Infectious agents contribute to about 20% of all human cancers. Among them, hepatitis B and C viruses, human papilloma virus, Epstein Barr virus and Heliobacter pylori together cause more than 2 million cancers annually. The initial emphasis of our research was human hepatitis B virus (HBV). We investigated replication and the role of the immune system in the clearance of HBV from acutely infected liver. More recently we have investigated the effect of innate immune responses on the outcome of a second oncogenic human virus, hepatitis C virus (HCV) and the related, neuropathic West Nile virus (WNV). More than 300 million people are chronically infected with HBV and HCV and are at risk for developing hepatocellular carcinoma, an often-fatal cancer of the liver.

Currently we are focusing on the regulation of the interferon (IFN) response and on mechanisms by which host and viral proteins attenuate IFN signaling. Hence, our research interests focus on host-virus interactions that determine the balance between survival of the host and the pathogen, particularly innate immunity. Discovered just a little more than 50 years ago, IFN has proven to be an indispensable component of the innate immune system. Mutations abrogating its function are lethal for all vertebrates coexisting with pathogens. Not surprisingly, viruses have evolved mechanisms to antagonize the IFN response to gain a small advantage necessary for propagation. In doing so, they activate cellular negative feedback loops intrinsic to all signal transduction pathways, including those for IFNs. The premise of our research program then is to shed light on the regulation of the IFN response and to exploit the knowledge gained from our studies for the development of more effective IFN-based therapies.

We are investigating HCV with an emphasis on the IFN response against this virus. This interest was in part spurred by clinical observations indicating that only a fraction of HCV-infected patients could be cured with IFN therapy. An obvious hypothesis was that certain HCV isolates would express proteins that antagonize the IFN response, as observed earlier with certain paramyxoviruses or members of the herpes family of viruses. However, we identified IFN-α as a potent inhibitor of so-called IFN-resistant and -sensitive HCV isolates, raising the possibility that IFN resistance observed in vivo, could be due to a deficient host response to IFNα rather than the emergence of IFN-resistant viral variants, as it was believed. Notably, the transcriptomes of normal or HCV expressing cells did not differ significantly even in the presence of IFN. However, those results differed from observations we, and others, made with tissues from HCV infected patients. They revealed that HCV replication in vivo induced either directly or indirectly an innate immune response characterized by the expression of interferon-induced genes (ISGs). Thus, while the virus responds readily to IFN in tissue culture, it appears refractory to the response that it induces in vivo. Whether or not induction of ISGs therefore plays a role in the outcome of IFN therapy is an important question that needs to be resolved in the future.

We are also pursuing a molecular analysis of liver biopsy samples from HCV-infected individuals. The purpose of this collaborative effort between clinicians at Fox Chase Cancer Center and the University of Pennsylvania and our laboratory is to identify molecular markers that can predict outcome of IFN therapy. So far, we have investigated whether a correlation exists between HCV and ISG expression levels, in hepatocytes isolated from liver sections using laser capture microdissection (LCM), and the outcome of IFN therapy. In a next step, we plan to analyze specific components of the IFN signal transduction pathway. For example, we would like to explore whether HCV replication and ISG-induction causes down regulation of IFNAR1. In other words, we would like to establish a link between the regulation of IFN signaling and mechanisms that play a role in determining success or failure of IFN therapy.

About six years ago, we discovered that in contrast to HCV, WNV expression, once established, significantly attenuated the response to IFNα. The question of how WNV could inhibit IFN signaling began to captivate our research interests and led to the identification of a novel mechanism used by a virus to suppress the IFN response: WNV down regulates expression of one of the two components of the IFN receptor, termed IFNAR1, and in turn, prevents activation of downstream signaling components and activation of ISGs. Currently, we are investigating the mechanism by which WNV antagonizes IFN signaling. In addition, we are addressing unresolved questions about the physiological regulation of the IFN response. A better understanding of pathways that regulate the IFN response will pave the way for the development of screens to identify compounds that could be used to augment the therapeutic efficacy of IFN against viral infections, and perhaps even certain cancers where this cytokine has exhibited, so far, only modest therapeutic benefits.