Genetic variability of hepatitis C virus NS3 protein in human leukocyte antigen-A2 liver transplant recipients with recurrent hepatitis C

López‐Labrador, F. Xavier; Berenguer, Marina; Sempere, Amparo; Prieto, M.; Sirera, Rafael; González-Molina, A; Ortiz, Vicente; Marty, M; Berenguer, J; Gobernado, M

doi:10.1002/lt.20066

Cited by 18 publications

(14 citation statements)

References 40 publications

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“…These findings are in keeping with previous reports indicating that NS3 sequences are highly preserved after LT and that the emergence of mutations in T-cell epitopes of the NS3 protein were not related to the different outcome of liver disease recurrence (49,50). Most likely, the pattern of genetic evolution is diverse and has different implications in different domains of the HCV genome.…”

Section: Discussionsupporting

confidence: 91%

Evolution of the NS3 and NS5B Regions of the Hepatitis C Virus During Disease Recurrence After Liver Transplantation

Massaguer

Ramírez

Carrión

et al. 2007

American Journal of Transplantation

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In patients with hepatitis C virus (HCV)-related cirrhosis, infection recurrence is universal after liver transplantation (LT). The relevance of host and virusrelated factors on the outcome of hepatitis C recurrence is poorly understood. This study analyzed the relationship between the genetic evolution of the NonStructural (NS)3 protease and NS5B polymerase regions of HCV and the severity of hepatitis C recurrence. Thirty-three patients were classified as having mild (n = 16) or severe recurrence (n = 17), according to the degree of fibrosis in liver biopsies obtained 1 year after transplantation. Viral load and consensus sequences of the NS3 and NS5B domains were determined in a pre-LT and in four post-LT sequential serum samples. At week 12 after LT, viremia was significantly higher in patients with severe recurrence. NS3 and NS5b regions evolved independently after LT. The genetic evolution of NS3 domain was not related to the severity of the recurrence. However, the diversification in the NS5B region later than 12 weeks after LT was greater in patients with mild than in those with severe recurrence, suggesting a stronger immune pressure in the first group. These observations highlight the complex interplay between viral evolution and clinical outcomes in the LT setting.

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Section: Discussionsupporting

confidence: 91%

Evolution of the NS3 and NS5B Regions of the Hepatitis C Virus During Disease Recurrence After Liver Transplantation

Massaguer

Ramírez

Carrión

et al. 2007

American Journal of Transplantation

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“…The most studied HCV region is the hypervariable region 1 (HVR1) located at amino acid (aa) positions 384-410 in the structural protein E2. Sequence variation in HVR1 correlates with neutralization escape and is associated with viral persistence during chronic infection [6-11]. …”

Section: Introductionmentioning

confidence: 99%

Next-generation sequencing reveals large connected networks of intra-host HCV variants

et al. 2014

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BackgroundNext-generation sequencing (NGS) allows for sampling numerous viral variants from infected patients. This provides a novel opportunity to represent and study the mutational landscape of Hepatitis C Virus (HCV) within a single host.ResultsIntra-host variants of the HCV E1/E2 region were extensively sampled from 58 chronically infected patients. After NGS error correction, the average number of reads and variants obtained from each sample were 3202 and 464, respectively. The distance between each pair of variants was calculated and networks were created for each patient, where each node is a variant and two nodes are connected by a link if the nucleotide distance between them is 1. The work focused on large components having > 5% of all reads, which in average account for 93.7% of all reads found in a patient.The distance between any two variants calculated over the component correlated strongly with nucleotide distances (r = 0.9499; p = 0.0001), a better correlation than the one obtained with Neighbour-Joining trees (r = 0.7624; p = 0.0001). In each patient, components were well separated, with the average distance between (6.53%) being 10 times greater than within each component (0.68%). The ratio of nonsynonymous to synonymous changes was calculated and some patients (6.9%) showed a mixture of networks under strong negative and positive selection. All components were robust to in silico stochastic sampling; even after randomly removing 85% of all reads, the largest connected component in the new subsample still involved 82.4% of remaining nodes. In vitro sampling showed that 93.02% of components present in the original sample were also found in experimental replicas, with 81.6% of reads found in both. When syringe-sharing transmission events were simulated, 91.2% of all simulated transmission events seeded all components present in the source.ConclusionsMost intra-host variants are organized into distinct single-mutation components that are: well separated from each other, represent genetic distances between viral variants, robust to sampling, reproducible and likely seeded during transmission events. Facilitated by NGS, large components offer a novel evolutionary framework for genetic analysis of intra-host viral populations and understanding transmission, immune escape and drug resistance.

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“…HVR1 sequence variation correlates with neutralization escape and is associated with viral persistence during chronic infection171819202122. Although some neutralizing epitopes have been discovered in conserved regions of HCV structural proteins23, the variant-specificity of humoral protective responses2425 points to the essential role played by the variable epitopes in controlling HCV infections.…”

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confidence: 99%

Hepatitis C Virus Antigenic Convergence

Campo

Dimitrova

Yokosawa

et al. 2012

Sci Rep

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Vaccine development against hepatitis C virus (HCV) is hindered by poor understanding of factors defining cross-immunoreactivity among heterogeneous epitopes. Using synthetic peptides and mouse immunization as a model, we conducted a quantitative analysis of cross-immunoreactivity among variants of the HCV hypervariable region 1 (HVR1). Analysis of 26,883 immunological reactions among pairs of peptides showed that the distribution of cross-immunoreactivity among HVR1 variants was skewed, with antibodies against a few variants reacting with all tested peptides. The HVR1 cross-immunoreactivity was accurately modeled based on amino acid sequence alone. The tested peptides were mapped in the HVR1 sequence space, which was visualized as a network of 11,319 sequences. The HVR1 variants with a greater network centrality showed a broader cross-immunoreactivity. The entire sequence space is explored by each HCV genotype and subtype. These findings indicate that HVR1 antigenic diversity is extensively convergent and effectively limited, suggesting significant implications for vaccine development.

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Genetic variability of hepatitis C virus NS3 protein in human leukocyte antigen-A2 liver transplant recipients with recurrent hepatitis C

Cited by 18 publications

References 40 publications

Evolution of the NS3 and NS5B Regions of the Hepatitis C Virus During Disease Recurrence After Liver Transplantation

Evolution of the NS3 and NS5B Regions of the Hepatitis C Virus During Disease Recurrence After Liver Transplantation

Next-generation sequencing reveals large connected networks of intra-host HCV variants

Hepatitis C Virus Antigenic Convergence

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