Statistical analysis of combined substitutions in nonstructural 5A region of hepatitis C virus and interferon response

Witherell, Gary W.; Beineke, Philip

doi:10.1002/1096-9071(200101)63:1<8::aid-jmv1001>3.0.co;2-k

Cited by 91 publications

(55 citation statements)

References 44 publications

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“…This region has a particular importance since previous work by Enomoto et al [148] (1995) suggested that the genetic heterogeneity of the interferon sensitivity determining region domain of HCV NS5A (IFN sensitivity-determining region), linked to response to therapy in Japanese patients [148] . Although there seems not to be a consensus on this issue [85] , the published information supports the hypothesis that an association indeed exists between NS5A and response to therapy [149][150][151] . Some reports suggest that HCV NS5A protein can act in vivo repressing PKR function, and presumably allowing HCV to escape the antiviral effects of interferon [1,3,152,153] .…”

Section: Recombinationmentioning

confidence: 89%

Hepatitis C virus genetic variability and evolution

Echeverría

Moratorio

Cristina

et al. 2015

WJH

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Hepatitis C virus (HCV) has infected over 170 million people worldwide and creates a huge disease burden due to chronic, progressive liver disease. HCV is a singlestranded, positive sense, RNA virus, member of the Flaviviridae family. The high error rate of RNA-dependent RNA polymerase and the pressure exerted by the host immune system, has driven the evolution of HCV into 7 different genotypes and more than 67 subtypes. HCV evolves by means of different mechanisms of genetic variation. On the one hand, its high mutation rates generate the production of a large number of different but closely related viral variants during infection, usually referred to as a quasispecies. The great quasispecies variability of HCV has also therapeutic implications since the continuous generation and selection of resistant or fitter variants within the quasispecies spectrum might allow viruses to escape control by antiviral drugs. On the other hand HCV exploits recombination to ensure its survival. This enormous viral diversity together with some host factors has made it difficult to control viral dispersal. Current treatment options involve pegylated interferon-α and ribavirin as dual therapy or in combination with a direct-acting antiviral drug, depending on the country. Despite all the efforts put into antiviral therapy studies, eradication of the virus or the development of a preventive vaccine has been unsuccessful so far. This review focuses on current available data reported to date on the genetic mechanisms driving the molecular evolution of HCV populations and its relation with the antiviral therapies designed to control HCV infection. Hepatitis C virus genetic variability and evolution no preventive vaccine, and though antiviral therapy has been improved in the past few years, not all patients eradicate the virus as a result of it. The main reason lies in the intrinsic genetic variability that characterises RNA viruses, such as HCV, whose RNA polymerase lacks proof-reading activity, leading to a high mutation rate and the generation of a wide range of genome variants better known as a quasispecies. Therefore this review summarises current data on HCV quasispecies dynamics, antiviral therapy and recombination events.Echeverría N, Moratorio G, Cristina J, Moreno P. Hepatitis C virus genetic variability and evolution. World J Hepatol 2015; 7(6): 831845 Available from:

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Section: Recombinationmentioning

confidence: 89%

Hepatitis C virus genetic variability and evolution

Echeverría

Moratorio

Cristina

et al. 2015

WJH

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“…15,16, In fact, after a statistical analysis of data from previously published studies, Witherell and Beineke 64 have recently proposed a redefinition of the classification of Enomoto et al, 16 in which only sequences with 1 to 2 aa changes are included in the intermediate type. The high frequency of aa changes within the ISDR in cirrhotic patients with HCC observed in this study would indicate that they may be infected by viral strains with increased sensitivity to interferon.…”

Section: Discussionmentioning

confidence: 99%

High amino acid variability within the NS5A of hepatitis C virus (HCV) is associated with hepatocellular carcinoma in patients with HCV-1b–related cirrhosis

et al. 2001

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“…Moreover, it was found that sequence diversity and mutations within the NS3-encoding region associated with differential regulation of IRF-3 and low-level viral protein and NS3/NS4A abundance corresponded to an incomplete block of IRF-3 activation and function (10). Similarly, sequence diversity within the various encoding regions of the HCV RNA has been associated with sensitivity or resistance to IFN therapy in infected patients (16,25,48). This work collectively indicates that HCV genetic variation can influence the host response to infection and that HCV resistance to IFN is most likely supported through the actions of multiple viral proteins acting on specific cellular targets to attenuate host cell antiviral action.…”

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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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Statistical analysis of combined substitutions in nonstructural 5A region of hepatitis C virus and interferon response

Cited by 91 publications

References 44 publications

Hepatitis C virus genetic variability and evolution

Hepatitis C virus genetic variability and evolution

High amino acid variability within the NS5A of hepatitis C virus (HCV) is associated with hepatocellular carcinoma in patients with HCV-1b–related cirrhosis

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

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