In response to invasion with bacterial or viral pathogens, cells are able to mount an immediate immune response through their ability to use specialized cellular molecules, referred to as pattern recognition receptors or PRRs, to detect unusual DNA, ssRNA or dsRNA structures. This leads to induction of the interferons and pro-inflammatory cytokines that are involved in the innate immune response.
Hepatitis C virus (HCV) is one of the RNA helicase RIG-I-activating viruses, because of its 5′ppp-structured RNA, 3′-structured genomic RNA and replicative RNA duplexes. In contrast to other RIG-I activating viruses such as Sendai virus, influenza, or vesicular stomatitis virus, HCV is a poor inducer of IFN and pro-inflammatory cytokines in cell culture systems. One reason for this is that the HCV NS3/4A protease cleaves cellular proteins (MAVS), resulting in a rapid disruption of the IFN induction pathway.
A recent paper shows that HCV infection can stimulate the IFN induction pathway up to 12 hrs post-infection, whereas detection of MAVS cleavage begins at 18 hrs post-infection and is maximal at 24 hrs. The data reveal that 12 hrs post-infection, HCV promotes a rapid inhibition of IFN induction at the level of translation, indicating a new mechanism of regulation. This regulation was linked to activation of the dsRNA-activated eIF2α kinase PKR. Altogether, the results show that HCV uses PKR to control the translation of newly transcribed IFN mRNAs before sufficient NS3/4A protein can be synthesized to efficiently restrain transcription of IFN.
Although PKR is also recognized in several virus infections for its antiviral proprieties, it may be more suitable to control its action in the case of HCV infection. Therefore, a carefully-controlled use of PKR inhibitors, in conjunction with IFN/ribavirin, might be beneficial for the treatment of chronically HCV-infected patients, since it would lead to a boost in the induction of innate immunity and a sustained inhibition of the virus propagation.
- Hepatitis C Virus: a mountain to climb
- The Interferon Antiviral Response
- Update on HBV and HCV Therapy