Papilloma viruses are DNA tumor viruses that infect higher vertebrates including humans. Human papilloma viruses (HPVs) include a group of """"""""high-risk"""""""" viruses that are the major etiologic factor for cervical cancer and genital carcinoma. Thus, a structural analysis of papilloma viruses bears significant medical relevance The long term objectives of this proposal are to 1) determine the atomic structure of papilloma viruses in order to understand molecular mechanisms in capsid assembly and disassembly (uncoating), and 2) understand the structural basis of papilloma virus surface antigenicity, and the mechanisms of viral neutralization by antibodies.
The specific aims build upon our recent determination of the atomic structure of the HPV16 L1 major capsid protein assembled m a T=1 structure. Structures of HPV11 and HPV5 L1 will be determined so that surface loop domains, predicted to be different between viral types, can be compared with the HPV16 structure. This comparison will help define the structural basis of surface antigenicity differences between viral subtypes, and may also provide insight into the location of the cell receptor binding sites. The interaction between viral surface epitopes and neutralizing antibodies will be studied by determining the structure of a complex between HPV 16 L1 and an Fab from a neutralizing monoclonal antibody. This structure will define antibody binding sites at high resolution and provide insight into the mechanism of viral neutralization. The structure of bovine papillomavirus will be determined to extend the current HPV16 structure from a T=1 to a complete T=7 particle. The complete virion structure will identify the contacts between """"""""hexavalent"""""""" L1 pentamers as well as other bonds important for virion assembly (e.g. disulfide bonds). The structure of the minor capsid protein L2, in complex with L1 will be determined. This structure will define the domain of L2 that interacts with L1 and will hopefully provide initial information on how the L2 protein interacts with the viral genome and contributes to viral infectivity. Thus, these studies will not only provide information relevant to fundamental problems in structural virology but will also provide a basis for designing improved vaccines against papilloma viruses, and facilitating drug design to block viral entry and uncoating.
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