Our lab continues to study the role that human papillomaviruses plays in cervical cancer as a model to study epithelial malignancies. Two broad avenues of investigation are pursued: in the first we are trying to understand the mechanisms by which the HPV oncoproteins E6 and E7 disrupt normal cell cycle control leading to cellular immortalization. By extensive mutagenesis of E7 we showed that neither disruption of Rb/E2F complexes nor targeting Rb for degradation by E7 is sufficient for immortalization or overcoming DNA-damage induced G1 arrest. We identified a new complementation group with the C-terminus of E7 that is Rb-independent and necessary for transformation. We also showed that E6 induces telomerase activity by activating transcription of the TERT gene. Although E6 does not alter levels of MYC, mutation of MYC binding sites on TERT promoter eliminates E6-induction of TERT. The ubiquitin ligase, E6AP, was shown to be required for TERT transcription. A new target of E6/E6AP, called NFX-1, was identified; it binds to the TERT promoter and apparently cooperates with MYC to regulate transcription. Additionally, preliminary data suggests that HPVs may induce TERT to provide a growth advantage to the cells, independent of telomere elongation. 

The second avenue of investigation is focused on seroepidemiological studies to understand the natural history of HPV infection and to determine the risk factors in addition to HPV that lead to the development of cancer. We have characterized the kinetics of appearance and persistence of HPV antibodies and have shown that there are type-specific and Ig-specific differences, and we have shown an increased prevalence of HPV 16 and 18 antibodies in cases with all types of anogenital cancer. We have extended our studies on serum antibodies to cervical antibodies as well. Current efforts are focused on identifying the epitopes on HPV virions that are recognized in natural infection and following vaccination. To determine why only some infected people get cancer we have been comparing HLA genotypes of cases versus controls and have identified DRB1 alleles that confer risk to HPV 16 associated cervical cancer. 

Helt AM, Funk JO, Galloway DA. Inactivation of both Rb and p21 by the human papillomavirus type 16 E7 oncoprotein is necessary to abrogate cell cycle arrest in human epithelial cells. J Virol 76:10559-68, 2002.

Madeleine MM, Brumback B, Cushing-Haugen K, Smith AJ, Nelson JL, Schwartz SM, Daling JR, Galloway DA. Class II HLA alleles and the risk of squamous cell cervical cancer in a population-based study. J Infect Dis 186:1565-74, 2002.

Gewin LC, Galloway DA. E box-dependent activation of telomerase by HPV 16E6 does not require induction of c-myc. J Virol 75:7198-201, 2001.

Carter JJ, Koutsky LA, Hughes JP, Lee S-K, Kuypers J, Kiviat NB, Galloway DA. Comparison of HPV 16, 18, and 6 capsid antibody responses following incident infection. J Infect Dis 181:1911-9, 2000.