Elsevier

Advanced Drug Delivery Reviews

Volume 59, Issue 12, 10 October 2007, Pages 1196-1199
Advanced Drug Delivery Reviews

Commentary
HCV research and anti-HCV drug discovery: Toward the next generation☆

https://doi.org/10.1016/j.addr.2007.08.021Get rights and content

Abstract

Hepatitis C virus (HCV) causes persistent infection and induces chronic hepatitis, liver cirrhosis and finally hepatocellular carcinoma. Current therapies for HCV infection have not been satisfactory, and more effective anti-viral treatments are needed. In this regard, detailed analysis of HCV has been hampered by a lack of appropriate viral culture systems and small animal models of infection. However, rapid progress in HCV research has recently been achieved, such as a subgenomic replicon system, a viral culture system using JFH-1 clone and the Alb-uPA/SCID mouse transplanted with human liver cells. Such progress will propel HCV research and anti-HCV drug discovery toward the next generation.

Section snippets

Discovery of hepatitis C virus (HCV) and development of prototype treatment for HCV infection

HCV was identified by Chiron's research group in 1989 after a long and extensive search for the causative agent for non-A, non-B hepatitis [1], [2]. The difficulty of this discovery was supported by the fact that HCV was identified only by cDNA cloning of a viral genome, not by conventional virological approaches or immunological methods. After HCV cDNA cloning, anti-HCV screening was introduced for blood transfusion and new infections were substantially reduced. The discovery of HCV has thus

Basic research into HCV

Human immunodeficiency virus (HIV) was discovered only 6 years before HCV was cloned. Recent rapid progress in treatment for HIV infection has decreased AIDS-related mortality by more than 80%. For HCV treatment, however, only combination therapy using IFN and ribavirin has been approved, and around half of treated patients achieve SVR with the current therapy. To achieve higher SVR rates, other anti-HCV drugs should be approved and combined with the current IFN-based therapy. However,

Isolation of JFH-1 clone and virus culture system

Virus culture of HCV became possible using an odd virus strain isolated from a Japanese patient with fulminant hepatitis (JFH-1 strain) [20]. The JFH-1 strain was isolated from a 32-year-old man admitted with acute liver failure and developed fulminant hepatitis [21]. The entire HCV cDNA was isolated from his acute-phase serum. Based on sequence analysis, the JFH-1 strain belongs to genotype 2a and sequence deviates slightly from other genotype 2a clones isolated from patients with chronic

HCV life cycle and discovery of new anti-viral targets

To date, interferon and ribavirin have been used in clinics with limited efficacy. Using in vitro enzyme assay and replicon cell lines, NS3 protease and NS5B RNA polymerase inhibitors have been developed. These new inhibitors have been tested in clinical and pre-clinical trials. The HCV infection system using a JFH-1 clone may provide a good method for screening new anti-viral agents. Furthermore, stable JFH-1 cDNA transfected cell lines capable of producing infectious virus may be suitable for

HCV vaccine development, why not?

After HCV cloning, the number of new infections was reduced substantially. However, high-risk groups for HCV infection remain, such as health workers and intravenous drug users. Development of a prophylactic vaccine for HCV thus remains important. A great deal of research has already been focused on the development of a HCV vaccine (reviewed in [41]). However, the development of an HCV vaccine has been met with skepticism, given the difficulty of demonstrating the presence of neutralizing

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    ☆

    This commentary is part of the Advanced Drug Delivery Reviews theme issue on “Toward Evidence Based Control of Hepatitis C Virus Infection”.

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