Molecular Characterization of Hepatitis C Virus

Reed, Karen E.; Rice, Charles M.

doi:10.1159/000060472

Cited by 50 publications

(37 citation statements)

References 218 publications

(252 reference statements)

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“…37 Therefore, the TLR3-mediated signaling pathway, which recognizes dsRNA, must be involved in antiviral innate immunity during HCV replication. Recently, it has been shown that several signaling molecules, such as TRIF, TBK1, IKK⑀, and IRF-3, play critical roles in TLR3-induced IFN-␤ production.…”

Section: Discussionmentioning

confidence: 99%

Interaction between the HCV NS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses†

et al. 2005

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Section: Discussionmentioning

confidence: 99%

Interaction between the HCV NS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses†

et al. 2005

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“…The virus is a member of the Flaviviridae and contains a 9.6-kb single-stranded positive-sense RNA genome that encodes one large polyprotein whose translation is mediated through an internal ribosome entry site (IRES) found within the viral 5Ј nontranslated region (5Ј NTR). The HCV polyprotein is postranslationally cleaved into at least 10 mature proteins through host peptidase and viral protease activities (35). The HCV nonstructural (NS) proteins are sufficient to support viral replication (4,31,32).…”

mentioning

confidence: 99%

Viral Evolution and Interferon Resistance of Hepatitis C Virus RNA Replication in a Cell Culture Model

Sumpter

Wang

Foy

et al. 2004

J Virol

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Hepatitis C virus (HCV) replicates through an error-prone process that may support the evolution of genetic variants resistant to the host cell antiviral response and interferon (IFN)-based therapy. We evaluated HCV-IFN interactions within a long-term culture system of Huh7 cell lines harboring different variants of an HCV type 1b subgenomic RNA replicon that differed at only two sites within the NS5A-encoding region. A replicon with a K insertion at HCV codon 2040 replicated efficiently and exhibited sequence stability in the absence of host antiviral pressure. In contrast, a replicon with an L2198S point mutation replicated poorly and triggered a cellular response characterized by IFN-␤ production and low-level IFN-stimulated gene (ISG) expression. When maintained in long term-culture, the L2198S RNA evolved into a stable high-passage (HP) variant with six additional point mutations throughout the HCV protein-encoding region that enhanced viral replication. The HP RNA transduced Huh7 cells with more than 1,000-fold greater efficiency than its L2198S progenitor or the K2040 sequence. Replication of the HP RNA resisted suppression by IFN-␣ treatment and was associated with virus-directed reduction in host cell expression of ISG56, an antagonist of HCV RNA translation. Accordingly, the HP RNA was retained within polyribosome complexes in vivo that were refractory to IFN-induced disassembly. These results identify ISG56 as a translational control effector of the host response to HCV and provide direct evidence to link this response to viral sequence evolution, ISG regulation, and selection of the IFN-resistant viral phenotype.Hepatitis C virus (HCV) is a global public health threat that persistently infects an estimated 2% of the world population (46). Although initial HCV infection is usually subclinical, damage accumulates over time in the liver and can result in the development of cirrhosis and end-stage liver disease that often includes hepatocellular carcinoma (37). The virus is a member of the Flaviviridae and contains a 9.6-kb single-stranded positive-sense RNA genome that encodes one large polyprotein whose translation is mediated through an internal ribosome entry site (IRES) found within the viral 5Ј nontranslated region (5Ј NTR). The HCV polyprotein is postranslationally cleaved into at least 10 mature proteins through host peptidase and viral protease activities (35). The HCV nonstructural (NS) proteins are sufficient to support viral replication (4,31,32). HCV RNA replication proceeds in association with intracellular membranes through a viral replicase that includes the NS proteins. The HCV replicase is particularly dependent on the enzymatic activities of the NS5B RNA-dependent RNA polymerase (RdRp) (5) and the NS3/NS4A protease-helicase (reviewed in reference 35). Like other RNA viruses, the replicase of HCV is error prone due to the lack of proofreading function of the NS5B RdRp. Because of this error-prone replication and an overall high replication rate, HCV infection often involves genetically ...

