Summary auto-generated
Ribavirin is an antiviral compound used in combination therapies for chronic hepatitis C virus (HCV) infection, but its direct antiviral mechanisms remain unclear. This study investigated ribavirin's immune-modulatory effects in patients with chronic HCV and mouse models. In a 24-week placebo-controlled trial of ten HCV patients, ribavirin treatment transiently decreased HCV-specific antibodies and alanine aminotransferase (ALT) levels, but serum HCV RNA remained stable, suggesting immune rather than direct antiviral effects. In vitro studies showed ribavirin inhibited T-cell proliferation and altered cytokine production, reducing IL-4 while increasing TNF-α expression. Mouse immunization experiments demonstrated that ribavirin treatment increased IL-2 and IFN-γ production 25-125 fold, while maintaining constant IL-4 levels. Critically, ribavirin treatment of HBeAg-transgenic mice caused dose-dependent reduction in Th2-mediated antibody responses (IgG1) while increasing Th1-mediated responses (IgG2a) and IFN-γ production. These findings indicate ribavirin modulates the balance between Th1 and Th2 immune responses rather than acting primarily as a direct antiviral agent.
Key findings
- Ribavirin treatment decreased HCV-specific antibodies in patients independent of viral load, suggesting immune-modulatory rather than direct antiviral mechanisms
- Ribavirin inhibited T-cell proliferation and differentially suppressed Th2-like cytokines (IL-4) while enhancing Th1-like cytokines (IFN-γ, TNF-α) at comparable doses
- In mouse models, ribavirin enhanced HBV-specific IL-2 and IFN-γ production by 25-125 fold while maintaining constant IL-4 and IL-6 levels
- Ribavirin treatment of HBeAg-transgenic mice showed dose-dependent suppression of Th2-mediated IgG1 anti-HBe antibodies while promoting Th1-mediated IgG2a responses
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Abstract
Ribavirin is effective in combination therapies against chronic hepatitis C virus (HCV) infection, although its direct antiviral properties are unclear. We therefore studied the immune-modulatory effects of ribavirin on hepatitis B virus (HBV)- and HCV-specific immune responses. During a 24 week placebo-controlled ribavirin trial in ten patients with chronic HCV infection, HCV antibodies and alanine aminotransferase (ALT) levels decreased transiently whereas the serum levels of HCV RNA remained stable. Effects of ribavirin on human and murine phytohaemagglutinin (PHA)-activated T cells included inhibition of in vitro proliferation and modulation of IL-2, IL-4, IFN-gamma and TNF-alpha levels. HBcAg- and HBeAg-specific IL-2 and IFN-gamma levels were > or = 25-fold higher in mice immunized with HBV core- or e- antigens (HBcAg, HBeAg) while receiving ribavirin compared to untreated mice, but IL-4 and IL-6 remained constant. Concordantly, a slight shift was observed in the IgG subclass distribution of the humoral responses of ribavirin-treated mice to HBeAg and HCV NS3 protein. Ribavirin treatment of HBeAg-transgenic (HBeAg-Tg) mice induced a dose-dependent down-regulation of T helper (Th)2-mediated antibody production to HBeAg. In ribavirin-treated HBeAg-Tg mice anti-HBe IgG1 (positively regulated by Th2 cytokines) decreased simultaneously as both anti-HBe IgG2a (positively regulated by Th1 cytokines) levels and in vitro T- cell IFN-gamma production increased, indicating a change in the Th1/Th2 balance. Thus, the present data suggest that ribavirin is not strictly an antiviral compound, but rather it alters the T-cell balance in the immune system.