The dawn of a new era in HCV therapy

Ciesek, Sandra; Manns, Michael P.

doi:10.1038/nrgastro.2010.219

Cited by 58 publications

(43 citation statements)

References 7 publications

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“…This therapeutic strategy suffers both from a low efficacy in the case of genotype 1 infection and from non-negligible side effects for treated patients. The development of more efficient and safer new anti-HCV molecules is thus highly expected (3,4). HCV is an obligatory intracellular parasite and requires host cell factors in addition to its own components to achieve its complete life cycle (5).…”

Section: Hepatitis C Virus (Hcv)mentioning

confidence: 99%

Hepatitis C Virus NS5B and Host Cyclophilin A Share a Common Binding Site on NS5A

Rosnoblet¹,

Fritzinger²,

Legrand

et al. 2012

Journal of Biological Chemistry

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Background: HCV replication requires the interaction of the viral polymerase NS5B with both viral and host proteins. Results: We performed the molecular characterization of the interactions between HCV NS5B, NS5A, and host CypA. Conclusion: HCV NS5B and host CypA share a binding site on HCV NS5A. Significance: The NS5A-D2 site, which interacts with both the HCV polymerase NS5B and the host CypA, might regulate the HCV replication.

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Section: Hepatitis C Virus (Hcv)mentioning

confidence: 99%

Hepatitis C Virus NS5B and Host Cyclophilin A Share a Common Binding Site on NS5A

Rosnoblet¹,

Fritzinger²,

Legrand

et al. 2012

Journal of Biological Chemistry

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“…The standard-of-care treatment for HCV infection uses a combination of pegylated IFN-α and ribavirin, which is effective in approximately 50% of treated patients but has many side effects. Two direct-acting antiviral drugs targeting the virus protease NS3 have recently been approved in the United States for triple therapy with IFN-α and ribavirin to improve success rates and to shorten treatment (7). To solve the global HCV problem and to eradicate the virus, more effective, tolerable, and affordable drugs against HCV, as well as a vaccine, are needed.…”

mentioning

confidence: 99%

Structural basis of hepatitis C virus neutralization by broadly neutralizing antibody HCV1

Kong

Giang

Robbins

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

132

188

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Hepatitis C virus (HCV) infects more than 2% of the global population and is a leading cause of liver cirrhosis, hepatocellular carcinoma, and end-stage liver diseases. Circulating HCV is genetically diverse, and therefore a broadly effective vaccine must target conserved T-and Bcell epitopes of the virus. Human mAb HCV1 has broad neutralizing activity against HCV isolates from at least four major genotypes and protects in the chimpanzee model from primary HCV challenge. The antibody targets a conserved antigenic site (residues 412-423) on the virus E2 envelope glycoprotein. Two crystal structures of HCV1 Fab in complex with an epitope peptide at 1.8-Å resolution reveal that the epitope is a β-hairpin displaying a hydrophilic face and a hydrophobic face on opposing sides of the hairpin. The antibody predominantly interacts with E2 residues Leu 413 and Trp 420 on the hydrophobic face of the epitope, thus providing an explanation for how HCV isolates bearing mutations at Asn 415 on the same binding face escape neutralization by this antibody. The results provide structural information for a neutralizing epitope on the HCV E2 glycoprotein and should help guide rational design of HCV immunogens to elicit similar broadly neutralizing antibodies through vaccination.neutralizing determinant | protective determinant | antigen-antibody complex | type I' β-turn H epatitis C virus (HCV) infects >2% of the world population, with an estimated >500,000 new infections annually in the highest endemic country, Egypt (1, 2). In the United States, the rate of symptomatic HCV infection declined over the last decade and began to level out at ∼4 million cases around 2005 (3). Alarmingly, however, in developed countries, new cases are often associated with the younger age group (15-24 y) because of illegal injection drug use (4). Although some HCV-infected individuals can resolve infection without drug treatment, ∼70% develop chronic hepatitis and, over a period of 20-30 y, 20-30% will develop liver cirrhosis and 1-5% hepatocellular carcinoma (5). Furthermore, HCV infection is associated with several extrahepatic manifestations, neuropathy, and autoimmune diseases including mixed cryoglobulinemia and Sjögren's syndrome (6). The standard-of-care treatment for HCV infection uses a combination of pegylated IFN-α and ribavirin, which is effective in approximately 50% of treated patients but has many side effects. Two direct-acting antiviral drugs targeting the virus protease NS3 have recently been approved in the United States for triple therapy with IFN-α and ribavirin to improve success rates and to shorten treatment (7). To solve the global HCV problem and to eradicate the virus, more effective, tolerable, and affordable drugs against HCV, as well as a vaccine, are needed. Potent direct-acting antiviral drugs against additional viral targets are currently under development and show promise in IFN-free treatments (8). In the past few years, progress has also been made in vaccine development for prophylaxis and therapeutic purposes (9, 1...

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“…Approximately 20% of chronic hepatitis C patients develop cirrhosis, and of these, 4% will develop hepatocellular carcinoma and 6% will develop end-stage liver disease (37). There is no available HCV vaccine, and commonly used interferon-based treatment is toxic, prolonged, expensive, not consistently successful, and not effective in the most advanced forms of disease (5).…”

mentioning

confidence: 99%

Computational Reconstruction of Bole1a, a Representative Synthetic Hepatitis C Virus Subtype 1a Genome

Munshaw

Bailey

Liu

et al. 2012

J Virol

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Hepatitis C virus (HCV) research is hampered by the use of arbitrary representative isolates in cell culture and immunology. The most replicative isolate in vitro is a subtype 2a virus (JFH-1); however, genotype 1 is more prevalent worldwide and represents about 70% of infections in the United States, and genotypes differ from one another by 31% to 33% at the nucleotide level. For phylogenetic and immunologic analyses, viruses H77 and HCV-1 (both subtype 1a) are commonly used based on their historic importance. In an effort to rationally design a representative subtype 1a virus (Bole1a), we used Bayesian phylogenetics, ancestral sequence reconstruction, and covariance analysis on a curated set of 390 full-length human HCV 1a sequences from GenBank. By design, Bole1a contains variations present in widely circulating strains and matches more epitope-sized peptides in a full-genome comparison to subtype 1a isolates than any other sequence studied. Parallel analyses confirm that selected epitopes from the Bole1a genome were able to elicit a robust T cell response. In a proof of concept for infectivity, the envelope genes (E1 and E2) of Bole1a were expressed in an HIV pseudoparticle system containing HCV envelope genes and HIV nonenvelope genes with luciferase expression. The resulting Bole1a pseudoparticle robustly infected Hep3B cells. In this study, we demonstrate that a rationally designed, fully synthetic HCV genome contains representative epitopes and envelope genes that assemble properly and mediate entry into target cells.

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The dawn of a new era in HCV therapy

Cited by 58 publications

References 7 publications

Hepatitis C Virus NS5B and Host Cyclophilin A Share a Common Binding Site on NS5A

Hepatitis C Virus NS5B and Host Cyclophilin A Share a Common Binding Site on NS5A

Structural basis of hepatitis C virus neutralization by broadly neutralizing antibody HCV1

Computational Reconstruction of Bole1a, a Representative Synthetic Hepatitis C Virus Subtype 1a Genome

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