Ribavirin polarizes human T cell responses towards a Type 1 cytokine profile

Background/Aims: The therapeutic benefit of ribavirin, a nucleoside analog, in the treatment of chronic HCV infection is seen even in the absence of a ny apparent direct antiviral effect. We surmised that ribavirin may act by eliciting altered virus-specific immune responses. Because antiviral immuni ty is predominantly mediated by cytotoxic T cells and antiviral cytokines, we sought to determine whether ribavirin could promote antiviral (Type 1) c ytokine expression in human T cells. Methods: Isolated human T cells were activated in vitro with enterotoxin B or with phorbol ester plus ionomycin, Cytokine ELISAs were performed on cul ture supernatants, cytokine mRNA was detected following RT-polymerase chain reaction of T cell RNA, and T cell proliferation measured using MTT assay. Results: Ribavirin enhanced a Type 1 (IL-2, IFN gamma, TNF alpha) while sup pressing a Type 2 cytokine response (IL-4, IL-5 and IL-10), at the level of both protein and mRNA expression. Ribavirin mediated comparable effects on cytokine expression both following activation of specific T cell subpopula tions with superantigen and following activation of a larger percentage of T cells via pharmacologic means. The in vitro effect on cytokine expression following ribavirin treatment was comparable in both CD4(+) or CD8(+) T ce ll subsets and was observed in a dose range that promoted T cell proliferat ion. Conclusions: These data support the view that ribavirin promotes a Type 1 c ytokine-mediated immune response, a property which may account in part for its ability to enhance the antiviral activity of interferon-alpha in the tr eatment of chronic HCV infection.