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Differential Effects of the Type I Interferons ₄, β, and on Antiviral Activity and Vaccine Efficacy¹

Stephanie L. Day^2,*, Ian A. Ramshaw^*, Alistair J. Ramsay and Charani Ranasinghe^*

^* Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia; and Gene Therapy Program, Clinical Sciences Building, Louisiana State University Health Sciences Center, New Orleans, LA 70112

The type I IFNs exert a range of activities that include antiviral, antiproliferative, and immunomodulatory effects. To study this further, we have constructed recombinant vaccinia viruses expressing HIV or hemagglutinin (HA) Ags along with murine type I IFNs, IFN-₄ (HA-VV-IFN-₄), IFN-β (HA-VV-IFN-β), or IFN- (HIV-VV-IFN-), a recently discovered member of this family. Our aims were to characterize IFN- functionality as a type I IFN and also to study the biological properties of these factors toward the development of safer and more effective vector-based vaccines. HIV-VV-IFN- and HA-VV-IFN-β grew to lower titers than did their parental controls in murine cell lines. In vivo, however, HIV-VV-IFN- growth was not attenuated, while IFN-β demonstrated potent local antiviral activity with no replication of HA-VV-IFN-β detected. Flow cytofluorometric analysis of B lymphocytes incubated with virally encoded IFN- showed up-regulation of activation markers CD69 and CD86, while RT-PCR of IFN--treated cells revealed that gene expression levels of antiviral proteins were elevated, indicating the induction of an antiviral state. The use of these constructs in a poxvirus prime-boost immunization regime led to robust humoral and cellular immune responses against the encoded Ags, despite the lack of replication in the case of HA-VV-IFN-β. Thus, coexpression of these factors may be beneficial in the design of safer vector-based vaccines. Our data also indicate that while IFN- exhibits certain biological traits similar to other type I IFNs, it may also have a specific role in mucosal immune regulation that is quite distinct.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded by National Health and Medical Research Council Program Grant 299907.

² Address correspondence and reprint requests to Dr. Stephanie Day, Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia. E-mail address: stephanie.day{at}anu.edu.au

³ Abbreviations used in this paper: VV, vaccinia virus; ECTV, ectromelia virus; FPV, fowlpox virus; HA, hemagglutinin; MOI, multiplicity of infection; 2'5'OAS, 2'5'oligoadenylate synthetase; PI, postinfection; PKR, protein kinase R; SFU, spot forming units; WR, Western reserve.