Enhancement by muramyl peptides of the protective response of interferon-α/β against encephalomyocarditis virus infection

Abstract

The use of interferon-α (IFN-α) in the treatment of infectious diseases has shown limited efficacy and dose-limiting toxicity. We have selected safe immunomodulators of the muramyl peptide family with the potential of enhancing the efficacy of IFN-α without resulting in increased toxicity. One of these synthetic muramyl dipeptide (MDP) derivatives, namely murabutide which is in a clinical stage of development, has been recently found to synergize with IFN-α2a in the selective induction of anti-inflammatory mediators and to enhance the biological activities of the therapeutic cytokine. The present study was performed to assess the antiviral activity of such muramyl peptides and a possible potentiation of the antiviral activity of IFN-α/β by associated therapy using the classical assay of Encephalomyocarditis virus (EMCV) infection. In vitro, pretreatment of Moloney Sarcoma virus (MSV)-transformed cell line with MDP derivatives followed by treatment with IFN-α/β showed a synergistic protection against the cytopathogenic effect of a subsequent EMCV infection. None of the MSV cultures could be protected by stimulation with muramyl peptides alone. In vivo, all of the muramyl peptide derivatives tested were found to be more potent than the parent molecule MDP in inducing protection against death or in the prolongation of the mean survival time of infected mice. Sequential administration of suboptimal doses of exogenous IFN-α/β and muramyl peptides established a strong antiviral state and considerably improved the protective effect of the cytokine, frequently leading to an abortive infection. Our findings suggest that combination therapy with safe muramyl peptides and IFN-α/β could constitute a highly effective and new regimen for the treatment of viral infections in humans.