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Journal of Virology, August 2000, p. 6741-6747, Vol. 74, No. 15
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Identification of a Gammaherpesvirus Selective Chemokine Binding Protein That Inhibits Chemokine Action

Victor van Berkel,1 John Barrett,2 H. Lee Tiffany,3 Daved H. Fremont,1 Philip M. Murphy,3 Grant McFadden,2 Samuel H. Speck,1,* and Herbert W. Virgin IV1,*

Center for Immunology and Departments of Pathology and Immunology and Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri1; Department of Microbiology and Immunology, University of Western Ontario, and the J. P. Robarts Research Institute, London, Ontario, Canada2; and Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland3

Received 17 December 1999/Accepted 24 April 2000

Chemokines are involved in recruitment and activation of hematopoietic cells at sites of infection and inflammation. The M3 gene of gamma HV68, a gamma-2 herpesvirus that infects and establishes a lifelong latent infection and chronic vasculitis in mice, encodes an abundant secreted protein during productive infection. The M3 gene is located in a region of the genome that is transcribed during latency. We report here that the M3 protein is a high-affinity broad-spectrum chemokine scavenger. The M3 protein bound the CC chemokines human regulated upon activation of normal T-cell expressed and secreted (RANTES), murine macrophage inflammatory protein 1alpha (MIP-1alpha ), and murine monocyte chemoattractant protein 1 (MCP-1), as well as the human CXC chemokine interleukin-8, the murine C chemokine lymphotactin, and the murine CX3C chemokine fractalkine with high affinity (Kd = 1.6 to 18.7 nM). M3 protein chemokine binding was selective, since the protein did not bind seven other CXC chemokines (Kd > 1 µM). Furthermore, the M3 protein abolished calcium signaling in response to murine MIP-1alpha and murine MCP-1 and not to murine KC or human stromal cell-derived factor 1 (SDF-1), consistent with the binding data. The M3 protein was also capable of blocking the function of human CC and CXC chemokines, indicating the potential for therapeutic applications. Since the M3 protein lacks homology to known chemokines, chemokine receptors, or chemokine binding proteins, these studies suggest a novel herpesvirus mechanism of immune evasion.

* Corresponding author. Mailing address for Dr. Virgin: Department of Pathology, Box 8118, 660 South Euclid Ave., St. Louis, MO 63110. Phone: (314) 362-9223. Fax: (314) 362-4096. E-mail: virgin{at}immunology.wustl.edu. Mailing address for Dr. Speck: Department of Pathology, Box 8118, 660 South Euclid Ave., St. Louis, MO 63110. Phone: (314) 362-0367. Fax: (314) 362-4096. E-mail: speck{at}pathbox.wustl.edu.

Journal of Virology, August 2000, p. 6741-6747, Vol. 74, No. 15
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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