HIV-positive individuals have a higher prevalence of HPV infection and its pre-neoplastic sequelae than age-adjusted populations. While prophylactic vaccines will soon be available commercially for the prevention of HPV infection and cervical cancer, these vaccines will have little or no benefit for HIV-positive women who are already HPV-infected. In addition, theses vaccines do not prevent infection with several HPV types that account for 20-30% of cervical cancers. Therapeutic and preventative strategies to combat these HPV lesions are desperately needed. In this application, we will examine two compounds which show dramatic potential for preventing and treating this sexually transmitted disease. The first compound is carrageenan, which was recently shown by Dr. John Schiller's laboratory to be a potent inhibitor of papillomavirus infection in vitro by blocking cellular attachment. This is a non-toxic compound used in food preparations and, in consultation with Dr. Schiller, we will evaluate carrageenan's ability to inhibit vaginal papillomavirus infections. The second compound is dihydroartemisinin (derived from the Chinese herb, Artemisia annua). Dihydroartemisinin strongly induces apoptosis in HPV-expressing cervical cells and prevents tumor formation in vivo (using a canine oral papillomavirus model). In this application we propose to develop the first in vivo assay for papillomavirus infection of the female genital tract. Our first two years (the R21 phase) will focus on adapting the canine oral papillomavirus (COPV), which normally infects the oral mucosa, to infect and induce tumors in vaginal mucosa. In humans, the oral and genital mucosae are infected by the same HPV types. In the dog, COPV prefers the oral mucosa but it can also spread to the genital tract if the animals are mildly immunosuppressed. We plan to use documented methods of immunosuppression to develop a simple and reproducible assay for papillomavirus infection of vaginal epithelium. In the R33 phase of the application, we will formulate dihydroartemisinin derivatives and carrageenan and test them for their ability to inhibit papillomavirus infection, replication and tumor formation. We will also determine if viral persistence and latency are altered by these compounds. The combined use of this new animal model along with the newly identified inhibitors of papillomvirus infection offer exciting possibilities for extending these trials into humans. ? ? ?
