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Neutralizing antibodies in patients with chronic hepatitis C, genotype 1, against a panel of genotype 1 culture viruses: lack of correlation to treatment outcome.

Pedersen J, Jensen TB, Carlsen TH, Schønning K, Christensen PB, Laursen AL, Krarup H, Bukh J, Weis N - PLoS ONE (2013)

Bottom Line: The results were expressed as the highest dilution yielding 50% neutralization (NAb50-titer).However, NAb50-titers varied significantly with a mean reciprocal NAb50-titer of 800 (range: 100-6400) against DH6/JFH1 compared to a mean NAb50-titer of 50 (range: <50-400) against all other included isolates.In conclusion, pre-treatment levels of neutralizing antibodies against HCV genotype 1 isolates could not predict treatment outcome in patients with chronic HCV infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark.

ABSTRACT
The correlation of neutralizing antibodies to treatment outcome in patients with chronic hepatitis C virus (HCV) infection has not been established. The aim of this study was to determine whether neutralizing antibodies could be used as an outcome predictor in patients with chronic HCV, genotype 1, infection treated with pegylated interferon-α and ribavirin. Thirty-nine patients with chronic hepatitis C, genotype 1a or 1b, with either sustained virologic response (n = 23) or non-sustained virologic response (n = 16) were enrolled. Samples taken prior to treatment were tested for their ability to neutralize 6 different HCV genotype 1 cell culture recombinants (1a: H77/JFH1, TN/JFH1, DH6/JFH1; 1b: J4/JFH1, DH1/JFH1, DH5/JFH1). The results were expressed as the highest dilution yielding 50% neutralization (NAb50-titer). We observed no genotype or subtype specific differences in NAb50-titers between patients with chronic HCV infection with and without sustained virologic response when tested against any of the included culture viruses. However, NAb50-titers varied significantly with a mean reciprocal NAb50-titer of 800 (range: 100-6400) against DH6/JFH1 compared to a mean NAb50-titer of 50 (range: <50-400) against all other included isolates. Subsequent studies demonstrated that the efficient neutralization of DH6/JFH1 could be linked to engineered adaptive mutations in the envelope-2 protein. In analysis of envelope 1 and 2 sequences of HCV, recovered from a subset of patients, we observed no apparent link between relatedness of patient sequences with culture viruses used and the corresponding neutralization results. In conclusion, pre-treatment levels of neutralizing antibodies against HCV genotype 1 isolates could not predict treatment outcome in patients with chronic HCV infection. High neutralization susceptibility of DH6/JFH1 could be correlated with adaptive envelope mutations previously highlighted as important for neutralization. Our study emphasizes the importance of using multiple culture viruses for neutralization studies and contributes to the current knowledge about neutralizing epitopes, important for future therapeutic- and vaccine-studies.

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Phylogenetic analysis of the Core-E1 sequences of the HCV, genotype 1a and 1b, isolates from 38 patients.The analysis includes the Core-E1-sequences (nts. 868–1288; GenBank accession number AF009606) (one of the 39 included patients could not be subtyped and is not included in the tree), the corresponding sequence of the included genotype 1 culture viruses (circled) and culture viruses of other HCV genotypes. The QC69 (genotype 7a) is included as an out-group. The percentage of 1000 replicates in which the associated taxa cluster together in the bootstrap test is shown when >80%. The phylogenetic tree was constructed using the neighbor-joining method in the MEGA5 software. Each patient was assigned with a study number (also shown in Table 2) and the treatment outcome (SVR and non-SVR) is noted. The scale indicates the evolutionary rate of the branches.
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pone-0062674-g001: Phylogenetic analysis of the Core-E1 sequences of the HCV, genotype 1a and 1b, isolates from 38 patients.The analysis includes the Core-E1-sequences (nts. 868–1288; GenBank accession number AF009606) (one of the 39 included patients could not be subtyped and is not included in the tree), the corresponding sequence of the included genotype 1 culture viruses (circled) and culture viruses of other HCV genotypes. The QC69 (genotype 7a) is included as an out-group. The percentage of 1000 replicates in which the associated taxa cluster together in the bootstrap test is shown when >80%. The phylogenetic tree was constructed using the neighbor-joining method in the MEGA5 software. Each patient was assigned with a study number (also shown in Table 2) and the treatment outcome (SVR and non-SVR) is noted. The scale indicates the evolutionary rate of the branches.

Mentions: During initial follow-up the HCV infected patients had not been subtyped; by Core-E1 sequence analysis [35], 26 and 12 patients were identified to be infected with HCV genotype 1a and 1b, respectively; one patient sample could not be subtyped (Figure 1).


