EARLY EVENTS IN CLINICAL HUMAN PAPILLOMAVIRUS INFECTION

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The early events in the natural history of human papillomavirus (HPV) infections and the influence of the type-specific immune response on the outcome of these early infections is not known. The specific objective of this proposal is to characterize HPV infections in a cohort of college women and to evaluate in detail the specific immune response following infection. For each of 3 consecutive years, approximately 550 women seeking routine gynecologic care at a University Health Clinic will be screened for the presence of cervical HPV infection by PCR. Those testing positive (estimated at 200 per year) will be evaluated every 6 months for 2-4 years at which time clinical and epidemiologic information will be collected and cervical specimens,will be examined for HPV DNA by PCR and for cytologic abnormalities by Papanicolaou smear. Evaluation for concurrent infection with Neisseria gonorrhea, Chlamydia trachomatis, cytomegalovirus. and herpes simplex will be performed at each visit. The presence of HPV in specimens amplified with L1 consensus primers will be detected by dot blot hybridization using a generic probe and 25 type specific probes. When HPV DNA is detected by FCC. viral load will be quantified using the hybrid capture assay. Attempts will be made to distinguish reinfection from reactivation or persistence using nucleotide sequencing. Serial samples of blood and genital secretions will be collected to determine the presence of systemic and local antibody to capsid proteins of HPV-16, 18, 6. and 11 by ELISA using virus-like particles (VLP) produced in Insect cells infected with recombinant baculoviruses expressing L1 and 1-2 genes of the respective HPVs. The data will be analyzed to achieve the following specific objectives: 1) estimation of the incidence and cumulative prevalence rates of HPV infection among cohort women, 2) detailed characterization of the immune response to HPV infection, 3) determination of the role of HPV genotype, viral burden, viral persistence. local and systemic immune response, and the presence of other sexually transmitted diseases and other factors (age, smoking, oral contraceptives) on development of squamous intraepithelial lesions of the cervix, and 4) establishing if infection with an HPV results in immunity to reinfection with the same type. It is anticipated that an understanding of the early events of HPV infections will be useful in devising strategies for prevention and control of cervical cancer.