Elsevier

Virus Research

Volume 102, Issue 1, 1 June 2004, Pages 19-25
Virus Research

Interfering with hepatitis C virus RNA replication

https://doi.org/10.1016/j.virusres.2004.01.011Get rights and content

Abstract

The emergence of RNA interference (RNAi) as a powerful tool for silencing gene expression has spurred considerable interest in its experimental and therapeutic potential. RNAi is a cellular process of gene silencing in which small duplexes of RNA specifically target a homologous sequence for cleavage by cellular ribonucleases. The introduction of 21–23 nucleotide RNA duplexes, termed small interfering RNAs (siRNAs), into mammalian cells can specifically degrade homologous mRNAs. RNAi efficiently silences the expression of both cellular and viral RNAs. A number of groups have demonstrated that siRNAs interfere with hepatitis C virus (HCV) gene expression and replication. Additionally, cellular genes are efficiently silenced in the presence of replicating HCV. These studies lay the foundation for using RNAi as an experimental tool for studying HCV replication and defining host genes that are significant for viral replication. The potential for RNAi as an antiviral therapy remains less clear, as it will face many of the challenges that have hindered nucleic acid therapies in the past.

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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