Marit Orav will defend her doctoral thesis “Study of the initial amplification of the human papillomavirus genome” on 21 January 2016 at 9.15 in the Institute of Technology (Nooruse 1-121) of University of Tartu.
Supervisor: vanemteadur Ene Ustav, Tartu ülikool
Opponent: Laimonis A Laimins, PhD, professor, Northwestern University Feinberg School of Medicine (USA)
Human papillomaviruses (HPVs) infect the keratinocytes of cutaneous and mucosal epithelial tissue. Human papillomavirus infections are most commonly asymptomatic but may lead to the formation of benign lesions in the infected tissue. Persistent HPV infection may lead to the malignant progression of the virus-induced lesions. HPV infection is implicated in the development of cervical and other anogenital cancers as well as head and neck cancers. The introduction of preventive HPV vaccines has led to a decrease in the prevalence of HPV infections and cervical lesions; however, the vaccines currently on the market are only targeted against nine of the most common HPV types. Additionally, because of the high cost of the vaccines, they are largely unattainable in developing countries. Currently, there are no therapeutic procedures or drugs available to treat HPV infections by specifically targeting HPV replication.
Cultivating keratinocytes and mimicking the HPV life cycle under laboratory conditions is complicated and expensive. Additionally, the traditional methods used to study HPV infection in tissue do not enable research into the very early events that occur during HPV replication. Therefore, the exact mechanism underlying HPV genomic replication and the cellular proteins involved in the process have not been identified, which in turn is hampering the development of anti-HPV drugs.
The general objectives of the research detailed in the present thesis involve developing a cellular assay capable of supporting HPV replication and utilizing the developed cellular assay to investigate the initial amplification replication of the HPV genome. We discover that homologous recombination, which is essential for the repair of cellular DNA lesions, is involved in HPV replication. The engagement of homologous recombination during viral replication results in the generation of multimeric HPV genomes, which are likely important during the long-term maintenance of HPV genomes during persistent infection.
We analyze the intermediates that are generated during HPV infection in host cells, and discover that two separate mechanisms are likely used during the replication of the HPV genome. Utilizing two different replication mechanisms would enable papillomaviruses to maintain HPV genomic replication under changing host cell environments, and contribute to highly efficient viral replication. Demonstrating the presence of two different replication mechanisms during papillomavirus replication could have significant implications for the treatment of HPV-associated lesions. Specific inhibitors of HPV replication are not currently used for the treatment of HPV-associated afflictions; however, the involvement of two different mechanisms in the replication of the HPV genome indicates that any potential drug should be able to target both of these mechanisms to eradicate HPV infection.
Senior Research Fellow