Related Experiment Videos
Serial density analysis of hepatitis C virus particle populations in chronic hepatitis C patients treated with
T Kanto1, N Hayashi, T Takehara
1First Department of Medicine, Osaka University Medical School, Japan.
Insights
High-density hepatitis C virus (HCV) immune complexes may explain why some patients maintain normal ALT levels despite persistent viremia after interferon treatment. This suggests a role for viral particle density in treatment outcomes.
Area of Science:
- Hepatology
- Virology
- Immunology
Background:
- Interferon therapy for chronic hepatitis C often leads to parallel biochemical and virological responses.
- Some patients exhibit persistent ALT normalization but continued viremia post-therapy, a discrepancy not fully understood.
- High-density hepatitis C virus (HCV) particles, existing as immune complexes, are hypothesized to have reduced infectivity.
Purpose of the Study:
- To investigate if high-density HCV contributes to response discrepancies in interferon-treated chronic hepatitis C patients.
- To clarify the association between high-density HCV and patient outcomes after therapy.
Main Methods:
- Sera from chronic hepatitis C patients (sustained responders with viremia, sustained responders without viremia, transient responders, nonresponders) treated with interferon-alpha were analyzed.
- Serum samples before and after therapy were ultracentrifuged on 35% sucrose to separate high-density (bottom fraction) and low-density (top fraction) HCV particles.
- The ratio of high-density to low-density HCV was determined by quantifying HCV-RNA titers in each fraction using competitive reverse transcription and polymerase chain reaction, expressed as the bottom/top (B/T) ratio.
Main Results:
- Before therapy, B/T ratios were 1:1 across all patient groups.
- After therapy, B/T ratios remained 1:1 in transient responders and nonresponders.
- Five of six sustained responders with viremia (SR + ve) showing a 1:1 post-therapy B/T ratio relapsed within a year.
- Conversely, all SR + ve patients with post-therapy B/T ratios of 10-100:1 maintained ALT normalization despite viremia.
Conclusions:
- High-density HCV dominance post-therapy is associated with persistent ALT normalization in viremic patients.
- This phenomenon can be attributed to the predominance of neutralized immune complexed HCV particles.
- Viral particle density and immune complex formation are critical factors influencing hepatitis C treatment outcomes.
Abstract:
In interferon treatment of chronic hepatitis C patients, the biochemical and virological responses mostly parallel each other. However, some patients who show persistent ALT normalization display continued viremia after cessation of therapy. High-density hepatitis C virus (HCV) particles, which are immune complex forms, are reported to be less infectious both in vitro and in vivo. To assess whether high-density HCV contributes to the response discrepancies and to clarify the association with patient outcome, sera were examined from chronic hepatitis C patients who were treated with interferon-alpha. This study included 10 sustained responders with viremia (SR + ve), 5 SR without viremia, 3 transient responders (TR), and 3 nonresponders (NR). The SR + ve patients were defined as those with continued ALT normalization and serum HCV-RNA positivity at 24 weeks after therapy completion. Serum samples obtained before and 24 weeks after therapy were ultracentrifuged on 35% sucrose. The ratio between high-density and low-density HCV was determined by quantification of HCV-RNA titers in the bottom and top fractions by competitive reverse transcription and by the polymerase chain reaction, and expressed as the bottom/top (B/T) ratio. The B/T ratios before therapy were 1:1 in all groups of patients, and 1:1 after therapy in TR and NR groups. Five out of 6 SR + ve patients who showed 1:1 ratio after therapy relapsed within 1 year. In contrast, all SR + ve patients whose ratios were 10-100:1 continued to show ALT normalization. These findings demonstrate that patients who have high-density HCV dominance after therapy show persistent ALT normalization despite viremia, which can be explained by predominance of the neutralized immune complex.