Positive-stranded RNA viruses include those viruses with positive-sense ssRNA genomes, that is, their genomic RNA is the polarity of mRNA and is decoded directly by translation to protein. Among the positive-stranded viruses is hepatitis C virus (HCV), a member of the Flaviviridae family. HCV possesses a * 9.6 kb positive-sense ssRNA genome enclosed within an enveloped virion that encodes a polyprotein precursor of * 3,000 amino acids which is processed by viral and cellular proteases to produce ten mature viral proteins (Knipe et al. 2007; Samuel 2010b).
HCV infection is a major global problem, with estimates of over 100 million individuals persistently infected, and an estimated * 350,000 deaths annually due to cirrhosis and heptacellular carcinoma (Perez et al. 2006). The treatment for chronic hepatitis infection is a combination therapy of pegylated type I IFN-a and ribavirin. Among the IFN inducible genes is ADAR1 p150. The site of HCV replication is the cytoplasm, and ADAR1 p150 localizes in part to the cytoplasm. Retrospective analysis of chronic hepatitis C virus-infected patients for responsiveness to treatment with IFN and ribavirin has revealed that patient genotype, in addition to the HCV virus genotype, viral load, and cirrhosis status are important factors in determining therapy responsiveness (Hwang et al. 2006; Welzel et al. 2009). And, ADAR1 is among the genes identified that associated with the responsiveness trait when DNA polymorphisms of responders and nonresponders of Taiwanese (Hwang et al. 2006) and European (Welzel et al. 2009) origins were analyzed. In addition to the IFN-inducible ADAR1, other IFN system components including the IFN receptor, JAK1 signaling kinase and IFN induced protein 44 were noted.
So far only limited mechanistic studies have been described to assess the potential role that ADAR1 plays directly on HCV replication. In Huh7 cells stably transfected with an HCV replicon, IFN a treatment was reported to inhibit replicon expression in part through the involvement of ADAR1 (Taylor et al. 2005). Adenovirus VAI RNA, identified initially as an IFN system antagonist of PKR (Kitajewski et al. 1986; Samuel 2001), also impairs ADAR1 activity in vitro (Lei et al. 1998). Inhibition of both PKR and ADAR1 by VAI RNA stimulated HCV replicon expression and decreased the amount of I-containing RNA found in replicon cells (Taylor et al. 2005). Consistent with the notion that ADAR1 was targeted by VAI RNA to inhibit HCV replicon expression, siRNA knockdown of ADAR1 was observed to stimulate replicon expression. While the HCV replicon system has provided a valuable approach to analyze HCV RNA replication (Appel et al. 2006), the availability of the JFH infectious virus and hepatoma cell culture system now makes possible mechanistic analyses of innate immune responses in HCV virus-infected cells (Lemon 2010). The infectious HCV virus cell culture system provides an approach to further assess the role of ADAR1 in the antiviral actions of IFN. Potential targets of ADAR1 relevant to the IFN response against HCV include microRNAs as well as the RNA-dependent protein kinase PKR. IFN modulation of cellular microRNAs has been reported as a component of the HCV antiviral response (Pedersen et al. 2007). HCV is known to use the abundant liver-specific miR122 to enhance replication (Skalsky and Cullen 2010; You et al. 2011), and ADAR is known to affect both the production and targeting of some cellular micro RNAs (Wulff and Nishikura 2011). Activation of the IFN-inducible PKR by HCV impairs cap-dependent translation and production of IFN response proteins (Garaigorta and Chisari 2009) as well as the production of IFN (Arnaud et al. 2010), and ADAR is known to function as a suppressor of PKR activation (Nie et al. 2007; Toth et al. 2009; Li et al. 2010).
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