The orf virus OV20.0L gene product is involved in interferon resistance and inhibits an interferon‐inducible, double‐stranded RNA‐dependent kinase

Abstract

The parapoxvirus orf virus was resistant to type 1 (IFN-alpha) and type 2 (IFN-gamma) interferons in cultures of ovine cells. The recently identified orf virus OV20.0L gene exhibits 31% predicted amino acid identity to the vaccinia virus E3L interferon-resistance gene, and is referred to as the (putative) orf virus interferon-resistance gene (OVIFNR). The objective of this study was to determine whether OVIFNR was involved in interferon resistance. Recombinant OVIFNR as a thioredoxin fusion protein (OVIFNR-Tx) inhibited the activation (by autophosphorylation) of an interferon-inducible, double-stranded (ds) RNA-dependent kinase (PKR) of sheep, which was shown to bind dsRNA (poly I:C). PKR in other species is involved in the inhibition of protein synthesis as part of the antiviral state in infected cells. Virus-infected cell lysates, but not control lysates, from cells grown in the presence of cytosine arabinoside also contained PKR inhibitory activity, which indicated that the inhibitory activity was associated with early viral gene expression. Significantly, the OVIFNR gene expressed in interferon-treated ovine fibroblasts protected the unrelated Semliki Forest virus from the antiviral effect of both type 1 and type 2 interferons. Taken together, the results indicate that the OVIFNR gene functions as an interferon-resistance gene, the product of which inhibits PKR in a similar way to the vaccinia virus E3L gene product.

Genomes of the Parapoxviruses Orf Virus and Bovine Papular Stomatitis Virus

“…The E3L gene product provides IFN resistance to VACV-infected cells and broad host range to virus infection in tissue culture and is a virulence determinant (4,9). The ORFV NZ2 strain E3L homologue is also involved in IFN resistance (31) and is 93% and 53% identical to its OV-SA00 and BPSV counterparts, respectively. ORFV and BPSV 020 are most similar at the carboxy-terminal half of the protein, which is predicted to bind dsRNA through a conserved binding motif (10).…”

Immunomodulatory Effects of Inactivated Parapoxvirus Ovis (Orf Virus) on Human Peripheral Immune Cells: Induction of Cytokine Secretion in Monocytes and Th1-Like Cells

“…To evade the host immune defense, poxviruses utilize a variety of immunomodulatory cellular proteins, which enable them to replicate in spite of an active immune response (1,16,17,28). Such proteins have been described for PPVO; these include a viral interleukin 10 (IL-10) homologue (11, 12), a granulocyte-macrophage colony-stimulating factor, an IL-2-inhibiting protein (8), and the product of a gene with homology to the vaccinia virus E3L gene, which counteracts interferon-induced cell resistance (18,19,21,30).The immunostimulating and modulating capacities made PPVO an interesting candidate for new antiviral strategies (36). The immunomodulatory properties of the virus could be used by means of a noninfectious preparation of inactivated PPVO to influence the clinical course of other viral infections.…”

Orf Virus Encodes a Novel Secreted Protein Inhibitor of Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-2

“…For example, the orthopoxviruses vaccinia virus and cowpox virus encode soluble receptor proteins that bind to and inactivate the host cytokines interleukin-1␤ (IL-1␤), tumor necrosis factor alpha (TNF-␣), and interferons (IFNs) as well as complement components (1,2,8,31,50,58,62). Viral proteins that do not bind directly to IFNs but instead interfere with downstream signalling molecules following ligand-receptor coupling also inhibit the antiviral activity of interferons (10,27,44). By studying these viral immunomodulator proteins, insight into the mechanisms of not only virus virulence but also host protective immunity to virus infection is gained.…”