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Attenuation of a vaccine strain of vaccinia virus via inactivation of interferon viroceptor
Author(s) -
Dénes Béla,
Gridley Daila S.,
Fodor Nadja,
Takátsy Zsuzsanna,
Timiryasova Tatyana M.,
Fodor István
Publication year - 2006
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.907
Subject(s) - vaccinia , virology , virus strain , strain (injury) , virus , modified vaccinia ankara , interferon , biology , microbiology and biotechnology , recombinant dna , genetics , gene , anatomy
Background Interferons (IFNs) play an important role in host antiviral responses, but viruses, including vaccinia viruses (VV), employ mechanisms to disrupt IFN activities, and these viral mechanisms are often associated with their virulence. Here, we explore an attenuation strategy with a vaccine strain of VV lacking a virus‐encoded IFN‐γ receptor homolog (viroceptor). Methods To facilitate the monitoring of virus properties, first we constructed a Lister vaccine strain derivative VV‐RG expressing optical reporters. Further, we constructed a VV‐RG derivative, VV‐RG8, which lacks the IFN‐γR viroceptor (B8R gene product). Replication, immunological and pathogenic properties of the constructed strains were compared. Results Viruses did not show significant differences in humoral and cellular immune responses of immune‐competent mice. Replication of constructed viruses was efficient both in vitro and in vivo , but showed marked difference in kinetics of propagation. In cultured CV‐1 epithelial cells, the VV‐RG8 strain retained the propagation potential of the parental virus, while, in the C6 glial cells, significant delay was observed in the kinetics of the VV‐RG8 replication cycle compared to VV‐RG. The pathogenesis of the viruses was tested by survival assay and biodistribution in nude mice. High dose inoculation of nude mice with VV‐RG8 caused less pronounced virus dissemination, improved weight gain, and increased survival rate, as compared with the VV‐RG strain. Conclusions The replication‐competent virus VV‐RG8 carrying a mutation at the B8R gene is less pathogenic for mice than the parental vaccine virus. We anticipate that step‐wise inactivation of VV vaccine genes involved in evasion of host immune response may provide an alternative approach for generation of hyper‐attenuated replication‐competent vaccines. Copyright © 2006 John Wiley & Sons, Ltd.