Defining this activity is crucial as these factors might be exploited in the development of microbicides and because vaginal microbicide application should not interfere with critical host defenses. This proposal focuses on the factors that protect against genital herpes, a major co-factor for HIV. We found that cervicovaginal lavage (CVL) samples obtained from healthy women substantially reduce HSV infection in vitro. A murine model of genital herpes provides strong support for the in vivo significance of these findings as CVL protects mice from vaginal herpes. Our studies suggest that the human neutrophil peptides (HNP) 1-4, epithelial defensins HD-5 and HD-6, and secretory leukocyte protease inhibitor (SLPI) contribute to this innate protection. HSV has evolved multiple strategies to circumvent host defenses. We hypothesize that HSV also has developed strategies to escape the anti-viral effects of cervical secretions. Consistent with this notion, we found that exposure of human epithelial cells to HSV leads to a rapid reduction in SLPI, which has intrinsic anti-HSV activity, and thus should reduce anti-viral activity in cervical secretions. In addition to serving as an escape mechanism, the changes in the mucosal environment triggered by HSV may enhance HIV infection. Exposure of epithelial cells, macrophages or dendritic cells (DC) to HSV induces a rapid increase in pro-inflammatory cytokines. These changes may promote HIV infection or replication and may contribute to the epidemiological findings of enhanced HIV acquisition in the setting of HSV infection. Hypothesis: We predict that cervical secretions obtained from women with active genital herpes will have substantially less anti-HSV activity compared with healthy control subjects because of a viral-induced reduction in SLPI and other antimicrobial peptides. Moreover, we theorize that the changes in mucosal mediators triggered by HSV modify the genital tract milieu rendering it more susceptible to HIV infection. If validated, these findings might provide insight into the epidemiological observations that HSV increases the risk of HIV.
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