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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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Neutralizing antibodies in 26 patients chronically infected with hepatitis C virus, genotype 1a.Plasma samples from 26 patients with chronic HCV infection, genotype 1a, taken prior to treatment initiation with pegylated interferon-α and ribavirin, were tested against genotype 1a and 1b Core-NS2 recombinants in a two-fold dilution series starting from 1∶50. The NAb50-titers are the highest dilution where the patient samples were able to neutralize 50% of the virus. Each bar shows the percentage of patients in the SVR (n = 14) and non-SVR (n = 12) group in relation to their NAb50-titer.
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pone-0062674-g004: Neutralizing antibodies in 26 patients chronically infected with hepatitis C virus, genotype 1a.Plasma samples from 26 patients with chronic HCV infection, genotype 1a, taken prior to treatment initiation with pegylated interferon-α and ribavirin, were tested against genotype 1a and 1b Core-NS2 recombinants in a two-fold dilution series starting from 1∶50. The NAb50-titers are the highest dilution where the patient samples were able to neutralize 50% of the virus. Each bar shows the percentage of patients in the SVR (n = 14) and non-SVR (n = 12) group in relation to their NAb50-titer.

Mentions: All patient plasma samples were tested in the in vitro neutralization assays at a 1∶50 dilution and grouped according to treatment outcome (Figure 2). The mean of the percentage of neutralization did not differ significantly between the two patient groups, however all samples showed a high percentage of neutralization against the DH6/JFH1 recombinant compared to the other culture viruses. This initial analysis was followed by dose-response analysis of the patient samples, to determine the highest dilution at which each virus infection was 50% neutralized (NAb50-titer). The results are shown in Table 2, ordered according to treatment outcome and HCV subtype. Correlating the NAb50-titers in the two groups (SVR vs. non-SVR) for each virus, showed no significant difference between the groups as calculated by Fischers exact test (Figure 3). Analyzing only genotype 1a patient samples, revealed no difference in NAb50-titers on a subtype specific level either (Figure 4). There were too few genotype 1b patients to make comparison in that group. Thus, the pre-treatment level of NAb did not correlate with treatment outcome.


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)

Neutralizing antibodies in 26 patients chronically infected with hepatitis C virus, genotype 1a.Plasma samples from 26 patients with chronic HCV infection, genotype 1a, taken prior to treatment initiation with pegylated interferon-α and ribavirin, were tested against genotype 1a and 1b Core-NS2 recombinants in a two-fold dilution series starting from 1∶50. The NAb50-titers are the highest dilution where the patient samples were able to neutralize 50% of the virus. Each bar shows the percentage of patients in the SVR (n = 14) and non-SVR (n = 12) group in relation to their NAb50-titer.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0062674-g004: Neutralizing antibodies in 26 patients chronically infected with hepatitis C virus, genotype 1a.Plasma samples from 26 patients with chronic HCV infection, genotype 1a, taken prior to treatment initiation with pegylated interferon-α and ribavirin, were tested against genotype 1a and 1b Core-NS2 recombinants in a two-fold dilution series starting from 1∶50. The NAb50-titers are the highest dilution where the patient samples were able to neutralize 50% of the virus. Each bar shows the percentage of patients in the SVR (n = 14) and non-SVR (n = 12) group in relation to their NAb50-titer.
Mentions: All patient plasma samples were tested in the in vitro neutralization assays at a 1∶50 dilution and grouped according to treatment outcome (Figure 2). The mean of the percentage of neutralization did not differ significantly between the two patient groups, however all samples showed a high percentage of neutralization against the DH6/JFH1 recombinant compared to the other culture viruses. This initial analysis was followed by dose-response analysis of the patient samples, to determine the highest dilution at which each virus infection was 50% neutralized (NAb50-titer). The results are shown in Table 2, ordered according to treatment outcome and HCV subtype. Correlating the NAb50-titers in the two groups (SVR vs. non-SVR) for each virus, showed no significant difference between the groups as calculated by Fischers exact test (Figure 3). Analyzing only genotype 1a patient samples, revealed no difference in NAb50-titers on a subtype specific level either (Figure 4). There were too few genotype 1b patients to make comparison in that group. Thus, the pre-treatment level of NAb did not correlate with treatment outcome.

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