Host immunity in human papillomavirus infection and prophylactic vaccination

Persistent genital human papillomavirus (HPV) infections are now known to be necessary but not sufficient causes of cervical cancer. This dissertation addresses both viral and host immune factors that are hypothesized to contribute significantly to the outcome of HPV infections. Genetic sequence variation within HPV types, one mechanism thought to contribute to HPV oncogenicity, was considered in these studies. Cloning experiments were performed to detect multiple HPV type 16 variant infections in clinical specimens. Results of these studies provide evidence that only one HPV16 variant predominates in a lesion over time, indicating that either viral or host restraints exist to suppress the expansion of one variant population over another. In addition, the sensitivity and specificity of HPV16 variant detection by two commonly applied laboratory methods was assessed. These analyses are important for the application of appropriate detection techniques when studying the prevalence and disease associations of HPV16 variants within large-scale epidemiological studies.; Host immunological factors that may modulate the outcome of HPV infection were also considered within the scope of this dissertation work. Cell mediated immune responses were characterized in women immunized with an HPV recombinant subunit vaccine as well as in women presumed to have been naturally exposed to HPV16. Thirty-five participants of an HPV11 viral like particle (VLP)-based vaccine trial were followed over 36 months in which two priming immunizations and two booster immunizations were administered. Results from these studies indicate that sustained humoral and cellular immune responses (both T helper type 1 and 2) were generated by HPV11 VLP vaccination and provide evidence that these subunit vaccine agents are immunogenic, however, long-term host protection remains to be proven.; In general host-pathogen interactions elicited by natural HPV infection are poorly understood. Therefore, we characterized HPV16-specific memory responses in women naturally exposed to HPV16 with no history of HPV-associated lesions. Standard lymphocyte proliferation assays and ELISPOT cytokine analyses indicated that approximately half of the HPV exposed women produced Th1 (IFNγ) memory responses against HPV16 E6, E7 or L1 peptides. These studies detailing naturally induced immune responses against HPV proteins in healthy women may facilitate future vaccine design and development.