The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20071854
The Journal of Experimental Medicine, Vol. 205, No. 4, 981-992
The Rockefeller University Press, 0022-1007 $30.00
© Xu et al.
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ARTICLE

 The orthopoxvirus type I IFN binding protein is essential for virulence and an effective target for vaccination

Ren-Huan Xu1, Matthew Cohen1, Yong Tang2, Eric Lazear3, J. Charles Whitbeck3, Roselyn J. Eisenberg4, Gary H. Cohen3, and Luis J. Sigal1

1 Program of Viral Pathogenesis, Division of Basic Science and 2 Division of Medical Sciences, Fox Chase Cancer Center (FCCC), Philadelphia, PA 19111
3 Department of Microbiology, School of Dental Medicine and 4 Laboratories of Microbiology and Immunology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104

CORRESPONDENCE Luis J. Sigal: Luis.Sigal{at}fccc.edu

Nonliving antiviral vaccines traditionally target proteins expressed at the surface of the virion with the hope of inducing neutralizing antibodies. Orthopoxviruses (OPVs), such as the human smallpox virus and the mouse-equivalent ectromelia virus (ECTV; an agent of mousepox), encode immune response modifiers (IRMs) that can increase virulence by decreasing the host immune response. We show that one of these IRMs, the type I interferon (IFN) binding protein (bp) of ECTV, is essential for ECTV virulence and is a natural target of the antibody response. More strikingly, we demonstrate that immunization with recombinant type I IFN bp protects mice from lethal mousepox. Collectively, our experiments have important implications for our understanding of the role of IRMs in OPV virulence and of type I IFNs in OPV infections. Furthermore, our work provides proof of concept that effective antiviral vaccines can be made to prevent disease by targeting virulence factors as an alternative to the traditional approach that attempts to prevent infection by virus neutralization.

Abbreviations used: bp, binding protein; D-LN, draining lymph node; {Delta}166, ECTV with EVM166 deleted; ECTV, ectromelia virus; EGFP, enhanced GFP; EVM166, ECTV Moscow open reading frame no. 166; IRM, immune response modifier; MEF, mouse embryonic fibroblast; OPV, orthopoxvirus; PI, post infection; Rec, recombinant; Rev166, {Delta}166 revertant to WT; SPR, surface plasmon resonance; VACV, vaccinia virus; VARV, variola virus; VSV, vesicular stomatitis virus.

M. Cohen's present address is Division of Infectious Diseases, Dept. of Medicine, University of Pennsylvania, Philadelphia, PA 19104.


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