The Prognostic Relevance of the Nonstructural 5A Gene Interferon Sensitivity Determining Region Is Different in Infections with Genotype 1b and 3a Isolates of Hepatitis C Virus

Sáiz, Juan‐Carlos; López-Labrador, Francesc-Xavier; Ampurdanès, Sergi; Dopazo, Joaquín; Forns, Xavier; Sánchez-Tapias, José-Marı́a; Rodés, Juan

doi:10.1086/515243

Cited by 109 publications

(102 citation statements)

References 7 publications

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“…Recent studies from other areas of Europe confirmed the correlation between NS5A mutations and interferon sensitivity showing the comparative frequency of the HCV-1b mutant types as seen in Japan. 26,27 The differences of patients' backgrounds or the virological diversity among various geographic areas should be considered, and further careful, comparative studies are needed to make these points clear.…”

Section: Discussionmentioning

confidence: 99%

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Mutations in nonstructural protein 5A gene and response to interferon in hepatitis C virus genotype 2 infection

et al. 1999

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An association has been reported between mutations in the amino acid residues 2209-2248 of the nonstructural protein 5A (NS5A) gene (interferon-sensitivity determining region [ISDR]) and interferon efficacy in hepatitis C virus (HCV)-1b infection. This relationship was analyzed in chronic HCV-2 infection. Forty patients with HCV-2a and 35 with HCV-2b were treated with interferon alfa for 6 months with a total dose of 468 to 860 million units. Pretreatment NS5A sequences were determined by direct sequencing. A higher complete and sustained response rate was observed in HCV-2a than in HCV-2b (70% vs. 34%; P ‫؍‬ .003). Serum HCV-RNA levels were lower in complete responders than nonresponders in HCV-2a (P ‫؍‬ .049) and HCV-2b (P ‫؍‬ .02). The number of amino acid mutations was greater in complete responders than nonresponders in NS5A2193- The current primary therapy for chronic hepatitis C is parenteral administration of type 1 interferons (interferon alfa and beta), while the rate of sustained and complete responses with virus eradication is obtained in only up to 30% of the patients. 1-3 To date, hepatitis C virus (HCV) is classified into at least 9 major genotypes and more than 30 subtypes. 4,5 In Japan, about 70% of the patients with chronic hepatitis C are infected with HCV genotype 1b (HCV-1b), and the rest are infected with HCV genotype 2 (HCV-2) 6 (25% with HCV-2a and 5% with HCV-2b). While the complete response is as low as 10% to 20% in HCV-1b infection, it is considered more than 60% in HCV-2 infection in Japan. [7][8][9][10][11][12] Such differences in interferon efficacy among various HCV genotypes suggest that a certain kind of genetic change of the virus could affect the sensitivity to interferon.We recently identified a region that is associated with the response to interferon in HCV-1b genomes in Japan. 13 An increase in the number of amino acid changes in the nonstructural protein 5A gene (NS5A) (NS5A2209-2248, interferon sensitivity determining region [ISDR]) makes HCV more sensitive to interferon. 14 However, the mechanism of the different response to interferon therapy among patients with HCV-2 infection is still unclear. Some studies suggested that a lower viral load is associated with the good response to interferon in HCV-1b or non-1b, 12,15 the mechanism of which is still unknown. In previous studies, interferon effect and pretreatment viral load were also associated with the mutations in ISDR in HCV-1b. 13,16 Thus, the relation between NS5A structure and interferon effect or viral load in HCV genotypes other than HCV-1b is of great interest.Several studies that focused on biological functions of NS5A revealed some aspects of its properties. In particular, Gale et al. 17 suggested that the NS5A protein inhibits an RNA-dependent protein kinase (PKR), which plays a major role in the viral protection by inhibiting viral protein translation. The NS5A protein of HCV-1b and -1a forms a complex with the PKR and inhibits the phosphorylation of eukaryotic translation initiation factor-2 (eIF-2). Mor...

