HCV innate immune responses

Abstract

Hepatitis C virus (HCV) establishes a persistent infection in more than 70% of infected individuals. This striking ability to evade the powerful innate immune system results from viral interference occurring at several levels of the interferon (IFN) system. There is strong evidence from cell culture experiments that HCV can inhibit the induction of IFNβ by cleaving important proteins in the virus sensory pathways of cells such as MAVS and TRIF. There is also evidence that HCV interferes with IFNα signaling through the Jak-STAT pathway, and that HCV proteins target IFN effector systems such as protein kinase R (PKR). These in vitro findings will have to be confirmed in clinical trials investigating the molecular mechanisms of HCV interference with the innate immune system in liver samples.

Keywords: HCV; Jak-STAT; MAVS; Toll-like receptors; interferon; viral interference.

Figure 1.

Induction of IFNβ by viral infections.

Figure 2.

Type I IFNs signal through the Jak-STAT pathway. PTP1B, protein tyrosine phosphatase 1B; SHP1/2, SH2 domain-containing protein tyrosine phosphatase1 or 2; TCPTP, T cell protein tyrosine phosphatase.

Figure 3.

HCV induces the over-expression of PP2Ac via an ER stress response pathway. PP2A inhibits PRMT1, the enzyme responsible for STAT1 methylation. The resulting hypomethylation of STAT1 facilitates the binding of PIAS1, an inhibitor of DNA binding of activated STAT1. Tyrosine phosphorylation is shown by Y, and arginine methylation by R.