Neutralizing antibodies in patients with chronic hepatitis C, genotype 1, against a panel of genotype 1 culture viruses: lack of correlation to treatment outcome.

Pedersen J, Jensen TB, Carlsen TH, Schønning K, Christensen PB, Laursen AL, Krarup H, Bukh J, Weis N - PLoS ONE (2013)

Phylogenetic analysis of the Core-E1 sequences of the HCV, genotype 1a and 1b, isolates from 38 patients.The analysis includes the Core-E1-sequences (nts. 868–1288; GenBank accession number AF009606) (one of the 39 included patients could not be subtyped and is not included in the tree), the corresponding sequence of the included genotype 1 culture viruses (circled) and culture viruses of other HCV genotypes. The QC69 (genotype 7a) is included as an out-group. The percentage of 1000 replicates in which the associated taxa cluster together in the bootstrap test is shown when >80%. The phylogenetic tree was constructed using the neighbor-joining method in the MEGA5 software. Each patient was assigned with a study number (also shown in Table 2) and the treatment outcome (SVR and non-SVR) is noted. The scale indicates the evolutionary rate of the branches.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3646876&req=5

pone-0062674-g001: Phylogenetic analysis of the Core-E1 sequences of the HCV, genotype 1a and 1b, isolates from 38 patients.The analysis includes the Core-E1-sequences (nts. 868–1288; GenBank accession number AF009606) (one of the 39 included patients could not be subtyped and is not included in the tree), the corresponding sequence of the included genotype 1 culture viruses (circled) and culture viruses of other HCV genotypes. The QC69 (genotype 7a) is included as an out-group. The percentage of 1000 replicates in which the associated taxa cluster together in the bootstrap test is shown when >80%. The phylogenetic tree was constructed using the neighbor-joining method in the MEGA5 software. Each patient was assigned with a study number (also shown in Table 2) and the treatment outcome (SVR and non-SVR) is noted. The scale indicates the evolutionary rate of the branches.
Mentions: During initial follow-up the HCV infected patients had not been subtyped; by Core-E1 sequence analysis [35], 26 and 12 patients were identified to be infected with HCV genotype 1a and 1b, respectively; one patient sample could not be subtyped (Figure 1).

Bottom Line: The results were expressed as the highest dilution yielding 50% neutralization (NAb50-titer).However, NAb50-titers varied significantly with a mean reciprocal NAb50-titer of 800 (range: 100-6400) against DH6/JFH1 compared to a mean NAb50-titer of 50 (range: <50-400) against all other included isolates.In conclusion, pre-treatment levels of neutralizing antibodies against HCV genotype 1 isolates could not predict treatment outcome in patients with chronic HCV infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark.

ABSTRACT
The correlation of neutralizing antibodies to treatment outcome in patients with chronic hepatitis C virus (HCV) infection has not been established. The aim of this study was to determine whether neutralizing antibodies could be used as an outcome predictor in patients with chronic HCV, genotype 1, infection treated with pegylated interferon-α and ribavirin. Thirty-nine patients with chronic hepatitis C, genotype 1a or 1b, with either sustained virologic response (n = 23) or non-sustained virologic response (n = 16) were enrolled. Samples taken prior to treatment were tested for their ability to neutralize 6 different HCV genotype 1 cell culture recombinants (1a: H77/JFH1, TN/JFH1, DH6/JFH1; 1b: J4/JFH1, DH1/JFH1, DH5/JFH1). The results were expressed as the highest dilution yielding 50% neutralization (NAb50-titer). We observed no genotype or subtype specific differences in NAb50-titers between patients with chronic HCV infection with and without sustained virologic response when tested against any of the included culture viruses. However, NAb50-titers varied significantly with a mean reciprocal NAb50-titer of 800 (range: 100-6400) against DH6/JFH1 compared to a mean NAb50-titer of 50 (range: <50-400) against all other included isolates. Subsequent studies demonstrated that the efficient neutralization of DH6/JFH1 could be linked to engineered adaptive mutations in the envelope-2 protein. In analysis of envelope 1 and 2 sequences of HCV, recovered from a subset of patients, we observed no apparent link between relatedness of patient sequences with culture viruses used and the corresponding neutralization results. In conclusion, pre-treatment levels of neutralizing antibodies against HCV genotype 1 isolates could not predict treatment outcome in patients with chronic HCV infection. High neutralization susceptibility of DH6/JFH1 could be correlated with adaptive envelope mutations previously highlighted as important for neutralization. Our study emphasizes the importance of using multiple culture viruses for neutralization studies and contributes to the current knowledge about neutralizing epitopes, important for future therapeutic- and vaccine-studies.

Show MeSH
Related in: MedlinePlus