Hepatitis C virus (HCV) is an important blood-borne pathogen that infects 1 % to 2% of the US population. Infection with HCV results in chronic hepatitis in the majority of infected individuals and may progress to hepatocellular carcinoma or end-stage liver disease requiring liver transplantation. Interferon (IFN)-a is currently the primary FDA-approved drug for treatment of chronic infection with hepatitis C virus. However, the response rate to treatment is less than 50% for the most common genotype in the US and is much lower in black patients. The mechanism of the anti-HCV activity of IFN is poorly understood. In our preliminary study we used a transcriptional microarray analysis, an approach that permits the expression level of thousands of genes to be monitored simultaneously, to investigate global gene expression in patients' peripheral blood mononuclear cells (PBMC) treated with IFN prior to the start of therapy and correlated this expression response with the long term outcome of INF treatment. Our results demonstrated that: 1) The overall transcriptional response to IFN in HCV infected patients initiating IFN treatment is significantly greater in subjects later classified as sustained virological responders than in subjects classified as nonresponders; and 2) The overall transcriptional response to IFN is greater in white patients than in black patients. The difference in transcriptional activity is most evident in the overall pattern of IFN-induced gene expression rather than in a selective effect on specific IFN-stimulated genes (ISG). In this application we propose to further investigate the effect of racial and viral factors on IFN transcriptional responses associated with different treatment outcomes.
The specific aims of this proposal are: 1) To compare IFN-induced transcriptional response in PBMC from HCV-uninfected Blacks and Whites and to assess a genetic component of the transcriptional response by calculating sib correlations. The hypothesis is that the significant differences in IFN transcriptional response found between black and white patients with chronic HCV infection is not primarily caused by the viral infection or other environmental factors but is rather due to genetic differences between these two groups. 2) To examine the effect of HCV on IFN-induced transcriptional response of PBMC. The hypothesis is that the presence of HCV viremia modifies the IFN transcriptional response of PBMC. 3) To characterize liver transcriptional response to IFN in patients with different treatment outcomes. The hypothesis is that IFN transcriptional response in liver tissue is correlated with the virological response to IFN treatment, especially the acute decline in HCV RNA level after the first dose of IFN. Together these studies should lead to a deeper understanding of the mechanism of IFN action, and more specifically, to the reasons for its failure in many patients. The knowledge provided by this study will impact future efforts to further improve the efficacy of IFN therapy for chronic hepatitis C, especially in black patients for whom a more effective treatment is urgently needed.
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