Interfering with hepatitis C virus RNA replication
Section snippets
RNA interference
Mechanisms of gene silencing by the targeting of RNAs for degradation are conserved in plants, fungi, and animals. While post-transcriptional gene silencing (PTGS) has been described in plants for over a decade, the demonstration in 2001 that the closely related process of RNAi has activity in mammalian cells has greatly expanded the size of its scientific audience (Elbashir et al., 2001). It has since been concluded that the molecular machinery of gene silencing appears to be ancient and
Hepatitis C virus
HCV is a major public health problem, with 170 million chronically infected people throughout the world (Anonymous, 1997). Chronically infected individuals are a reservoir for new infections as well as being at risk for progression to cirrhosis and hepatocellular carcinoma. Consequently, HCV infection is the leading indicator of liver transplant (Fishman et al., 1996). Antiviral therapy consisting of peginterferon-alfa 2a-ribavirin shows sustained response in only about half of the treated
HCV is sensitive to RNAi
While the initial demonstrations of RNAi in mammalian cells showed silencing of cellular transcripts, virologists quickly began to study the relevance of RNAi to their virus of interest. The leap for hepatitis C virologists is relatively small. As an RNA virus, the genome may be susceptible to cleavage. Since HCV replication generates dsRNAs, HCV may naturally activate RNAi, which would in turn serve as an innate host defense against virus infection. Finally, a great need exists for the
Prospects and questions for HCV and RNAi
Numerous questions follow these initial studies that demonstrated the sensitivity of HCV to RNAi. Some of these include the following: (i) Is RNAi an innate antiviral pathway in mammals? (ii) What is the mechanism of HCV clearance? (iii) How do we exploit RNAi to define the significance of host interactions for the HCV life cycle? (iv) What is the therapeutic potential of RNAi?
Conclusions
Recent studies have solidified the use of siRNAs to inhibit the expression of target RNAs, whether they are cellular or viral in origin. RNAi as an “experimental tool” will undoubtedly be exploited to define HCV replication and pathogenesis. These experimental approaches can be applied to understanding HCV RNA replication and the significance of host genes at various stages of the viral life cycle. A consensus has been achieved that HCV is sensitive to the introduction of siRNAs. Although RNAi
Acknowledgements
G.R. and C.M.R. are supported in part by grants from the Public Health Service (CA57973 and AI40034) and the Greenberg Medical Research Institute. G.R. is supported by postdoctoral fellowship PF-02-016-01-MBC from the American Cancer Society. We thank Catherine Murray for critical reading of the manuscript.
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2009, VirologyCitation Excerpt :It is mediated by small interfering RNAs (siRNAs) of a length of 21 to 23 nucleotides (Hannon, 2002) that lead to the sequence-specific degradation of homologous messenger RNAs (mRNAs). Using chemically synthesized or vector-expressed siRNAs, many clinically relevant viruses including the human immunodeficiency virus, HBV, and hepatitis C virus could be inhibited in vitro (Randall and Rice, 2004; Stevenson, 2003; Wu and Nandamuri, 2004). A number of recent studies have demonstrated the effectiveness of specific siRNAs for inhibiting the HBV gene expression and viral replication (Giladi et al., 2003; Guo et al., 2005; Hamasaki et al., 2003; Klein et al., 2003; Konishi et al., 2003; McCaffrey et al., 2003; Morrissey et al., 2005; Shlomai and Shaul, 2003; Uprichard et al., 2005; Wu et al., 2005).
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