Poxvirus genomes encode a secreted, soluble protein that preferentially inhibits P chemokine activity yet lacks sequence homology to known chemokine receptors

Abstract

Poxvirus genomes encode several proteins which inhibit specific elements of the host immune response. We show the '35K' virulence gene in variola and cowpox viruses, whose vaccinia and Shope fibroma virus equivalents are strongly conserved in sequence, actually encodes a secreted soluble protein with high-affinity binding to virtually ail known β chemokines, but only weak or no affinity to the (α and γ classes. The viral protein completely inhibits the biological activity of monocyte chemotactic protein-1 (MCP-1) by competitive inhibition of chemokine binding to cellular receptors. As all β chemokines are also shown to cross-compete with MCP1 binding to the viral protein, we conclude that this viral chemokine inhibitor (vCCl) not only interacts through a common binding site, but is likely a potent general inhibitor of β chemokine activity. Unlike many poxvirus virulence genes to date, which are clearly altered forms of acquired cellular genes of the vertebrate immune system, this viral chemokine inhibitor (vCCl) shares no sequence homology with known proteins, including known cellular chemokine receptors, all of which are multiple membrane-spanning proteins. Thus, vCCl presumably has no cellular analogue and instead may be the product of unrelenting sequence variations which gave rise to a completely new protein with similar binding properties to native chemokine receptors. The proposed function of VCCl is inhibition of the proinflammatory (antiviral) activities of β chemokines.