Faculty Summaries
Christoph Seeger, PhD
Christoph Seeger, PhD
Professor
Christoph.Seeger@fccc.edu
Office Phone: 215-728-4312
Office: R212-216
  • Introduction

    Chronic HBV infections in over 400 million people worldwide remain a major burden for public health, because they are usually non-curable and cause liver disease including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). While interferon is not very effective against HBV (unlike HCV, a positive strand RNA virus), therapies with reverse transcriptase inhibitors (i.e. lamivudine, adefovir, tenofovir, entecavir) reduce the burden of infections, but cannot cure them. As expected, such treatment can drive the selection of resistant HBV variants. Therefore, future therapies depend on new information about HBV biology that uncovers novel and better drug targets.

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  • HBV – mechanism of CCC DNA synthesis

    Investigations on HBV and related animal viruses, particularly duck hepatitis B virus (DHBV), have provided a detailed model for the hepadnavirus replication cycle. However, the mechanism responsible for the conversion of the relaxed circular (RC) viral DNA genome into covalently closed circular (CCC) DNA, the template for viral RNA transcription, is not yet known. Likewise, the mechanism regulating amplification of CCC DNA in mammalian hepadnaviruses is still elusive.  Research from our laboratory showed that the conversion of DHBV RC into CCC DNA occurs independently of viral enzymatic functions, and requires instead cellular DNA repair enzymes. We propose a novel hypothesis stipulating that HBV, and DHBV, use the cellular nucleotide excision repair machinery for the conversion of RC DNA into CCC DNA. To investigate our hypothesis, we seek to identify the cellular enzymes required for the conversion of RC into CCC DNA. We anticipate to fill a major gap in our understanding of hepadnavirus biology, the mechanism of CCC DNA synthesis, and to reveal a completely novel strategy used by an animal virus to replicate DNA. The information gained from our research could be exploited for the identification of cellular genes that might provide targets for future antiviral therapies, required for the cure of over 400 million HBV infected people.

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  • HBV- novel strategy for antiviral therapy

    Although HBV replication can be inhibited with nucleoside analogs, infected hepatocytes remain infected because CCC DNA, the template for transcription of viral RNAs persists in infected cells. So far, a therapeutic strategy to functionally inactivate or even destroy CCC DNA in infected hepatocytes is lacking. We propose to use transcription activator-like effector nucleases (TALENs) specific for CCC DNA to cleave and mutate CCC DNA in regions essential for viral DNA replication. Hence, our goal is to obtain proof of principle for the idea that an infected hepatocyte can be cured of HBV through inactivation and possibly destruction of CCC DNA. Preliminary experiments from our laboratory already demonstrated that CCC DNA is indeed susceptible to cleavage by TALENs. We are investigating whether TALENs can functionally inactivate CCC DNA by insertion/deletion of bases during the repair reaction, or to even destroy CCC DNA and to determine whether TALEN-based antiviral therapy could lead to the cure of infected cells.

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