Dr. Stephen J. Polyak

Our laboratory focuses on virus-host interactions involved in pathogenesis, immune responses and antiviral resistance associated with hepatitis C virus (HCV) infections. HCV infection is rapidly emerging as the next millenium's first serious infectiousagent. Incredibly, 4 times as many people are infected with HCV than HIV in the US. This amounts to 4 million people in the US alone. Worldwide, an estimated 40 million people are infected. Moreover, up to 85% of people who are exposed to HCV do not get rid of the virus and end up becoming persistently infected for the remainder of their lives. Persistently infected individuals are then at increased risk for the development of a spectrum of liver diseases including cirrhosis and liver cancer. In fact, HCV infection is currently the leading indication for liver transplantation in the US. Thus, HCV represents a serious global socio-economic health problem.

Recombinant interferon-alpha (IFN) was the first FDA-approved treatment for HCV. While approximately 40-50% of HCV infected individuals respond biochemically to IFN therapy by normalizing liver enzyme values, only 10% of patients have sustained virologic responses to therapy. Despite increases in response rates with IFN plus ribavirin combination therapy and pegylated IFN therapy, a large number of patients still fail to respond. HCV appears to be resistant to IFN therapy in many individuals. Furthermore, many patients are ineligible or unable to tolerate or afford IFN-based therapies.

We have developed model systems to study the interaction between HCV proteins and cellular proteins including signal transduction pathways that contribute to HCV pathogenesis, evasion of immune responses and antiviral resistance. We are also actively engaged in the study of HCV quasispecies with respect to resistance to antiviral therapy, HCV persistence and progression of liver disease. Systems developed include regulated expression of HCV proteins, high-throughput screening assays for measurement of IFN efficacy, and the HCV replicon and infectious culture systems. All of these studies are performed in cultured human hepatocytes (liver cells), which are the natural reservoir for HCV infection and replication in vivo.

For example, we have developed model systems to study the interaction between HCV proteins and IFN signal transduction pathways. For example, we have found that the HCV NS5A protein induces the expression of the CXC chemokine, interleukin-8 (IL-8; CXCL-8). This may represent a new mechanism by which an HCV protein can inhibit the antiviral actions of IFN. One NIH project funded by NIDDK focuses on how HCV induces CXCL-8. We have found that sensing of virus infection by the dsRNA sensor RIG-I protein leads to CXCL-8 induction.

Another project is focused on the HCV core protein during acute HCV infection. Our role in this NIAID funded HCV Cooperative Center grant is to clone and sequence the HCV core gene from patients with acute HCV infection and compare sequence and biological activities of core isolates from patients who resolve their infection versus patients who become chronically infected.

More recently, we have developed model systems to study the antiviral, immunomodulatory, anti-inflammatory, and anti-oxidant properties of botanical preparations with purported hepatoprotective effects. This project, funded by NCCAM, is focused on Silymarin, derived from the Milk Thistle plant. We have shown that Silymarin inhibits HCV infection in cell culture, and are currently engaged in defining the bioactive components of the extract as well as the molecular mechanisms of action.

Since HCV-host interactions are initiated immediately upon HCV infection, they likely affect the outcome of acute HCV infection. Furthemore, because these interactions persist throughout the duration of infection, they also contribute to HCV pathogenesis, immune responses and antiviral resistance.

Our laboratory is also involved in research on complementary and alternative medical approaches to hepatitis, and novel antivirals for HCV.

We are particularly interested in partnering with companies and other academic researchers for collaborative research into the mechansisms of cytokine and chemokine mediated effects on the interferon system. We are also interested in obtaining and testing lead moleculesthat inhibit chemokine mediated signal transduction.

Our research is highly relevant to industries interested in understanding HCV replication, the functions of HCV proteins, mechanisms of IFN treatment failure, and signaling pathways used by chemokines. We are also beginning to understand the long held view that botanical medicines improve health. In fact, we have recently found that silymarin inhibits HCV infection and has immunmodulatory effects on T cells. With this knowledge, improved therapies may be developed.