Mechanisms of Resistance to Antiviral Therapy by Hepatitis C Virus

Stephen J. Polyak, PhD

Investigators at the Harborview Medical Center Research and Training are interested in the virological factors which contribute to the generalized antiviral resistance associated with hepatitis C virus (HCV) infections. HCV infection is rapidly emerging as the next millenium's first serious infectious agent. 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 notget 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 socio-economic health threat.

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. Thus, HCV appears to be resistant to IFN therapy in most individuals.

We are currently focusing on the molecular mechanisms employed by HCV proteins to render cells resistant to the antiviral actions of IFN.

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Recent Publications

Polyak SJ, Paschal D, McArdle S, Moradpour D, Gale MJ Jr, Katze MG, Gretch DR. Characterization of the Effects of Hepatitis C Virus Non-Structural 5A Protein Expression In Human Cell Lines and Interferon-Sensitive Virus Replication. Hepatology 1999; 29:1262.

Gale MJ Jr, Blakely CM, Kwieciszewski B, Tan SL, Dossett M, Tang NM, Korth MJ, Polyak SJ, Gretch DR, Katze MG. Control of PKR protein kinase by the hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation. Mol Cell Biol 1998; 18: 5208-18.

Polyak SJ, McArdle S, Liu S-L, Sullivan D, Chung M, Hofgårtner WT, Carithers RL, McMahon BJ, Mullins JI, Corey L, Gretch DR. Evolution of Hepatitis C virus quasispecies in the hypervariable region 1 and the interferon sensitivity determining region during interferon therapy and natural infection. J Virol 1998; 72:4288-96.

Hofgartner W, Polyak SJ, Sullivan DG, Carithers RL, Gretch DR. Mutations in the NS5A gene of Hepatitis C virus in North American patients infected with HCV genotype 1a and 1b. J Med Virol 1997; 53:118-26.

Polyak SJ, Faulkner G, Carithers RL, Corey L, Gretch DR. Characterization of Hepatitis C virus quasispecies heterogeneity by gel shift analysis: correlation with response to interferon therapy. J Infect Dis 1997; 175:1101-7.

Gale MJ, Korth MJ, Tang NM, Tan S-L, Hopkins DA, Dever TE, Polyak SJ, Gretch DR, Katze MG. Evidence that Hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology 1997; 230:217- 27.

Gretch DR, Polyak SJ, Wilson JJ, Carithers RL, Perkins JD, Corey L. Tracking hepatitis C virus quasispecies major and minor variants in symptomatic and asymptomatic liver transplant recipients. J Virol 1996; 70:7622-31.

Lieber A, He CY, Polyak SJ, Gretch D, Barr D, Kay MA. Elimination of Hepatitis C viral RNA in infected human hepatocytes by Adenovirus-mediated expression of ribozymes. J Virol 1996; 70:8782-91.

Polyak SJ, Tang N, Wambach M, Barber GN, Katze MG. The 58kDa cellular inhibitor, P58, complexes with the interferon-induced, double-stranded RNA-dependent protein kinase, PKR, to regulate its autophosphorylation and activity. J Biol Chem 1996; 271:1702-7.

Wilson JJ, Polyak SJ, Day TD, Gretch DR. Characterization of simple and complex Hepatitis C virus quasispecies by heteroduplex gel shift analysis: correlation with nucleotide sequencing. J Gen Virol 1995; 76:1763-71.

Journal Links

Hepatology Online journal