Structural and Functional Studies of L1, the Major Capsid Protein of Papillomaviruses

Human papillomaviruses (HPV) that infect the genital tract, most often HPV 16, are the primary causative agent associated with human anogenital tract cancer, particularly cervical cancers. Approximately 500,000 women develop cervical cancer each year, and 200,000 women die from it, making this disease the second-most common cause of cancer deaths in women worldwide. Significant advances have been made recently in the development of a prophylactic vaccine against papillomavirus infections. Expression of the major capsid protein, L1, leads to self- assembly into virus-like particles (VLPs) that induce high titer neutralizing antisera and protect animals against high dose experimental infection. The initial clinical trials of HPV VLP-based vaccines in humans are now under way. Very little is known about the fine structure of papillomavirus capsids, such as the portions of the L1 protein exposed on the virion surface. These parts of L1 presumably contain the neutralizing epitopes of papillomaviruses which are considered the most important components for HPV vaccine development. In addition, these surface structures may be critical for early events of papillomavirus infection such as cell binding, penetration and uncoating. The proposed study will attempt to increase our understanding of the location of neutralizing epitopes and cell surface receptor binding sites, which might further the development of prophylactic vaccines and therapeutics directed against papillomavirus virions for the prevention of HPV associated diseases.