Research & Initiatives

​The work in our laboratory focuses on the pathogenesis of human papillomaviruses (HPV); small DNA viruses that exhibit epithelial tropism. Of the over 400 types of HPV identified, 12-15 are categorized as high-risk and are the causative agents of cervical cancer as well as other genital malignancies. High-risk HPVs are also associated with a high number of head and and neck cancers, predominantly HPV16.  The life cycle of HPV is dependent on cellular factors and epithelial differentiation. Differentiation triggers the productive phase of the life cycle, which includes viral genome amplification, late gene expression and virion production. Paradoxically, these events occur in differentiated cells that normally would have exited the cell cycle. To ensure virion production, HPV proteins push cells back into the cell cycle upon differentiation, providing an environment that is conducive to viral replication. The ability of the HPV oncoproteins E6 and E7 to target critical regulators of cell cycle progression results in the bypass of checkpoints that would normally eliminate abnormal cells. This results in the accumulation of genetic alterations that eventually lead to transformation and cancer development. However, the mechanisms by which the differentiation-dependent phase of the viral life cycle is regulated are unclear. Our lab is interested in defining signaling pathways modulated by HPV that promote viral replication during the different phases of the viral life cycle. Understanding how HPV alters the cellular environment to promote viral replication may identify cellular pathways that can be targeted therapeutically to treat HPV-associated diseases. 

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Current Projects

1. What is the role of the cellular DNA damage response in the viral life cycle? We have found that high-risk HPVs use DNA repair pathways for productive viral replication in differentiating epithelial cells. We are interested in determining how HPV proteins activate and utilize DNA damage response (DDR) pathways to promote viral replication, as well as understanding the impact of DDR activation on host genomic stability and the development of HPV-associated cancers.

2. How is the viral life cycle epigenetically regulated? HPV genomes are histone-associated in the virion as well as in infected cells, adopting a nucleosome pattern similar to that found in cellular DNA. We have found that certain histone post-translational modifications are required for HPV replication. We are interested in understanding how these epigenetic modifications on cellular, as well as viral DNA support HPV replication, and in turn, viral persistence. Identifying epigenetic modifiers and modifications that are required for viral replication may allow for the development of novel therapeutics to treat HPV-associated infections and malignancies.

3. How does HPV prevent activation of an anti-viral innate immune response? Pattern recognition receptors present in the cytoplasm detect pathogen associated molecular patterns, most commonly nucleic acids, and stimulate an inteferon (IFN) response that results in the production of hundreds of IFN-stimulated genes that block viral infection.  We have recently published that high-risk HPVs hijack a non-cell death function of apoptotic caspases to suppress activation of an IFN response upon differentiation, allowing for viral genome amplification to proceed.  What stimulates the IFN response in the absence of caspase activity and how caspases suppress this response are areas of current investigation.