MHV-68 producing mIFNα1 is severely attenuated in vivo and effectively protects mice against challenge with wt MHV-68

Eleonora Aricò, Domenica M Monque, Giuseppina D'Agostino, Federica Moschella, Massimo Venditti, Ulrich Kalinke, Deborah J Allen, Anthony A Nash, Filippo Belardelli, Maria 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-α (IFN-α) on both the lytic and latent phase of MHV-68 infection, as exerted by the constitutive release of IFN-α1 by a clone of MHV-68 genetically modified to produce this cytokine (MHV-68mIFNα1). Although the MHV-68mIFNα1 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-68mIFNα1 attenuation did not result in a reduced level of long-term spleen latency establishment. These results prompted us to evaluate the efficacy of MHV-68mIFNα1 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-68mIFNα1, 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-68mIFNα1 to produce IFN-α 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.
Original languageEnglish
Pages (from-to)3935-44
Number of pages10
JournalVaccine
Volume29
Issue number23
DOIs
Publication statusPublished - 23 May 2011

Keywords

  • Animals
  • Cell Line
  • Female
  • Herpesviridae Infections
  • Humans
  • Interferon-alpha
  • Mice
  • Mice, Inbred C57BL
  • Organisms, Genetically Modified
  • Recombination, Genetic
  • Rhadinovirus
  • Spleen
  • Tumor Virus Infections
  • Vaccines, Attenuated
  • Vaccines, Inactivated
  • Virus Replication

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