Human papillomavirus (HPV) infections are among the most common sexually transmitted diseases, infecting perhaps one-quarter of the sexually experienced population. There are at least 100 different HPV types, and certain high-risk types are associated with genital neoplasia. Understanding the process by which genital HPV leads to malignancy has been hampered by the absence of readily available culture methodology, a large percentage of latent and subclinical infections, and a prolonged time between early infection and the development of genital neoplasia. Abundant data suggest that the clinical expression of genital HPV, including genital neoplasia, occurs more rapidly in the immunocompromised host, and this group of patients may be the ideal population in which to study the natural history of HPV infections. Further, the solid organ transplant population may be the best population to study because of the abrupt and predictable nature of their immunosuppression. Accordingly, this project will establish 3 cohorts of HPV-infected women including renal transplant recipients, women with end-stage renal disease, and HIV- infected women who will be followed prospectively at 4 month intervals with routine gynecologic evaluation and colposcopy, cervicovaginal lavage for HPV-PCR, cultures for genital copathogens, and cervical biopsies as indicated. About 240 women will be evaluated annually, and HPV-positive women will be followed prospectively. The primary focus of this project is to determine the natural course of HPV gene expression, DNA replication, virion production, and viral integration using innovative molecular techniques such as RT-PCR and in situ hybridization, and to correlate these data with clinical, and histopathologic findings in the 3 cohorts. Changes in viral expression will be evaluated according to underlying disease, degree of immunosuppression, and HPV type. We hypothesize that HPV early gene expression will be up-regulated in the immunocompromised cohorts and that these molecular events will correlate with clinical and / or pathologic disease progression. This project represents a multidisciplinary effort including clinical infectious diseases, gynecology / oncology, epidemiology, and molecular virology that is essential to accomplish these goals. The information gained from a detailed analysis of these data could provide important new insights into the early markers of disease progression, and could apply not only to a large immunocompromised population, but to immunocompetent patients as well.
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