Enhanced expression of interferon-regulated genes in the liver of patients with chronic hepatitis C virus infection: detection by suppression-subtractive hybridization

Abstract

Hepatitis C virus (HCV) infection causes acute and often also chronic liver disease. Worldwide, prevalence of infection is estimated to exceed that of human immunodeficiency virus infection fourfold. Because of the lack of appropriate animal models, knowledge of interactions between virus and host is still limited. Assumptions regarding pathogenesis or the activation status of innate antiviral host responses, for instance, derive mainly from clinical observations and from expression analyses of selected genes. To obtain a more objective insight into virus-host interrelationships, we used suppression-subtractive hybridization to compare gene expression in HCV-infected and non-HCV-infected liver tissues samples. Four differentially expressed genes were found: (i) the gamma interferon (IFN-gamma)-inducible chemokine IP-10 gene; (ii) the IFN-alpha/beta-inducible antiviral MxA gene; (iii) the gene encoding IFN-alpha/beta-inducible p44, shown to be associated with ultrastructural cytoplasmic entities within hepatocytes of non-A, non-B hepatitis-infected chimpanzees; and (iv) the gene encoding IFN-alpha/beta/gamma-inducible IFI-56K, a protein recently shown to interact with the eukaryotic translation initiation factor eIF-3. Compared to hepatic gene expression in patients with liver diseases unrelated to viral infections, expression in patients with chronic HCV infection was up to 50-fold higher. While in patients with chronic HBV infection IP-10 was slightly activated as well, the IFN-alpha/beta-regulated genes were not. Revealing a dominance of hepatic interferon-regulated processes in chronic HCV infection, data on the enhanced expression of the IFN-gamma regulated IP-10 support earlier findings and may explain the composition of the hepatic cellular infiltrate. The data on enhanced expression of IFN-alpha/beta inducible genes might be germane to therapeutic considerations.

FIG. 1

Transcriptional expression of IP-10, MxA, p44, and IFI-56K in liver tissue from patients with chronic HCV or HBV infection and from patients with no known hepatic viral infection. RNA preparations from individuals with chronic HCV or HBV infection and from patients with liver disorders unrelated to any known virus infection were analyzed for IP-10 (A), MxA (B), p44 (C), and IFI-56K (D) transcript expression by competitive RT-PCR. Data were related to the amount of albumin-specific mRNA as a reference transcript. Expression of the four interferon-regulated genes was found to be higher in chronically HCV-infected patients than in both chronically HBV-infected patients and the control group (P values are indicated, t test for independent samples). Data on gene expression found within the original tester and driver material are included as open symbols. Comparable results were obtained when data were related to β-actin as a reference transcript.