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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 relationship of the envelope sequence of the patient derived viruses and the culture viruses with associated NAb50-titer.16 patient derived viruses and 6 culture viruses divided into three groups according to the sequence of the E1E2 analyzed in a phylogenetic tree (see Figure 7). The clusters are marked by different colors of the names of the samples and viruses, including a box framing the viruses in the cluster. Blue = genotype 1b, cluster 1; Red = genotype 1a, cluster 2; Green = genotype 1a, cluster 3. Only plasma samples with NAb50-titer ≥100 against genotype 1a viruses (green squares) and genotype 1b viruses (grey squares) are shown. The patient number is written in the squares and the titer against the virus is written in parentheses.
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pone-0062674-g008: Phylogenetic relationship of the envelope sequence of the patient derived viruses and the culture viruses with associated NAb50-titer.16 patient derived viruses and 6 culture viruses divided into three groups according to the sequence of the E1E2 analyzed in a phylogenetic tree (see Figure 7). The clusters are marked by different colors of the names of the samples and viruses, including a box framing the viruses in the cluster. Blue = genotype 1b, cluster 1; Red = genotype 1a, cluster 2; Green = genotype 1a, cluster 3. Only plasma samples with NAb50-titer ≥100 against genotype 1a viruses (green squares) and genotype 1b viruses (grey squares) are shown. The patient number is written in the squares and the titer against the virus is written in parentheses.

Mentions: In order to be able to determine the genetic relationship between E1E2 of the included culture viruses and the patient derived viruses, the sequences were aligned and compared in a phylogenetic analysis (Figure 7). The genotype 1a and 1b clustered into two major groups. However, significant differences were also shown for the genotype 1a viruses, dividing them into two major genotype 1a clusters with DH6 in one cluster and H77 and TN in another. The major clusters are illustrated by different colors in Figure 7, and the clusters with the associated NAb50-titers are illustrated in Figure 8. There was no apparent link between relatedness of patient sequences with culture viruses used, and the corresponding neutralization results.


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 relationship of the envelope sequence of the patient derived viruses and the culture viruses with associated NAb50-titer.16 patient derived viruses and 6 culture viruses divided into three groups according to the sequence of the E1E2 analyzed in a phylogenetic tree (see Figure 7). The clusters are marked by different colors of the names of the samples and viruses, including a box framing the viruses in the cluster. Blue = genotype 1b, cluster 1; Red = genotype 1a, cluster 2; Green = genotype 1a, cluster 3. Only plasma samples with NAb50-titer ≥100 against genotype 1a viruses (green squares) and genotype 1b viruses (grey squares) are shown. The patient number is written in the squares and the titer against the virus is written in parentheses.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0062674-g008: Phylogenetic relationship of the envelope sequence of the patient derived viruses and the culture viruses with associated NAb50-titer.16 patient derived viruses and 6 culture viruses divided into three groups according to the sequence of the E1E2 analyzed in a phylogenetic tree (see Figure 7). The clusters are marked by different colors of the names of the samples and viruses, including a box framing the viruses in the cluster. Blue = genotype 1b, cluster 1; Red = genotype 1a, cluster 2; Green = genotype 1a, cluster 3. Only plasma samples with NAb50-titer ≥100 against genotype 1a viruses (green squares) and genotype 1b viruses (grey squares) are shown. The patient number is written in the squares and the titer against the virus is written in parentheses.
Mentions: In order to be able to determine the genetic relationship between E1E2 of the included culture viruses and the patient derived viruses, the sequences were aligned and compared in a phylogenetic analysis (Figure 7). The genotype 1a and 1b clustered into two major groups. However, significant differences were also shown for the genotype 1a viruses, dividing them into two major genotype 1a clusters with DH6 in one cluster and H77 and TN in another. The major clusters are illustrated by different colors in Figure 7, and the clusters with the associated NAb50-titers are illustrated in Figure 8. There was no apparent link between relatedness of patient sequences with culture viruses used, and the corresponding neutralization results.

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