Involvement of Differential Relationship between HCV Replication and Hepatic PRR Signaling Gene Expression in Responsiveness to IFN-Based Therapy

Aim. To gain an insight into the effect of HCV replication-associated interference with the IFN system on hepatic mRNA expression involved in IFN production. Methods. Relative mRNA expression of TLR3/RIG-I signaling genes involved in IFN-β production was correlated with positive- and negative-strand HCV RNAs in pretreatment liver tissues responsive and nonresponsive to peginterferon and ribavirin for chronic hepatitis C genotype 1. Treatment response was analyzed for per protocol population at weeks 12 ( ) and 24 ( ) and at 24 weeks aftertreatment ( ). Results. HCV replication had no relation to the expression of TLR3, RIG-I, TRIF, IPS-1, IRF3, and IFN-β mRNAs in responders. In striking contrast, positive- and/or negative-strand HCV showed positive correlations with TLR3, RIG-I, TRIF, IPS-1, and IRF3 mRNAs in week-12 nonresponders; with RIG-I, TRIF, IPS-1, and IRF3 mRNAs in week-24 nonresponders; and with TLR3, RIG-I, and IRF3 mRNAs in posttreatment nonresponders. Thus mRNA expression of TLR3/RIG-I signaling genes was increased in relation to viral replication in nonresponders. Conclusions. The findings in IFN nonresponders may imply a host feedback response to severe impairment of the IFN system associated with HCV replication. 1. Introduction Upon recognition of hepatitis C virus (HCV) infection by Toll-like receptor 3 (TLR3) and retinoic-acid inducible gene I (RIG-I), the innate immune response is promptly activated in hepatocytes. The two pattern recognition receptors (PRRs) recruit their respective adaptors, Toll/interleukin-1 receptor-domain containing adaptor inducing interferon (IFN)-β (TRIF) and IFN-β promoter stimulator-1 (IPS-1), that relay the signal to downstream IFN regulatory factor-3 (IRF3), leading to the induction of IFN-β, known as the “front line” of host antiviral defenses in the liver [1, 2]. HCV has evolved highly successful multiple mechanisms for counteracting host antiviral responses. HCV NS3/4A serine protease in infected cells cleaves TRIF and IPS-1 and thereby disrupts the signal for IFN-β induction [3–5]. HCV interferes with various aspects of the downstream IFN action [6]. For example, HCV disrupts JAK-Stat signaling by NS5A and inhibits protein kinase R by NS5A and E2 proteins. Recent studies demonstrated that interference of HCV proteins with IFN production and its action depends on the levels of HCV propagation [7, 8]. Under the circumstances, we hypothesized that HCV replication-associated interference with the host IFN system may cause changes in hepatic gene expression involved in IFN production at the mRNA levels