title: MHV-68 producing mIFNα1 is severely attenuated in vivo and effectively protects mice against challenge with wt MHV-68.
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.
authors.affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy. eleonora.arico@iss.it
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aricò
authors.forename: Domenica M
authors.initials: DM
authors.lastname: Monque
authors.forename: Giuseppina
authors.initials: G
authors.lastname: D'Agostino
authors.forename: Federica
authors.initials: F
authors.lastname: Moschella
authors.forename: Massimo
authors.initials: M
authors.lastname: Venditti
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Allen
authors.forename: James P
authors.initials: JP
authors.lastname: Stewart
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Nash
authors.forename: Filippo
authors.initials: F
authors.lastname: Belardelli
authors.forename: Maria
authors.initials: M
authors.lastname: Ferrantini
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D006566:Herpesviridae Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D030781:Organisms, Genetically Modified / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011995:Recombination, Genetic; D018144:Rhadinovirus / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D013154:Spleen; D014412:Tumor Virus Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D014613:Vaccines, Attenuated / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000276:immunology; D014779:Virus Replication
chemical_list: D016898:Interferon-alpha; D014613:Vaccines, Attenuated; D015164:Vaccines, Inactivated