The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/9/855/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 5, September 7, 1998 855-866

Articles

Chemokine Sequestration by Viral Chemoreceptors as a Novel Viral Escape Strategy: Withdrawal of Chemokines from the Environment of Cytomegalovirus-infected Cells

Bahram Bodaghi*, Thomas R. Jones{ddagger}, Donato Zipeto*, Claudio Vita§, Lei Sun{ddagger}, Lysiane Laurent*, Fernando Arenzana-Seisdedos*, Jean-Louis Virelizier*, and Susan Michelson*

From the * Unite d'Immunologie Virale, Institut Pasteur, 75724 Paris, France; the {ddagger} Department of Molecular Biology, Infectious Disease Section, Wyeth-Ayerst Research, Pearl River, New York 10965; and the § Département d'Ingénierie et d'Etudes des Protéines, CEA Saclay, 91190 Gif-sur-Yvette, France

Human cytomegalovirus (HCMV), a betaherpesvirus, has developed several ways to evade the immune system, notably downregulation of cell surface expression of major histocompatibility complex class I heavy chains. Here we report that HCMV has devised another means to compromise immune surveillance mechanisms. Extracellular accumulation of both constitutively produced monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor–superinduced RANTES (regulated on activation, normal T cell expressed and secreted) was downregulated in HCMV-infected fibroblasts in the absence of transcriptional repression or the expression of polyadenylated RNA for the cellular chemokine receptors CCR-1, CCR-3, and CCR-5. Competitive binding experiments demonstrated that HCMV-infected cells bind RANTES, MCP-1, macrophage inflammatory protein (MIP)-1β, and MCP-3, but not MCP-2, to the same receptor as does MIP-1{alpha}, which is not expressed in uninfected cells. HCMV encodes three proteins with homology to CC chemokine receptors: US27, US28, and UL33. Cells infected with HCMV mutants deleted of US28, or both US27 and US28 genes, failed to downregulate extracellular accumulation of either RANTES or MCP-1. In contrast, cells infected with a mutant deleted of US27 continues to bind and downregulate those chemokines. Depletion of chemokines from the culture medium was at least partially due to continuous internalization of extracellular chemokine, since exogenously added, biotinylated RANTES accumulated in HCMV-infected cells. Thus, HCMV can modify the chemokine environment of infected cells through intense sequestering of CC chemokines, mediated principally by expression of the US28-encoded chemokine receptor.

Key Words: RANTES • human cytomegalovirus • chemokine receptors • sequestration • monocyte chemoattractant protein 1

Address correspondence to Susan Michelson, Unité d'Immunologie Virale, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cédex 15, France. Phone: 33-1-45-68-82-64; Fax: 33-1-45-68-89-41; E-mail: michelso @pasteur.fr

Abbreviations used: β-gluc, β-glucuronidase; Fmoc, fluorenylmethyloxycarbonyl; HCMV, human cytomegalovirus; HFF, human foreskin fibroblast; MIP, macrophage inflammatory protein; MCP, monocyte chemoattractant protein; pi, postinfection; RANTES, regulated on activation, normal T cell expressed and secreted; RANTES-B, biotinylated recombinant human RANTES; RT-PCR, reverse transcriptase PCR.


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