CommentaryHCV 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
References (42)
- et al.
Novel cell culture systems for the hepatitis C virus
Antivir. Res.
(2001) - et al.
A novel sequence found at the 3′ terminus of hepatitis C virus genome
Biochem. Biophys. Res. Commun.
(1995) - et al.
Efficient replication of the genotype 2a hepatitis C virus subgenomic replicon
Gastroenterol.
(2003) - et al.
Isolation of a cDNA clone derived from a blood-borne non-A non-B viral hepatitis genome
Science
(1989) - et al.
An assay for circulating antibodies to a major etiologic virus of human non-A non-B hepatitis
Science
(1989) - et al.
Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon. A preliminary report
N. Engl. J. Med.
(1986) - et al.
Interferon-based therapy of hepatitis C
Adv. Drug Deliv. Rev.
(2007) - et al.
Construction and characterization of poliovirus subgenomic replicons
J. Virol.
(1988) - et al.
Subgenomic replicons of the flavivirus Kunjin: construction and applications
J. Virol.
(1997) - et al.
Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line
Science
(1999)
Efficient initiation of HCV RNA replication in cell culture
Science
Mutations in hepatitis C virus RNAs conferring cell culture adaptation
J. Virol.
Enhancement of hepatitis C virus RNA replication by cell culture-adaptive mutations
J. Virol.
Selectable subgenomic and genome-length dicistronic RNAs derived from an infectious molecular clone of the HCV-N strain of hepatitis C virus replicate efficiently in cultured Huh7 cells
J. Virol.
Persistent and transient replication of full-length hepatitis C virus genomes in cell culture
J. Virol.
Efficient replication of hepatitis C virus genotype 1a RNAs in cell culture
J. Virol.
Mutations that permit efficient replication of hepatitis C virus RNA in Huh-7 cells prevent productive replication in chimpanzees
Proc. Natl. Acad. Sci. U. S. A.
Transmission of hepatitis C by intrahepatic inoculation with transcribed RNA
Science
Transcripts from a single full-length cDNA clone of hepatitis C virus are infectious when directly transfected into the liver of a chimpanzee
Proc. Natl. Acad. Sci. U. S. A.
Hepatitis C virus replication in mice with chimeric human livers
Nat. Med.
Culture system for hepatitis C virus in sight at last
Science
Cited by (6)
Virologic response and characterisation of HCV genotype 2-6 in patients receiving TMC435 monotherapy (study TMC435-C202)
2013, Journal of HepatologyCitation Excerpt :However, these new agents require thrice-daily dosing, are associated with more frequent and severe anaemia and rash, and have only been investigated in vivo in a limited number of patients infected with HCV genotypes 2-4 [10–12]. Improved in vitro replication and infection models have allowed assessment of antiviral activity in non-genotype 1 HCV [11,13,14]. Nucleotide inhibitors generally have in vitro activity across genotypes and show promising results in non-genotype 1 patients [15].
A comparative analysis of the substrate permissiveness of HCV and GBV-B NS3/4A proteases reveals genetic evidence for an interaction with NS4B protein during genome replication
2010, VirologyCitation Excerpt :HCV protease NS3/4A is a target of choice to develop antiviral candidates, due to its critical role in HCV life cycle, including directing most of the viral polyprotein cleavages yielding mature nonstructural proteins and disrupting host innate immune responses to double-stranded RNAs through the cleavage of adaptor proteins in corresponding signaling pathways. A number of HCV NS3/4A protease inhibitors have been developed in the past decade and extensively studied using essentially HCV subgenomic replicon models (Bartenschlager, 2006), and more recently the infectious JFH1-based cell culture system (Wakita, 2007). Several protease inhibitor candidates have shown promising results in vitro (Pawlotsky et al., 2007) and two ketoamide peptidomimetic inhibitors (telaprevir and boceprevir) have advanced into phase 3 clinical trials (Berman and Kwo, 2009; Gentile et al., 2010).
Cellular models for the screening and development of anti-hepatitis C virus agents
2009, Pharmacology and TherapeuticsA recombinant replication-competent hepatitis C virus expressing Azami-Green, a bright green-emitting fluorescent protein, suitable for visualization of infected cells
2008, Biochemical and Biophysical Research CommunicationsOenothein B, dimeric hydrolysable tannin inhibiting HCV invasion from Oenothera erythrosepala
2019, Journal of Natural MedicinesEffect of hepatitis C virus infection on the mRNA expression of drug transporters and cytochrome P450 enzymes in chimeric mice with humanized liver
2010, Drug Metabolism and Disposition
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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”.