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Section: Discussionmentioning

confidence: 99%

“…Some studies did not find any correlation between NS5A structures and interferon effect, 19-25 while other studies did. 26,27 In addition, in HCV genotype 1a, 21-23 2c, 23 or 3a, 19,23,27 no clear association has been found. Therefore, the investigation on NS5A in HCV-2 is also important for elucidating the significance of NS5A in interferon resistance.…”

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confidence: 98%

Mutations in nonstructural protein 5A gene and response to interferon in hepatitis C virus genotype 2 infection

et al. 1999

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“…Mutation number in ISDR had no significant effect on response to IFN-based therapy in G1a [37,38] and G3a [36]. However, mutations in the region corresponding to the ISDR of G1b (2126-2228) was reported to be associated with outcome of therapy in HCV G2a, and more than two mutations in ISDR were associated with good response to PEG-IFN plus RBV [39].…”

Section: Amino Acid Substitutions In Ns5a and Response To Ifn-based Tmentioning

confidence: 86%

“…The sequence of ISDR was further examined in HCV G1a, G2 and G3a [36]. Mutation number in ISDR had no significant effect on response to IFN-based therapy in G1a [37,38] and G3a [36].…”

Section: Amino Acid Substitutions In Ns5a and Response To Ifn-based Tmentioning

confidence: 99%

Viral Factors Associated with Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection

Aizawa¹

2014

J Antivir Antiretrovir

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A first-generation protease inhibitor (PI) against HCV non-structural 3/4A serine protease was approved worldwide at the end of 2011. We are now facing a revolutionary change in therapeutic strategies for chronic HCV infection, from interferon (IFN)-based therapies to direct-acting antivirals (DAAs). The efficacy of antiviral therapy varies with HCV genotype. The most intractable and most common HCV worldwide is HCV genotype 1 (G1). Viral and host factors participating in the virological outcome of IFN-based therapy have been extensively examined. However, in the era of DAAs, the significance of these factors will gradually decrease. Instead, viral factors related to resistance against DAAs are becoming the main focus. In this review, the viral factors participating in the response to IFN-based therapies are summarized, and the issue of viral resistance to DAAs is discussed.

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“…Consequently, a lot of effort has been put into trying to identify specific sequences in the HCV viral quasispecies that may determine resistance or sensitivity to antiviral therapy. Unfortunately, results have been inconclusive (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) probably because IFN-a does not specifically target a particular HCV gene. IFN-a activity enhances host antiviral responses that, in turn, exert selection pressures on various viral genome regions.…”

Section: Introductionmentioning

confidence: 99%

Structural analysis of hepatitis C RNA genome using DNA microarrays

Martell¹

2004

Nucleic Acids Research

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Many studies have tried to identify specific nucleotide sequences in the quasispecies of hepatitis C virus (HCV) that determine resistance or sensitivity to interferon (IFN) therapy, unfortunately without conclusive results. Although viral proteins represent the most evident phenotype of the virus, genomic RNA sequences determine secondary and tertiary structures which are also part of the viral phenotype and can be involved in important biological roles. In this work, a method of RNA structure analysis has been developed based on the hybridization of labelled HCV transcripts to microarrays of complementary DNA oligonucleotides. Hybridizations were carried out at non-denaturing conditions, using appropriate temperature and buffer composition to allow binding to the immobilized probes of the RNA transcript without disturbing its secondary/tertiary structural motifs. Oligonucleotides printed onto the microarray covered the entire 5 0 non-coding region (5 0 NCR), the first threequarters of the core region, the E2-NS2 junction and the first 400 nt of the NS3 region. We document the use of this methodology to analyse the structural degree of a large region of HCV genomic RNA in two genotypes associated with different responses to IFN treatment. The results reported here show different structural degree along the genome regions analysed, and differential hybridization patterns for distinct genotypes in NS2 and NS3 HCV regions.

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The Prognostic Relevance of the Nonstructural 5A Gene Interferon Sensitivity Determining Region Is Different in Infections with Genotype 1b and 3a Isolates of Hepatitis C Virus

Cited by 109 publications

References 7 publications

Mutations in nonstructural protein 5A gene and response to interferon in hepatitis C virus genotype 2 infection

Mutations in nonstructural protein 5A gene and response to interferon in hepatitis C virus genotype 2 infection

Viral Factors Associated with Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection

Structural analysis of hepatitis C RNA genome using DNA microarrays

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