Worldwide, approximately 2% of the population is infected with HCV and 50-80% of those develop into persistent infections. Currently, the only approved therapy for treatment of chronic HCV infection is a 24-48 week course of the combination of pegylated IFNalpha2a or alpha2b and ribavirin with a response to treatment of 42% (genotype 1) and 82% (genotype 2/3) sustained viral clearance. Even in persons without sustained responses, IFN (alpha) therapy usually results in a rapid decline in HCV viral load; therefore, IFN will likely continue to be used in treatment either in combination therapies or as an initial pre-treatment to reduce viral load, despite the development of other antivirals. The mechanisms of actions of IFN (or resistance to IFN) during antiviral therapy for HCV are not understood; yet, understanding these mechanisms is critical for interpretation of future antiviral treatments for HCV, either in the context of IFN therapy, or with second and third generation antivirals targeting specific aspects of the pathway. Chimpanzees are the only animal model for HCV studies at this time. Pre-clinical trial evaluations will be performed in HCV chronically infected chimps. An ability to reduce viral load in these animals is crucial to many aspects of these types of studies. As the animals do not respond to human IFN, the studies outlined in this proposal aim to clone and express the chimp IFNalpha2 gene to provide species-specific therapy in four chimpanzees (two naive animals to analyze the magnitude of the IFN response; and two animals persistently infected with HCV to demonstrate a reduction in viral load and potential modulation of the IFN response). Subsequently, the response to dsRNA, (polyl:C) will be compared to that observed with IFN in the naive animals to investigate the initial molecular events occurring during virus infection (as mimicked by dsRNA) that are distinct (but overlapping in many cases) from the IFN pathway. Gene expression studies using RNA from liver biopsies and PBMCs will be performed with high density DNA microarrays with each treatment regime. The expected outcomes of these analyses are the identification of changes in host gene expression associated with HCV persistence following interferon therapy in comparison to the changes observed in naive animals. These data will help determine why interferon therapy is often unsuccessful for chronic HCV infections and provide cellular targets for future therapies.
| Lanford, Robert E; Guerra, Bernadette; Bigger, Catherine B et al. (2007) Lack of response to exogenous interferon-alpha in the liver of chimpanzees chronically infected with hepatitis C virus. Hepatology 46:999-1008 |
| Lanford, Robert E; Guerra, Bernadette; Lee, Helen et al. (2006) Genomic response to interferon-alpha in chimpanzees: implications of rapid downregulation for hepatitis C kinetics. Hepatology 43:961-72 |
