Comparative Analysis of Nearly Full-Length Hepatitis C Virus Quasispecies from Patients Experiencing Viral Breakthrough during Antiviral Therapy: Clustered Mutations in Three Functional Genes, E2, NS2, and NS5a

Xu, Zekuan; Fan, Xiaofeng; Xu, Yingqi; Bisceglie, Adrian M. Di

doi:10.1128/jvi.00896-08

Cited by 17 publications

(24 citation statements)

References 33 publications

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“…For NR samples, before-treatment quasispecies variants tended to group with quasispecies found after 12 weeks of treatment, and post-therapy sequences grouped together in another branch. The distinctive clustering of pre/post-therapy sequences had been described previously [22,42,47], demonstrating the evolutionary process occurred over time. In some cases, isolates identified in after-treatment samples had the longest distances from the main nodes in phylogenetic analysis.…”

Section: Discussionsupporting

confidence: 68%

“…According to the authors viral breakthrough could be attributed to the selection of pre-existing drug-resistant variants or the emergence of different quasispecies with reduced sensitivity to IFN. However, the study indicated that selection is mostly responsible for appearance of drug resistant quasispecies at breakthrough [42]. As breakthrough and relapse indicate rebound of infection after undetectable HCV RNA levels, is reasonable that the results presented herein are in agreement when considering the quasispecies composition and diversity at breakthrough and relapse time.…”

Section: Discussionsupporting

confidence: 66%

“…A study focusing on breakthrough response pattern, defined by patients who have an initial response followed by reactivation whilst receiving IFN therapy, did not identify quasispecies variants from breakthrough in baseline samples [42]. This study assumed that HCV variants sampled at the time of breakthrough represent drug-resistant quasispecies, and if present at baseline, they must be present very low frequency.…”

Section: Discussionmentioning

confidence: 99%

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Analysis of HCV quasispecies dynamic under selective pressure of combined therapy

et al. 2013

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BackgroundThe quasispecies composition of Hepatitis C virus (HCV) could have important implications with regard to viral persistence and response to interferon-based therapy. The complete NS5A was analyzed to evaluate whether the composition of NS5A quasispecies of HCV 1a/1b is related to responsiveness to combined interferon pegylated (PEG-IFN) and ribavirin therapy.MethodsViral RNA was isolated from serum samples collected before, during and after treatment from virological sustained responder (SVR), non-responder (NR) and the end-of-treatment responder patients (ETR). NS5A region was amplified, cloned and sequenced. Six hundred and ninety full-length NS5A sequences were analyzed.ResultsThis study provides evidence that lower nucleotide diversity of the NS5A region pre-therapy is associated with viral clearance. Analysis of samples of NRs and the ETRs time points showed that genetic diversity of populations tend to decrease over time. Post-therapy population of ETRs presented higher genetic distance from baseline probably due to the bottleneck phenomenon observed for those patients in the end of treatment. The viral effective population of those patients also showed a strong decrease after therapy. Otherwise, NRs demonstrated a continuous variation or stability of effective populations and genetic diversity over time that did not seem to be related to therapy. Phylogenetic relationships concerning complete NS5A sequences obtained from patients did not demonstrate clustering associated with specific response patterns. However, distinctive clustering of pre/post-therapy sequences was observed. In addition, the evolution of quasispecies over time was subjected to purifying or relaxed purifying selection. Codons 157 (P03), 182 and 440 (P42), 62 and 404 (P44) were found to be under positive selective pressure but it failed to be related to the therapy.ConclusionThese results confirm the hypothesis that a relationship exists between NS5A heterogeneity and response to therapy in patients infected with chronic hepatitis C.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

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Analysis of HCV quasispecies dynamic under selective pressure of combined therapy

et al. 2013

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“…In addition, analysis of the frequency of each degenerate nucleotide position in the codons for the top 5 hub positions for the Marked and Poor sequences (Table 4) revealed that the probability that a given viral RNA molecule in the quasispecies spectrum encoded all 5 of the hub consensus sequence residues was 93% for the Marked sequences and 82% for the Poor sequences. Finally, near-full-length HCV quasispecies variants have previously been analyzed in 2 genotype 1a patients, with 6 variants sequenced per patient (35,36). In one patient, the residues at the top 5 hubs from our All network were identical in the consensus sequence derived from the quasispecies variants and in all 6 of the variants, and in the other patient there was a single substitution at one hub position in one of the 6 quasispecies variants.…”

