Institute for Medical Virology and Epidemiology of Viral Diseases

The HPV replication cycle

HPV infect and complete their replication cycle in keratinocyte cells that are the main constituents of mucosal and cutaneous epithelium. In basal epithelial cells low levels of HPV genome replication and expression of early viral gene products can be observed. Production of infectious HPV occurs only in the upper layers of the infected epithelium. 

• We aim to understand the regulation of the different phases of the HPV replication cycle in order to identify key regulatory events that can be targeted by antivirals.

The HPV genome is a double-stranded, covalently closed DNA molecule of 8kbp that is packaged in a chromatinized form. The viral E1 and E2 proteins are the key replication activators and form a complex that recognizes the viral origin. E1 acts as DNA helicase and recruits host cell proteins to initiate the replication of the genome. E2 is not only a loader for the E1 helicase but also modulates viral transcription and acts as segregation factor for the viral genomes upon cell division.

Our studies have uncovered that HPV encode E8^E2, an alternative E2 protein, which limits viral replication in undifferentiated cells by repressing viral transcription and E1/E2-dependent DNA replication. Using a panel of different technologies (immunoprecipitation-mass spectrometry, fluorescence microscopy, RNA interference, transcription and replication reporter assays), we have identified the cellular NCoR/SMRT repressor complex as a mediator of E8^E2´s repression activities.

• we investigate the molecular mechanism of repression by the E8^E2-NCoR/SMRT complex
• we investigate the long-term phenotypes of E8^E2 knock out PV genomes in tissue culture and animal models

we identify and characterize post-translational modifications (phosphorylation, acetylation, etc.) of the viral replication proteins E1, E2 and E8^E2C