Sequence heterogeneity of NS5A and core proteins of hepatitis C virus and virological responses to pegylated-interferon/ribavirin combination therapy

El-Shamy, Ahmed; Shoji, Ikuo; Saito, Takafumi; Watanabe, Hisayoshi; Ide, Yoshihiro; Deng, Lin; Kawata, Satoshi; Hotta, Hak

doi:10.1111/j.1348-0421.2011.00331.x

Cited by 18 publications

(19 citation statements)

References 32 publications

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“…We have explored the response of HCV to IFN-␣ treatment, which is a major component of the current standard of care treatment for HCV infections. Previous studies that investigated whether HCV mutations were associated with unsuccessful IFN-␣ therapy have not yielded conclusive results (34,(59)(60)(61)(62)(63)(64)(65). In contrast to what has been generally observed with standard antiviral agents that target a defined viral function (53,54), a history of passage of HCV in the presence of low concentrations of IFN-␣ did not prepare the virus to overcome higher IFN-␣ doses, at least not immediately.…”

Section: Discussionmentioning

confidence: 82%

Response of Hepatitis C Virus to Long-Term Passage in the Presence of Alpha Interferon: Multiple Mutations and a Common Phenotype

Perales

Beach

Gallego

et al. 2013

J Virol

172

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H epatitis C virus (HCV) infects an estimated 180 million people worldwide, and about 75% of newly infected patients progress toward a chronic infection, which constitutes a risk for severe liver diseases such as cirrhosis and hepatocarcinoma (1-4). HCV is a hepacivirus in the Flaviviridae family characterized by the error-prone replication and quasispecies dynamics typical of RNA viruses (2,(5)(6)(7). No vaccine is available to prevent HCV infections or disease, and the current standard of care treatment consists of the combination of pegylated alpha interferon (IFN-␣) and the purine nucleoside analogue ribavirin (1-␤-D-ribofuranosyl-1-H-1,2,4-triazole-3-carboxamide) (8-10). Type I interferons (IFNs) such as IFN-␣ are members of a family of cytokines that constitute key components of the innate immune response to viruses, and their induction results in an antiviral state of the cell and suppression of viral replication (11)(12)(13)(14). Ribavirin is currently used to treat a number of human viral infections, and it can display multiple mechanisms of action, including enhancement of Th1 antiviral immune responses, upregulation of IFN-stimulated genes (ISGs), depletion of GTP pools, or viral RNA mutagenesis (see reviews in references 15, 16 and 17). However, on average only about 60% of the chronically infected patients show a sustained virological response to treatment with IFN-␣ plus ribavirin that results in virus clearance (18-21). The molecular and physiological bases of the therapeutic activity of the current combination treatment with IFN-␣ plus ribavirin are poorly understood. It might be possible to establish new treatment protocols based on recently developed directly acting antiviral agents (DAAs), with or without .Highly variable viruses exploit a number of strategies to counteract selective constraints intended to prevent their replication (reviewed in reference 7). Mutations that confer resistance to DAAs generally map in the target protein or in a protein that interacts with the target (28-30). However, the complexity of the cellular IFN response pathway is expected to require greater diversity of viral resistance mutations. Current evidence suggests that the response of HCV to IFN-␣-based therapy is influenced by several host (i.e., interleukin-28B [IL-28B] gene polymorphisms) and viral genetic (i.e., viral genotype and population complexity) factors (31-37).The advent of cell culture systems for sustained replication of HCV offers new prospects to approach the evolutionary dynamics of HCV and the host cell-virus relationship, including the anti-HCV activity of IFN-␣. Using these systems, Garaigorta and Chisari documented that HCV-induced protein kinase R (PKR) phosphorylation inhibited translation of IFN-stimulated genes (ISGs) in infected hepatocytes (38). Here we describe the adaptation of the HCV replication system of genotype 2a (39-41) to perform serial passages of HCV in the Huh-7.5 hepatocyte cell line with sustained, efficient viral replication for at least 100 serial passages. This cell ...

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Section: Discussionmentioning

confidence: 82%

Response of Hepatitis C Virus to Long-Term Passage in the Presence of Alpha Interferon: Multiple Mutations and a Common Phenotype

Perales

Beach

Gallego

et al. 2013

J Virol

172

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“…For peg-IFN + RBV therapy, the predictive value of the ISDR remained significant, but the criterion of ISDR ≥ 4 to predict SVR was replaced by ISDR ≥ 2[28-30] due to the selective impact of IFN monotherapy, whereby the prevalence of sensitive isolates with ISDR ≥ 4 decreased and that of HCV isolates of ISDR ≤ 3 increased. Therefore, the isolates with ISDR ≥ 2 were selected as sensitive isolates and those with ISDR ≤ 1 as resistant isolates for peg-IFN plus RBV therapy[22,23,30]. On the basis of these criteria, we assumed an increased genetic variability in the majority HCV sequence when the number of ISDR mutations was ≥ 2 throughout this study.…”

