To date, 60 different types of human papillomaviruses (HPVs) have been isolated and characterized with the aid of molecular cloning systems. Over twenty of these viral isolates have been associated with benign and malignant lesions of the anogenital tract. The presence of HPV in premalignant and invasive cancers, particularly of the cervix, is believed to be reflective of the oncogenic potential of these viruses. We propose to conduct a natural history study of HPV infections in high- risk minority populations including Native American, Hispanic, and Non-Hispanic white women. As part of these investigations we will establish a PCR-based HPV L1/E6 detection system that correlates with established Southern blot criteria of HPV type. This system will be utilized to determine the prevalence of various HPV types and their potential relationship to cervical disease in these randomly screened populations. Additionally, we will evaluate cervical sampling methodologies and analyze biological and behavioral factors affecting the detection of HPVs in serial cervical specimens. No diagnostic method currently available provides a sensitive, specific and reproducible approach to identifying and characterizing this highly heterogeneic group of viruses. A diagnostic possessing these characteristics which has been developed systematically in defined populations is needed before it can be determined if specific HPVs act as etiologic agents, cofactors or markers of developing cervical neoplasias. Prevalent novel HPVs identified in the populations studied will be subjected to direct automated DNA sequence analysis and the resultant data utilized to develop improved oligonucleotide probe systems. HPV types and specific DNA sequences will be evaluated as potential risk factors or markers of cervical disease. A simplified strategy for identification of known and novel HPV isolates which utilizes restricition map analysis of HPV L1 and E6/E7 PCR products will be developed. HPV E6-E7 PCR products obtained from """"""""normal"""""""", preinvasive, and invasive cervical lesions will be directly cloned and evaluated for in vitro transforming activities. Pathological findings and in vitro transforming activities will be compared between and within multiple HPV types in an attempt to identify HPV-specific sequences associated with cervical neoplasia.
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