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Christoph Seeger, PhD

Christoph Seeger, PhD
About

Research Program

Monitoring DHBV and HBV nuclear DNA by FISH
Gaps in knowledge: Where is cccDNA in the nucleus?
Physical map of hepatitis B virus (HBV)
HBV life cycle
Model for CCC DNA synthesis

 

Education and Training

Educational Background

  • Postdoctoral Fellow, University of California-San Francisco, San Francisco, CA
  • PhD, Biocenter, University of Basel, Basel, Switzerland, 1982
  • MS, Biocenter, University of Basel, Basel, Switzerland, 1979

Honors & Awards

  • Fellow, American Association for the Advancement of Science
  • Fellow, American Academy of Microbiology
Research Profile

Research Program

Research Interests

  • DNA repair enzymes involved in hepatitis B virus replication.
  • Use of CRISPR/Cas9 platforms for investigations on the HBV life cycle.
  • Development of imaging methods to visualize and monitor cccDNA.

Lab Overview

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 developing methods to visualize individual copies of cccDNA in HBV infected cells. We seek to determine the localization of cccDNA in nuclei of infected cells and to monitor the fate of cccDNA under conditions mimicking natural recovery from acute HBV infections. Our long-term goal is to provide novel insights into the biology of cccDNA that can be used for the development of therapies to cure chronic hepatitis B.

Lab Staff

Ji Sohn BS

Technical Specialist

Room: R216
215-728-4313

Pietro Mancuso

Scientific Technician II

Room: R216, 4313

Mingming Li

Student

Room: R216, 4313
Publications

Selected Publications

Li M, Sohn JA, Seeger C. Distribution of Hepatitis B Virus Nuclear DNA. J Virol, 92(1), 2018. PMC5730781

Seeger, C and Sohn, J.A. Complete spectrum of CRISPR/Cas9-induced mutations on HBV cccDNA. Molecular Therapy, 24:1258-66, 2016. https://www.ncbi.nlm.nih.gov/pubmed/27203444

Seeger, C and Sohn J.A. Targeting HBV cccDNA with CRISPR/Cas9. Molecular Therapy-Nucleic Acids, e216; doi:10.1038/mtna.2014.68, 2014. PubMed

Hu, J., Seeger, C.  Hepadnavirus assembly and reverse transcription require a multi-component chaperone complex which is incorporated into nucleocapsids. EMBO J. 16:59-68, 1997. https://www.ncbi.nlm.nih.gov/pubmed/9009268

Hu, J., Seeger, C.  Hsp90 is required for the activity of a hepatitis B virus reverse transcriptase. Proc. Natl. Acad. Sci. USA 93:1060-1064, 1996. https://www.ncbi.nlm.nih.gov/pubmed/8577714

Wang, G.-H., Seeger, C.  The reverse transcriptase of hepatitis B virus acts as a protein-primer for viral DNA synthesis. Cell 71:663-670, 1992. https://www.ncbi.nlm.nih.gov/pubmed/1384989

Seeger, C., Ganem, D., Varmus, H.E.  Biochemical and genetic evidence for the hepatitis B virus replication strategy. Science 232:477‑487, 1986. https://www.ncbi.nlm.nih.gov/pubmed/3961490

 

This Fox Chase professor participates in the Undergraduate Summer Research Fellowship
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