Section: Discussionmentioning

confidence: 99%

“…Taking into account the findings of previous studies[22,23,30], we assumed that viral variability would increase when the PKRBD and ISDR regions presented ≥ 2 mutations. Thus, our results show that patients who have undergone different treatments and who do not present viruses with genetic variability (either no increase or a return to the wild-type sequence) tend not to respond to a new treatment, regardless of its overall effectiveness.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C virus NS5A region mutation in chronic hepatitis C genotype 1 patients who are non-responders to two or more treatments and its relationship with response to a new treatment

Rueda¹,

Rodríguez²,

Quiles-Pérez³

et al. 2017

WJG

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AIMTo determine the number of mutations in the NS5A region of the hepatitis C virus (HCV) and its relationship to the response to antiviral therapy in patients with chronic hepatitis C genotype 1 who are non-responders to two or more treatments.METHODSSequences within HCV NS5A [PKR binding domain (PKRBD) and the interferon-sensitivity-determining region (ISDR)] were analysed via direct sequencing in a selected cohort of 72 patients, with a total of 201 treatments [interferon-alpha (IFN-α), n = 49; IFN-α + ribavirin (RBV), n = 75; pegylated (peg) IFN-α + RBV, n = 47; first-generation direct-acting antivirals (DAAs), n = 13; and second-generation DAAs, n = 17]. Of these, 48/201 achieved a sustained virological response (SVR) and 153/201 achieved no virological response (NVR).RESULTSFor both regions, treatments resulting in SVR were associated with more baseline mutations than were treatments resulting in NVR (SVR vs NVR; PKRBD: 5.82 ± 3 vs 4.86 ± 2 mutations, P = 0.045; ISDR: 2.65 ± 2 vs 1.51 ± 1.7 mutations, P = 0.005). A decrease or no change in the number of mutations over time between treatments in the PKRBD or ISDR, as shown by sequencing, was associated with patients who usually failed to respond to treatment (PKRBD, P = 0.02; ISDR, P = 0.001). Moreover, patients showing a post-treatment baseline viral load > 600000 IU/mL and increased ISDR mutations with respect to the previous treatment were 9.21 times more likely to achieve SVR (P = 0.001).CONCLUSIONThe obtained results show that among patients who have shown no response to two or more antiviral treatments, the likelihood of achieving SVR increases with the genetic variability in the ISDR region (≥ 2 mutations or number of substitutions from the HCV-J and HCV-1 prototype), especially when the viral load is greater than 600000 IU/mL.

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“…Specific mutations in the E2 [35], core [29,36,37], NS2 [29,35], NS5A [29,35,38], NS5B [16,35] and p7 [35,39] were found to correlate with response to IFN/RBV therapy. Although detectable, these genetic associations were inconsistent among HCV strains.…”

Section: Hcv Genetic Heterogeneity and Ifn/rbv Resistancementioning

confidence: 98%

“…Although detectable, these genetic associations were inconsistent among HCV strains. Changes in mutation rates corresponding to IFN response were observed in some regions of the HCV genome, including E2 [40,41], NS5A [31,36], P7 [39] and NS2 [42]. However, no strong linkage between the HCV genetic diversity and IFN/RBV sensitivity has been detected [29,32,33,36,38].…”

Section: Hcv Genetic Heterogeneity and Ifn/rbv Resistancementioning

confidence: 99%

Epistatic connectivity among HCV genomic sites as a genetic marker of interferon resistance

Lara¹,

Khudyakov²

2012

Antivir Ther

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The current standard-of-care therapy of patients with hepatitis C virus (HCV) infection involves treatment with interferon (IFN) and ribavirin. Host demographic and genetic factors as well as HCV genetic heterogeneity were shown to be associated with outcomes of therapy. Although resistance to IFN/RBV remains to be an important clinical and public health problem, there are no reliable genetic markers for the prediction of the therapy outcomes. Recently, it was shown that adaptation to IFN, a major constituent of the host innate immunity, is reflected in the HCV genetic composition and epistatic connectivity among polymorphic genomic sites, thus providing novel genetic markers of IFN resistance. Consideration of coordinated evolution among HCV genomic sites allows for the identification of these genetic markers from short regions of the HCV genome and accurate prediction of the therapy outcomes. The HCV genomic coevolution offers a general framework for the detection of predisposition to IFN resistance, and to resistance to direct-acting antivirals when they become introduced.

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Sequence heterogeneity of NS5A and core proteins of hepatitis C virus and virological responses to pegylated-interferon/ribavirin combination therapy

Abstract: world's population, are infected with HCV. Seventy percent of acute infections become persistent, and 50-75% 418

Cited by 18 publications

References 32 publications

Response of Hepatitis C Virus to Long-Term Passage in the Presence of Alpha Interferon: Multiple Mutations and a Common Phenotype

Response of Hepatitis C Virus to Long-Term Passage in the Presence of Alpha Interferon: Multiple Mutations and a Common Phenotype

Hepatitis C virus NS5A region mutation in chronic hepatitis C genotype 1 patients who are non-responders to two or more treatments and its relationship with response to a new treatment

Epistatic connectivity among HCV genomic sites as a genetic marker of interferon resistance

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