Poxvirus Genomes Encode a Secreted, Soluble Protein That Preferentially Inhibits β 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 all known beta chemokines, but only weak or no affinity to the alpha and gamma 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 beta chemokines are also shown to cross-compete with MCP1 binding to the viral protein, we conclude that this viral chemokine inhibitor (vCCI) not only interacts through a common binding site, but is likely a potent general inhibitor of beta 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 (vCCI) shares no sequence homology with known proteins, including known cellular chemokine receptors, all of which are multiple membrane-spanning proteins. Thus, vCCI 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 vCCI is inhibition of the proinflammatory (antiviral) activities of beta chemokines.

Human cytomegalovirus encodes a highly specific RANTES decoy receptor

“…Consequently, chemokines play a pivotal role in the resolution of virus infections, and, not surprisingly, several viruses have developed strategies to antagonize the antiviral activities of chemokines (4). For example, the myxoma virus M-T1 protein (5), the vaccinia virus p35 (6,7), and the murine gamma herpesvirus 68 M3 protein (8,9) mimic the ligandbinding domains of chemokine receptors. Each of these proteins binds multiple chemokines with high affinity, blocking their ability to interact with cellular receptors.…”

Eotaxin Is Specifically Cleaved by Hookworm Metalloproteases Preventing Its Action In Vitro and In Vivo

“…Further insight into the regulation of chemokines has come from the study of pathogens, in which a number of strategies have evolved to down-regulate chemokine functions as a means of inhibiting the recruitment of immune effector cells to the site of infection (4). For example, poxvirus genomes encode a secreted, 35-kDa chemokine-binding protein that can bind to and inhibit the actions of a variety of C-C chemokines (5,6). The CMV genome encodes a promiscuous chemokine receptor whose expression may act as a sink for soluble chemokine, thus down-regulating leukocyte recruitment at the site of viral proliferation (7,8).…”

Local Blockade of Allergic Airway Hyperreactivity and Inflammation by the Poxvirus-Derived Pan-CC-Chemokine Inhibitor vCCI

“…The entire coding region of the 32-kDa vCCI protein from the cowpoxvirus genome was fused to a segment encoding the Fc region of human IgG1, expressed and purified as previously reported (19).…”

“…It is the only CC-chemokine inhibitor known to bind specifically and generically to CC-chemokines (human and rodent) with high affinity and to completely inhibit their biological activity; the mechanism is one of competitive inhibition of CC-chemokine receptors (19). The dissociation constant of vCCI is in the subnanomolar range for all 15 different CC-chemokines that have been tested, and the affinity of CC-chemokines for vCCI is often higher than that for their native CCRs (19), arguing for an unusually effective inhibition.…”

“…It is the only CC-chemokine inhibitor known to bind specifically and generically to CC-chemokines (human and rodent) with high affinity and to completely inhibit their biological activity; the mechanism is one of competitive inhibition of CC-chemokine receptors (19). The dissociation constant of vCCI is in the subnanomolar range for all 15 different CC-chemokines that have been tested, and the affinity of CC-chemokines for vCCI is often higher than that for their native CCRs (19), arguing for an unusually effective inhibition. Although vCCI has no apparent amino acid or structural homology to known mammalian or other eukaryotic proteins, including CCRs (20), its broad high-affinity CC-chemokine binding suggested that it might be particularly useful dissecting the biological role of CC-chemokines in inflammatory diseases and as a clinical anti-inflammatory agent.…”