Christoph Seeger, PhD
Office Phone: 215-728-4312
We are interested in the biology of human pathogenic viruses with an emphasis on mechanisms of viral replication and host-virus interactions that play a role in innate immunity. Our investigations on hepatitis B virus (HBV) lead to the identification of the signals required for reverse transcription of the viral DNA and provided the basis for the current model for hepadnavirus replication. We discovered that the hepatitis B polymerase could be expressed in enzymatically active form in the presence of the heat shock protein 90 complex. Moreover, we demonstrated that recovery from chronic hepatitis B infections requires massive destruction of infected hepatocytes. Investigations on hepatitis C virus (HCV) lead to the discovery that HCV replication could occur in cells of non-hepatic origin in human and mouse cells and hence did neither depend on hepatocyte –or primate-specific factors. We demonstrated that IFN resistance observed in patients was not caused by the emergence of IFN-resistant variants, but rather reflected resistance of hepatocytes to induce an effective antiviral program normally induced by IFN. Furthermore, we discovered that, in contrast to HCV, West Nile virus (WNV) could block the IFN response by inhibiting the phosphorylation of the Janus kinases Jak1 and Tyk2.
In line with our interest in HBV biology, the goal of our current research effort is to investigate one of the least understood steps in HBV replication: the mechanism by which the viral genome is converted into a covalently closed circular (ccc) DNA form and how intracellular amplification of cccDNA is regulated. To conduct our studies, we have developed a CRISPR/Cas9 platform permitting HBV infection of cells with specific gene knockouts. In addition, we are exploring a novel strategy to eliminate cccDNA from infected cells with the help of the CRISPR/Cas9 system. Finally, we are using genome-wide CRISPR/Cas9 screening to identify genes that confer sensitivity or resistance to anticancer drugs used in the treamtment of hepatocellular carcinoma.