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“…The viral RNAdependent RNA polymerase is encoded by NS5B. 4 The functions of NS4B and NS5A are unknown.The chimpanzee is the only animal model for studying HCV infection. Humans and chimpanzees with persistent HCV infections mount an antibody response to most HCV proteins.…”

mentioning

confidence: 99%

“…The viral RNAdependent RNA polymerase is encoded by NS5B. 4 The functions of NS4B and NS5A are unknown.…”

mentioning

confidence: 99%

Protective Immune Response to Hepatitis C Virus in Chimpanzees Rechallenged Following Clearance of Primary Infection

et al. 2001

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Hepatitis C virus (HCV) infections were evaluated in chimpanzees that had previously cleared HCV and were rechallenged. Animals that had previously cleared HCV infection rapidly cleared homologous and heterologous virus upon rechallenge, indicative of a strong protective immunity. In one animal, sterilizing immunity was observed with regard to viremia, although viral RNA was transiently detected in the liver. Accelerated viral clearance following rechallenge with HCV was observed in animals that had not been exposed to HCV for over 16 Hepatitis C virus (HCV) infections represent a serious health problem. The majority of HCV infections develop into chronic infections that may progress to cirrhosis and hepatocellular carcinoma. 1 HCV is classified in the Hepacivirus genus of the Flaviviridae family. 2 The HCV genome is approximately 9.6 kb and consists of single-stranded RNA of positive polarity. The viral RNA has a single large open reading frame that encodes for a polyprotein of approximately 3,000 amino acids. 3 The structural proteins are located at the amino terminal end of the polyprotein and include the capsid protein and 2 envelope glycoproteins, E1 and E2. The nonstructural proteins are preceded by a p7 domain of unknown function and include NS2-NS5. The NS2 domain forms an autoprotease with the amino-terminal portion of NS3. The amino terminus of NS3 encodes a serine protease and the carboxy terminus encodes a helicase, which plays a role in viral RNA replication. NS4A is a cofactor for the serine protease. The viral RNAdependent RNA polymerase is encoded by NS5B. 4 The functions of NS4B and NS5A are unknown.The chimpanzee is the only animal model for studying HCV infection. Humans and chimpanzees with persistent HCV infections mount an antibody response to most HCV proteins. 5 HCV-specific antibody does not appear to protect humans and chimpanzees from infection and is actually associated with active viremia rather than viral clearance. The kinetics of antibody production to HCV proteins and the pattern of antibodies to individual proteins do not appear to predict disease outcome (clearance versus persistence).The humoral immune response to the nonstructural HCV proteins appears to be similar in humans and chimpanzees. 5 In contrast, antibody responses to HCV structural proteins are observed less frequently in chimpanzees than in humans for reasons not understood. [5][6][7][8][9][10][11] Studies in chimpanzees have revealed that antibody neutralization of HCV is not easily attained. 12,13 Recently, Cooper et al. observed that strong antibody responses to HCV proteins were not necessary for viral clearance in HCV-inoculated chimpanzees. 14 Several investigators have also observed that circulating HCV-specific antibodies do not prevent reinfection of chimpanzees with HCV. [15][16][17][18] Therefore, T cells may play a more critical role than antibodies in the resolution of HCV infection.HCV antigen-specific CD8 ϩ T cells have been observed in the peripheral blood and liver of humans and chimpanzees durin...

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Molecular Characterization of Hepatitis C Virus

Cited by 50 publications

References 218 publications

Interaction between the HCV NS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses†

Interaction between the HCV NS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses†

Viral Evolution and Interferon Resistance of Hepatitis C Virus RNA Replication in a Cell Culture Model

Protective Immune Response to Hepatitis C Virus in Chimpanzees Rechallenged Following Clearance of Primary Infection

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