Mutations of hepatitis C virus 1b NS5A 2209–2248 amino acid sequence do not predict the response to recombinant interferon-alfa therapy in French patients

Khorsi, Hafida; Castelain, Sandrine; Wyseur, Ann; Izopet, Jacques; Canva, V.; Rombout, A; Capron, Dominique; Capron, Jean‐Pierre; Lunel, F.; Stuyver, Lieven; Duverlie, Gilles

doi:10.1016/s0168-8278(97)80282-6

Cited by 121 publications

(91 citation statements)

References 12 publications

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“…Although a region within the nonstructural protein 5A, named the IFN sensitivity-determining region (11), and a highly conserved stretch of 12 aa in the E2 protein (20) have been suggested as potential determinants of IFN resistance, the evidence for this is inconsistent (25). In this respect and in accordance with several previous studies (14)(15)(16)(17)(18)(19)(21)(22)(23)(24), we failed to observe any correlation between mutations in these two regions and outcome of IFN therapy (P.F., unpublished data). The mechanism of treatment failure in patients who relapsed during or shortly after therapy is more difficult to interpret.…”

Section: Discussionsupporting

confidence: 92%

“…Among the latter, viral resistance to IFN is considered to play a major role, although the molecular basis of such resistance has not been fully defined (8)(9)(10). A specific region of the nonstructural 5A gene (11) has been suggested as a possible determinant of IFN sensitivity (12,13), but this hypothesis is still highly controversial (14)(15)(16)(17)(18)(19). More recently, a second region of potential interest has been identified within the envelope 2 glycoprotein (E2) (20), but its role in determining IFN resistance also remains unclear (21)(22)(23)(24).…”

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confidence: 99%

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Early changes in hepatitis C viral quasispecies during interferon therapy predict the therapeutic outcome

Farci

Strazzera²,

Alter³

et al. 2002

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

195

186

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Despite recent treatment advances, the majority of patients with chronic hepatitis C fail to respond to antiviral therapy. Although the genetic basis for this resistance is unknown, accumulated evidence suggests that changes in the heterogeneous viral population (quasispecies) may be an important determinant of viral persistence and response to therapy. Sequences within hepatitis C virus (HCV) envelope 1 and envelope 2 genes, inclusive of the hypervariable region 1, were analyzed in parallel with the level of viral replication in serial serum samples obtained from 23 patients who exhibited different patterns of response to therapy and from untreated controls. Our study provides evidence that although the viral diversity before treatment does not predict the response to treatment, the early emergence and dominance of a single viral variant distinguishes patients who will have a sustained therapeutic response from those who subsequently will experience a breakthrough or relapse. A dramatic reduction in genetic diversity leading to an increasingly homogeneous viral population was a consistent feature associated with viral clearance in sustained responders and was independent of HCV genotype. The persistence of variants present before treatment in patients who fail to respond or who experience a breakthrough during therapy strongly suggests the preexistence of viral strains with inherent resistance to IFN. Thus, the study of the evolution of the HCV quasispecies provides prognostic information as early as the first 2 weeks after starting therapy and opens perspectives for elucidating the mechanisms of treatment failure in chronic hepatitis C.

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Early changes in hepatitis C viral quasispecies during interferon therapy predict the therapeutic outcome

Farci

Strazzera²,

Alter³

et al. 2002

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

195

186

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“…Similarly, NS5A of HCV-1b, -1a, -2c, or -3a in Western countries is less variable compared with Japanese HCV-1b or HCV-2a. [19][20][21][22][23][24][25]27 These findings suggest the different mode of NS5A evolution in various genotypes, or even in the same genotype in different geographical areas. Recent studies demonstrated that the NS5A sequence is rather stable in each patient, 24 suggesting that more divergent genotypes would have an older history in the specific human populations.…”

Section: Discussionmentioning

confidence: 96%

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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“…15,16,[34][35][36][37][38] ‡According to references. [39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54] found between patients with and without HCC. When compared with the deduced consensus sequence derived from all sequenced isolates, 3 or more aa changes within the PKR-bd were observed in 60% of patients with HCC, but only in 6% of those without evidence of tumor.…”

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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Mutations of hepatitis C virus 1b NS5A 2209–2248 amino acid sequence do not predict the response to recombinant interferon-alfa therapy in French patients

Cited by 121 publications

References 12 publications

Early changes in hepatitis C viral quasispecies during interferon therapy predict the therapeutic outcome

Early changes in hepatitis C viral quasispecies during interferon therapy predict the therapeutic outcome

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

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

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