Jelizaveta Geimanen will defend her doctoral thesis titled “Study of the Papillomavirus Genome Replication and Segregation” on 14 April at 10.15 at Nooruse Street 1, room 121.
Supervisor: vanemteadur Ene Ustav (Tartu Ülikool)
Opponent: Eeva Auvinen, PhD, Docent in Virology, University of Helsinki Senior Laboratory Supervisor, Helsinki University Hospital Laboratory HUSLAB, Department of Virology and Immunology, Helsinki, Finland
Summary: Papillomavirus infections are common in both people and animals. Generally, these viruses may result in asymptomatic infections and can cause benign tumors as condylomas and papillomas in mucous membranes or warts and skin papillomas. However, in the case of persistent infections, these viruses may induce malignant tumors at various body sites. Currently, there are two commonly used HPV vaccines on the market. The Gardasil (against HPV6/ HPV11/ HPV16/ HPV18) and Cervarix (HPV16 / HPV18) vaccines are preventive, they do not eliminate existing infection and have no therapeutic effect in diseases caused by HPV. A multivalent HPV therapeutic vaccine candidate against six HPVs was reported; however, this vaccine is only in preclinical studies, so there is an urgent medical need for drugs that suppress HPV DNA replication.
HPV DNA replicates in the epithelial tissue, which is mostly composed of differentiating keratinocytes. HPV genomic DNA replication occurs in three clearly distinguishable phases, making the study and control of the virus complicated, because it is difficult to mimic all three stages of the virus infection cycle in the regular tissue culture cells under laboratory conditions.
We demonstrate that HPV genomes replicate efficiently in the human osteosarcoma cell line U2OS, which is capable of supporting the genome replication of many different subtypes (α-HPVs of high-risk HPV18 and HPV16; low-risk HPV6b and HPV11 and β-HPVs of HPV5 and HPV8). U2OS cells capable of supporting the maintenance of the HPV genomes provide a useful model system to study the mechanisms and regulation of viral DNA replication during various phases of the viral life cycle, including initial amplification, stable maintenance and late amplification.
We have demonstrated that two different mechanisms are involved in the HPV genome replication, shedding new light on the events that occur during the different phases of papillomavirus DNA replication.
Finally, an analysis of the papillomavirus and the Epstein-Barr virus genomes segregation functions are included. Our data demonstrated that BPV1 E2 protein and minichromosome maintenance element (MME), or EBNA1 and FR-element dependent stable maintenance functions are necessary for the stable episomal multicopy nuclear replication of the plasmids with hybrid replication origin in different types of dividing cells.