Analysis of an orf virus chemokine-binding protein: Shifting ligand specificities among a family of poxvirus viroceptors

Abstract

We identify a secreted chemokine inhibitor encoded by orf virus (ORFV), the prototypic poxvirus of the Parapoxvirus genus, and show that it is related to the poxvirus type II CC-chemokine-binding proteins (CBP-II) produced by members of the Orthopoxvirus and Leporipoxvirus genera. The ORFV chemokine-binding protein (CBP) is functionally similar to the CBP-II proteins in its ability to bind and inhibit many CC-chemokines with high affinity. However, unlike CBP-II, the ORFV CBP also binds with high affinity to lymphotactin, a member of the C-chemokine family, demonstrating that the ORFV CBP possesses an altered binding specificity. Interestingly, the amino acid sequence of ORFV CBP more closely resembles the granulocytemacrophage colony-stimulating factor͞IL-2 inhibitory factor also produced by ORFV, implicating the granulocyte-macrophage colonystimulating factor͞IL-2 inhibitory factor protein as a highly diverged, but related, member of the CBP-II protein family. Notably, these findings suggest that the genes that encode these proteins derive from a common poxvirus ancestral gene that has since been modified in binding specificity during speciation of the poxvirus genera. Overall, these findings illustrate the concept of evolution of viral proteins at the biophysical and molecular interface.

Effect of a Broad-Specificity Chemokine-Binding Protein on Brain Leukocyte Infiltration and Infarct Development

“…11 Many viruses secrete proteins that bind chemokines as a means of evading the host immune system and ensuring their own survival. 12 Recently, a novel type of chemokine-binding protein (CBP) has been identified from orf virus, [13][14][15] and fellow parapoxviruses, bovine papular stomatitis virus (BPSV), and pseudocowpox virus. 16,17 This CBP shows high-affinity binding for both human and mouse CC, CXC, and C chemokines and has been demonstrated to prevent inflammatory monocyte recruitment to the skin and to block dendritic cell trafficking to peripheral lymph nodes.…”

Conservation and variation of the parapoxvirus GM-CSF-inhibitory factor (GIF) proteins

“…This relationship is primarily due to sequence similarity found between the GIF protein and a chemokine-binding protein also encoded by the PPVs (ORF 112). This protein has been shown to be related to the vaccinia virus (VACV) chemokine-binding protein C23L and to possess both Cand CC-chemokine-binding activity (Seet et al, 2003). As we did not find any GM-CSF-or IL-2-binding activity with the BPSV GIF protein, we investigated whether the GIF proteins exhibited CC chemokine-binding activity.…”

“…It had previously been suggested that the ORFV GIF protein showed significant similarity to a family of poxvirus chemokine-binding proteins; more specifically, those found in members of the genera Orthopoxvirus and Leporipoxvirus that bound a variety of CC chemokines (Seet et al, 2003). In addition, significant similarity was also found between it and another ORFV protein, encoded by a gene found upstream of the GIF gene in the ORFV genome.…”

“…All three viruses can infect humans. As is common amongst other poxviruses, ORFV has been shown to encode factors that either mimic host immunoregulatory proteins (Fleming et al, 1997;Haig & Fleming, 1999;Seet et al, 2003) or have the potential for interacting with components of the host immune system (Haig et al, 1998;McInnes et al, 1998McInnes et al, , 2005Deane et al, 2000). In doing so, it is thought that these virus-encoded factors are capable of subverting the host immune response to infection, creating an environment suitable for efficient virus replication.…”

Past and Present Overview of “Orf”

“…The OVIFNR gene has interferon resistance function which frankly signifies the crucial role of interferon in host resistance to Orf virus infected animals (Haig and Mercer, 1998). The Orf virus synthesizes virus encoded cytokine binding protein (vCBP) discovered by Counago et al, (2010), that competitively inhibits binding site on the receptors of homogenous cytokines (Seet et al, 2003) and inhibits inflammation by preventing monocytes and DCs from transferring into the skin inflammatory lesions or peripheral lymph nodes. The ORFV121 encodes a novel NF-κB inhibitor thus inhibits the phosphorylation and nuclear translocation of NF-kB-p65 thereby culminating the translation of the host immune-related genes.…”