Papillomaviruses (PVs) have been shown to contribute to the pathogenesis of cancer of the cervix, vulva, penis and skin. Immunity to these viral infections plays a significant role in disease outcome, but the precise viral targets of immunity for prevention of infection and destruction of active lesions are poorly characterized. The long-range goal of this project is to determine which viral antigens and immune effector cells are involved in a successful immune response to papillomavirus infection. The objective of this application is to examine immunity during two early stages of human papillomavirus type 11 (HPV-11) and cottontail rabbit papillomavirus (CRPV) infection. The first is represented by antibody-mediated virus neutralization, which predominantly targets surface conformational, type-specific epitopes located in the hypervariable regions of papillomavirus L1 proteins. The second is cell-mediated immunity to epitopes on early viral proteins present in infected epithelial cells. The central hypothesis to be tested is that immunity to papillomavirus proteins can lead to protection and resolution of the disease. The rationale behind the research is that studies on viral immunity will provide essential information for the design of protective vaccines and immuno-therapeutic interventions for HPV infections. To accomplish the objectives of this application, the applicant will pursue two Specific Aims: (1) define the nature of the components of conformational and linear neutralizing epitopes on papillomavirus virions, and (2) determine the role of the papillomavirus early proteins in the induction of immunity to CRPV-induced papillomas. At the completion of this research, he expects to have mapped several critical amino acid residues on HPV-11 and CRPV virions that are recognized by a panel of neutralizing monoclonal antibodies (N-MAbs), and to have determined which CRPV early viral proteins are involved in increased immunity to papillomas as measured by papilloma regression. In addition, he plans to focus attention on mapping of cross-reactive, less-antigenic or """"""""secondary"""""""" neutralizing epitopes recognized by several of his N-MAbs. These latter epitopes may be an essential component of a more broadly effective (i.e., modified) VLP vaccine. Defining the major protective viral epitopes on PV virions and on the early viral proteins in papillomavirus-infected cells will be key to planning effective immunotherapeutic management of this infectious disease.
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