MHV-68 producing mIFN alpha 1 is severely attenuated in vivo and effectively protects mice against challenge with wt MHV-68

E. Arico, D.M. Monque, G. D'Agostino, F. Moschella, M. Venditti, U. Kalinke, D.J. Allen, A.A. Nash, F. Belardelli, M. Ferrantini

Research output: Contribution to journalArticlepeer-review

Abstract

Human gammaherpesviruses such as Epstein-Barr virus (EBV) cause lifelong infections and associated diseases, by virtue of their ability to establish latent infection. Many studies performed in the past years in murine herpesvirus 68 (MHV-68) model of infection suggested that the limited immunity generated against isolated viral components by subunit vaccines cannot counteract the multiple immune evasion strategies operated by gammaherpesviruses. Indeed, a significant inhibition of long-term latency establishment could be observed in mice vaccinated with strains of genetically modified MHV-68 defective in reactivation or establishment of latency. In this study, we focused on the effects of interferon-alpha (IFN-alpha) on both the lytic and latent phase of MHV-68 infection, as exerted by the constitutive release of IFN-alpha 1 by a clone of MHV-68 genetically modified to produce this cytokine (MHV-68mIFN alpha 1). Although the MHV-68mIFN alpha 1 recombinant virus exhibited in vitro replication features indistinguishable from those of the wild type MHV-68, its pathological properties were severely attenuated in vivo in immunocompetent mice and not in mice rendered genetically unresponsive to type I IFN, suggesting that a stronger immune response was primed in the presence of the cytokine. Notably, MHV-68mIFN alpha 1 attenuation did not result in a reduced level of long-term spleen latency establishment. These results prompted us to evaluate the efficacy of MHV-68mIFN alpha 1 in a prophylactic vaccination regimen aimed at inhibiting the symptoms of acute virus infection and the establishment of long-term latency after MHV-68 challenge. Our results show that mice vaccinated with MHV-68mIFN alpha 1, administered as a live-attenuated or partially inactivated (by Psoralen and UV treatment) vaccine, were protected against the challenge with wt MHV-68 from all phases of infection. The ability of MHV-68mIFN alpha 1 to produce IFN-alpha at the site of the infection, thus efficiently stimulating the immune system in case of virus reactivation from latency, makes this recombinant virus a safer live-attenuated vaccine as compared to the previously reported latency-deficient clones. (C) 2011 Elsevier Ltd. All rights reserved.
Original languageUndefined/Unknown
Pages (from-to)3935-3944
Number of pages10
JournalVaccine
Volume29
Issue number23
DOIs
Publication statusPublished - 2011

Keywords / Materials (for Non-textual outputs)

  • Gammaherpesviruses Type I IFN Genetically modified viruses Vaccine murine gammaherpesvirus 68 epstein-barr-virus immune-response gene-expression t-cells infection latency interferon vaccination replication

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