Section: Figurementioning

confidence: 99%

Genome-wide hepatitis C virus amino acid covariance networks can predict response to antiviral therapy in humans

Aurora¹,

Donlin²,

Cannon³

et al. 2008

J. Clin. Invest.

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Hepatitis C virus (HCV) is a common RNA virus that causes hepatitis and liver cancer. Infection is treated with IFN-α and ribavirin, but this expensive and physically demanding therapy fails in half of patients. The genomic sequences of independent HCV isolates differ by approximately 10%, but the effects of this variation on the response to therapy are unknown. To address this question, we analyzed amino acid covariance within the full viral coding region of pretherapy HCV sequences from 94 participants in the Viral Resistance to Antiviral Therapy of Chronic Hepatitis C (Virahep-C) clinical study. Covarying positions were common and linked together into networks that differed by response to therapy. There were 3-fold more hydrophobic amino acid pairs in HCV from nonresponding patients, and these hydrophobic interactions were predicted to contribute to failure of therapy by stabilizing viral protein complexes. Using our analysis to detect patterns within the networks, we could predict the outcome of therapy with greater than 95% coverage and 100% accuracy, raising the possibility of a prognostic test to reduce therapeutic failures. Furthermore, the hub positions in the networks are attractive antiviral targets because of their genetic linkage with many other positions that we predict would suppress evolution of resistant variants. Finally, covariance network analysis could be applicable to any virus with sufficient genetic variation, including most human RNA viruses.

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“…Quasispecies heterogeneity was shown in recent studies to be a possible independent predictor of response to interferon alfa therapy. Responsive patients typically possess less HCV quasispecies population in the pretreatment sera than do non-responsive patients 3031. A combination regimen of interferon alfa with ribavirin was demonstrated in clinical trials to produce higher rates of sustained virological, biochemical, and histological responses, particularly in patients with a relapse 2132.…”

Section: Discussionmentioning

confidence: 99%

Quasispecies of genotype 4 of hepatitis C virus genomes in Saudi patients managed with interferon alfa and ribavirin therapy

Al‐Qahtani

Kessie

Cruz

et al. 2010

Annals of Saudi Medicine

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BACKGROUND AND OBJECTIVES:Many patients with hepatitis C virus (HCV) infection do not respond to antiviral treatment, possibly due to viral quasispecies. We aimed to investigate whether the quasispeices population could be used as a predictor of response to therapy in our patients.METHODS:The quasispecies of HCV genotype 4 (HCV-4) were studied in 25 naïve Saudi patients at zero, three, and six months following interferon alfa and ribavirin combination therapy. Hypervariable region 1 within the E2/NS1 gene of the virus was analyzed by the single-strand conformation polymorphism (SSCP) technique after amplification.RESULTS:Pretreatment DNA bands by SSCP (2-7 bands) were detected in all patients. In those who achieved a complete virological response within six months (viral load <0.2 Meq/mL; n=7), bands ranged from 2-6 (mean = 3.71±1.25). In six of these seven patients, the number of SSCP bands remained either the same or decreased sequentially. In those patients who did not respond (viral load >0.2 Meq/mL; n=18), the bands also ranged from 2-7; mean 3.77±1.73. In six of these non-responding patients, the SSCP bands remained the same or decreased sequentially. There was no significant difference between pretreatment quasispecies composition and response (P=·53). Two of the four patients with pretreatment high viral load and the same or decreased composition of quasispecies bands responded to the therapy.CONCLUSION:Quasispecies in our studied patients cannot be used to predict responsiveness to treatment, but may offer an explanation for failure of most HCV-4 patients to respond to interferon alfa and ribavirin therapy.

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Comparative Analysis of Nearly Full-Length Hepatitis C Virus Quasispecies from Patients Experiencing Viral Breakthrough during Antiviral Therapy: Clustered Mutations in Three Functional Genes, E2, NS2, and NS5a

Cited by 17 publications

References 33 publications

Analysis of HCV quasispecies dynamic under selective pressure of combined therapy

Analysis of HCV quasispecies dynamic under selective pressure of combined therapy

Genome-wide hepatitis C virus amino acid covariance networks can predict response to antiviral therapy in humans

Quasispecies of genotype 4 of hepatitis C virus genomes in Saudi patients managed with interferon alfa and ribavirin therapy

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