MULTITARGETED MICROBICIDE COMBINATIONS TO BLOCK HIV

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Despite the steadily increasing number of women infected with human immunodeficiency virus (HIV) and the rise in unsafe sexual practices, there remains no effective topical microbicide against HIV infection. The overall goal of this program is to develop safe and effective topical antimicrobial agents for vaginal or rectal use that will block sexual transmission of HIV. Few products have entered clinical trials and only nonoxynol-9 (N-9)-containing products have advanced to efficacy trials. A valuable lesson learned from the N-9 trials is that the use of topical microbicides may alter innate immune responses of the female genital tract at a mucosal level and enhance sexual transmission of HIV. It is clear that early pilot in vivo studies are needed prior to the initiation of large-scale clinical trials. In collaborative studies, we have identified PRO 2000 as a lead candidate topical microbicide. It effectively inhibits HIV infection in vitro and is active against herpes simplex virus (HSV), an important co-factor in HIV transmission. Phase I trials showed that repeated intravaginal application of PRO 2000 was safe and well tolerated in healthy, sexually abstinent volunteers. While monitoring for cervicovaginal lesions has been a routine part of clinical safety microbicide trials, little is known about potential subtle changes in the cervicovaginal mucosal barrier, including induction of mucosal inflammation and interference with host defense mechanisms. The goal of Project 3 is to characterize the effect of PRO 2000 following intravaginal use on mediators of inflammation and immunity in female genital tract secretions and on the local virus population. This work will lay the groundwork for future clinical trials with combination microbicides evaluated in Projects 1 and 2.