Development of tools to interfere with Human Papillomavirus infectious cycle
Human papillomaviruses (HPV-s) are the main etiological agents of several different cancer types and benign lesions of the epithelium. Over 200 different HPV types have been identified so far. To date there are no specific antiviral compounds to combat HPV infections. The main aim of our research is to understand the HPV infectious cycle at molecular level with specific emphasis on the viral genome replication. Using this knowledge we are trying to develop tools to intervene with HPV life cycle at various stages of infection.
Specific subprojects of our research group are:
1) Identification of host cell factors regulating HPV replication. HPV genome replication requires two viral proteins E1 and E2. All other proteins directly involved in the replication process, and regulating it, are provided by the host cell. We are interested in identifying these host cell factors regulating the process. We have shown that HPV replication activates DNA damage response in cells and this process might be required to complete virus genome replication. Currently we are studying the involvement of serine/threonine kinase CK2 in the replication of various HPV types. We have shown that the activity of CK2 has positive effect on genome replication of various HPV types. We are also studying the role of POU-homeodomain transcription factor family in HPV replication and found out that a some of family members elicit strong negative effect on HPV genome replication.
2) Mechanisms of HPV replication. HPV genome is maintained in the infected cells as an 8000 basepair circular DNA episome. Some HPV types have a tendency to form oligomeric genomes in infected cells. It is believed that HPV replicates in an replication origin dependent bi-directional manner, generating Cairns type of DNA intermediates during the process. We have found however, that in addition to Cairns type of replication intermediates, intermediates with unknown DNA topology occur during HPV replication. It seems that the relative amount the unknown intermediates is in positive correlation with the presence of oligomeric HPV genomes in the cell. We currently trying to identify the nature of these replication intermediates in order to understand if a novel mechanism is involved in HPV genome replication.
3) Identification of drug candidates to combat HPV infection. We have developed a high-throughput screening assay to identify compounds that inhibit replication of various HPV types. Using this assay we have already identified a number of compounds that inhibit HPV replication and can be further developed to drug candidates. We are currently working to make the assay more sensitive and are planning to use novel compound libriaries to screen for HPV replication and virus entry inhibitors.
See full list of publications here.
Alla Piirsoo (alla.piirsoo [ät] ut.ee)
Marko Piirsoo (marko.piirsoo [ät] ut.ee)
Andres Männik (andres.mannik [ät] ut.ee)
Ene Ustav (ene.ustav [ät] ut.ee)
Regina Piptich (regina.pipits [ät] ut.ee)
Mart Ustav, professor
509 8600 (5047)
mart.ustav [ät] ut.ee