DNA Microarray Analysis of Chimpanzee Liver during Acute Resolving Hepatitis C Virus Infection

Abstract

Hepatitis C virus (HCV) poses a worldwide health problem in that the majority of individuals exposed to HCV become chronically infected and are predisposed for developing significant liver disease. DNA microarray technology provides an opportunity to survey transcription modulation in the context of an infectious disease and is a particularly attractive approach in characterizing HCV-host interactions, since the mechanisms underlying viral persistence and disease progression are not understood and are difficult to study. Here, we describe the changes in liver gene expression during the course of an acute-resolving HCV infection in a chimpanzee. Clearance of viremia in this animal occurred between weeks 6 and 8, while clearance of residual infected hepatocytes did not occur until 14 weeks postinfection. The most notable changes in gene expression occurred in numerous interferon response genes (including all three classical interferon antiviral pathways) that increased dramatically, some as early as day 2 postinfection. The data suggest a biphasic mechanism of viral clearance dependent on both the innate and adaptive immune responses and provide insight into the response of the liver to a hepatotropic viral infection.

Analysis of ISG Expression in Chronic Hepatitis C Identifies Viperin as a Potential Antiviral Effector *

“…The majority of ISGs identified in our study have also been identified in the experimental chimpanzee model of acute and chronic HCV infection [7][8][9] and in several small studies on human CHC. [22][23][24][25][26][27] Taken together, these studies suggest that the HCV chronically infected liver is capable of mounting an antiviral response.…”

“…Although many different functional groups of genes were identified (results not shown), a significant number (39) were known ISGs (Table 3), indicating an ongoing response to endogenous IFN or the dsRNA response to viral infection. This gene set is remarkably similar to that identified in the HCV experimentally infected chimpanzee [7][8][9] ; however, it represents the most comprehensive list of potential ISGs dif- …”

“…Although this is difficult to test in humans, the ISG response in experimentally infected chimpanzees is more robust in acute compared with chronic infection. 7,9 Weak induction of the ISG antiviral state coupled with an ineffective cellular immune response could therefore promote chronicity. An alternative scenario is the possibility that HCV can block the host antiviral response to IFN.…”

“…*Genes shown to be previously upregulated in microarray analysis performed on liver taken from HCV-infected chimpanzees. [7][8][9] Viperin mRNA Is Upregulated in the HCV-Infected Liver. Viperin is a recently recognized type I ISG, 4,10 and its mRNA was significantly expressed in all HCV-infected livers examined via microarray analysis (Table 3) and RT-PCR analysis (Fig.…”

“…6 Interestingly, both ISG6-16 and ISG-56 are significantly expressed in the livers from acutely and chronically experimentally HCV-infected chimpanzees, suggesting that these along with other ISGs may play a role in limiting virus replication or spread. [7][8][9] In this study, we used microarray analysis of percutaneous liver biopsies to better define the spectrum of ISG expression in the chronically infected HCV liver and to identify potential anti-HCV effector molecules. Similar to experimentally infected chimpanzees, we demonstrate significant upregulation of ISGs, suggesting an ongoing host cellular response to viral infection.…”