PAPILLOMAVIRUS MODEL SYSTEMS FOR MICROBICIDES

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Human papillomaviruses (HPVs) represent some of the most common of the sexually transmitted disease. More than 80 HPV types have been identified and several types have been strongly implicated as causative agents in the onset of cervical vaginal, penile, oral and skin cancers. HPV DNA is present in virtually all cases (93 percent) of cervical cancer and its precursor lesions. Current microbicidal compounds with papillomavirus activity have not been described. In addition, there are not published reports of animal models of genital papillomavirus infections for testing intra-vaginal formulations and co-incidental STD infections. Recently, several in vitro and in vivo papillomavirus infectivity models have been documented that make feasible the screening and testing of microbicidal compounds and formulations for potential anti- papillomavirus activity. The purpose of this renewal proposal is to establish the validity of two in vitro and two in vivo papillomavirus infectivity models for the testing of microbicidal papillomavirus compounds. The in vitro models we propose to use are (I) BPV-1-induced focus formation of mouse C127 cells, and (ii) transient in vitro HPV-11 (and HPV-40) infection of human A431 epithelial cells using an ELISA-based RT-PCR detection of HPV E1 E4 spliced mRNA transcripts. We will use the in vitro models to screen for effective anti-papillomavirus compounds to be later tested in two animal model systems. These include a novel human vaginal xenograft animal model system using infectious HPV-11 and HPV-40 virions, and a rabbit genital papillomavirus model recently developed in our laboratory. During the first 3 years of this Program Project, we have identified several potential papillomavirus microbicidal compounds and have begun to characterize in vivo model of genital papillomavirus infections. These microbicidal agents (neutralizing monoclonal antibodies and alkyl sulfates) represent the first compounds with anti-papillomavirus activity. We will continue their characterizing and expand the testing using formulations delivered intra-vaginally (into human vaginal xenografts and into intact rabbit vaginas) for in vivo efficacy.