The Poxvirus 35-kDa Protein

The 35-kDa protein or viral CC chemokine inhibitory protein (vCCI) is a secreted protein found in vaccinia virus (VACV) and other poxviruses that binds with high affinity almost all human and mouse CC chemokines [15-17]. The mechanism of action of the 35-kDa protein is competitive inhibition of CC chemokine binding to cellular receptors. The ortholog of myxoma virus (MYXV), named M-Tl, has the unique ability to interact with GAGs via a domain at its C-terminus that is not present in other 35-kDa family members [18]. This unique property of M-Tl would retain the protein in the vicinity of infected cells and may enhance its ability to protect the sites of infection from chemokine-mediated antiviral responses in vivo. Orf virus, a parapoxvirus that causes infections in sheep and cattle, and sporadically in humans, encodes a 35-kDa protein related vCKBP but with a broader chemokine binding specificity that includes the C chemokine lymphotactin [19]. 

The experimental evidence in mouse and rabbit models of infection indicates that the 35-kDa protein encoded by VACV, rabbitpox vims and MYXV inhibit the chemokine-mediated infiltration of immune cells into primary sites of infection but have little influence on the progression of disease [17,20,21]. The expression of the 35-kDa protein from VACV Western Reserve (WR), a strain that does not encode the vCKBP, causes a slight attenuation of the vims associated with reduced inflammatory pathology in the lungs [22]. 

The first illustration of the potential of 35-kDa protein as a therapeutic inhibitor of inflammatory disease in vivo was produced using a guinea pig skin inflammation model. Purified recombinant vCKBP completely inhibited local eosinophil infiltration induced by eotaxin, a feature of allergic inflammatory reactions [16]. Similarly, the related vCKBP from orf vims has been recently shown to inhibit migration of monocytes in a mouse acute skin inflammation model induced by LPS [23]. 

Intranasal administration of purified 35-kDa protein significantly reduced inflammation of the airway and lung parenchyma and improved the physiological function of the lungs during airway hyperreactivity in a mouse model of allergen-induced asthma without compromising systemic immunity or chemoattraction at extrapul-monary sites [24]. 

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Figure 16.1 Mechanisms of chemokine inhibition by the CKBPs encoded by pathogens. Chemokines interact with CACs present at the surface ofendothelial cells and are presented to the leukocytes. The chemokine receptors expressed at the surface of leukocytes interact with chemokines and intracellular signaling is triggered to induce cell migration. The CKBPs may have broad chemokine binding specificity, such as the poxvirus 35-kDa protein, the gammaherpesvirus M3 protein orthe MYXVM-...

The second class of CBPs are encoded by many but not all poxviruses, and are collectively called the Tl/35 kDa proteins (9,12). These proteins share sequence homology with each other (39-99%), however, they are structurally unlike any other known proteins. Shared structural features include eight cysteine residues (presumably allowing formation of four disulfide bonds) one potential N-linked glycosylation site and a strongly acidic nature. 

Graham KA, Lalani AS, Macen JL er aL The Tl/35 kDa family of poxvirus-secreted proteins bind chemokines and modulate leukocyte influx into virus-infected tissues. Virology 1997 229(l) 12-24. 

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