"Human papillomavirus Pathogenesis:  Relevance of Cellular Alterations to Viral Life Cycle Versus Oncogenesis"

In 2005, human papillomaviruses (HPVs) were among the first viruses to be declared by Health and Human Services to be human carcinogens. HPVs are classified as high risk or low risk depending upon the outcome of infection.  The high risk HPVs, exemplified by HPV 16, cause anogenital cancers as well as some head and neck cancers.  The low risk HPVs, exemplified by HPV 6, predominantly cause benign warts or papillomas.  Both high and low risk HPVs infect the basal cells of the epithelium but amplify their genomes and complete their life cycles in the differentiated (G0) compartment of the epithelium.  As such, all HPVs have to either maintain cells in S phase as they migrate off the basement membrane or induce cells to re-enter S phase.  The focus of this presentation will be to discriminate between shared activities of high and low risk HPVs, which presumably are required for completion of the viral life cycle, and activities unique to high risk HPVs.  The first part of the seminar will compare the effect of expression of the E7 proteins encoded by HPV 16 and HPV 6 with respect to three parameters: the percentage of primary human foreskin keratinocytes in S phase, differentiation, and binding to histone deacetylase and histone acetylation.  While both HPV 16 E7 and HPV 6 E7 increase the percentage of cycling cells in S phase and delay differentiation, HPV 16 E7 expression results in a greater increase of cells in S phase. Both HPV 16 E7 and HPV 6 E7 bind histone deacetylase but HPV 16 E7 binds with higher affinity; only expression of HPV 16 E7 causes an increase in acetylated histones.  Potential requirements for E7-mediated enhancement of the percentage of cycling HFKs in S-phase will be discussed. The second part of the seminar will demonstrate that both HPV 6 E7 and HPV 16 E7 target p130/Rb2, an Rb family member, for degradation, although the mechanisms for targeting p130/Rb2 may be different. Mutational analysis shows that p130 degradation correlates with delayed differentiation.  In the last part of the seminar, the preliminary results of trolling for cellular E7 binding partners and for proteins ubiquitinated in the presence of E7 will be presented.