Human Cytomegalovirus Inhibits Transcription of the CC Chemokine MCP-1 Gene

Human cytomegalovirus (HCMV) is a ubiquitous human pathogen. HCMV infection is associated with several clinical manifestations, including CMV mononucleosis, birth defects when infection occurs in pregnant women, and a variety of clinical syndromes in immunocompromised and immunosuppressed individuals (for a review, see reference 6). HCMV has been shown to exert a variety of effects on the gene expression of the infected host cell, including the induction of cellular transcription factors by viral attachment to the cell surface (37), modulation of the cell cycle with characteristic changes in gene expression (5, 9, 18), and direct effects on host cell promoters by viral gene products (16, 19). Some of the genes that have been shown to be induced by HCMV are likely to be involved in the host response to viral infection. These include several members of the cytokine family and several members of a subclass of cytokines, the chemokines. The chemokines are a group of cytokines that exhibit chemotactic activity for a variety of leukocytes (for reviews, see references 2 and 28). They are divided into four classes, CXC, CC, C, and CX3C, based on the arrangement of conserved cysteine residues near the N terminus of the protein. Chemokines are expressed by a variety of cell types, including monocytes, lymphocytes, epithelial cells, and fibroblasts. Expression of the chemokines has been shown to be induced by a variety of stimuli, including other cytokines, bacterial endotoxins, and viral infection. Because of their chemoattractant activity for leukocytes, it is believed that the chemokines are mediators of the inflammatory process and therefore play an important role in the resolution of viral infection. Consistent with this view, a mouse with a homozygous deletion of the gene for the CC chemokine MIP-1α has been shown to exhibit a dramatically reduced inflammatory response to coxsackievirus and influenza virus and to experience delayed viral clearance (8). Additionally, these mice show reduced natural killer (NK) cell-mediated inflammation in the liver during murine CMV infection (29). Several lines of evidence suggest that chemokines may play a role in HCMV infection. HCMV has been shown to induce the expression of the CXC chemokine interleukin-8 (IL-8) and the CC chemokine RANTES (10, 22, 23). In addition, elevated levels of the CC chemokine MCP-1 have been detected in the cerebrospinal fluid of human immunodeficiency virus-infected patients with CMV encephalitis (4). MCP-1 has been demonstrated to be induced by tumor necrosis factor alpha (TNF-α) and IL-1β, cytokines that have been shown to be stimulated by HCMV (10, 27, 32). Furthermore, the HCMV open reading frame (ORF) US28 encodes a putative seven-transmembrane-domain G-protein-coupled receptor that has been shown to be a functional receptor for MCP-1, RANTES, MIP-1α, and MIP-1β (12, 15, 24). In this report, we examine the effect of HCMV on the expression of the CC chemokine MCP-1. We have found that an unpurified stock of HCMV strongly induces MCP-1 mRNA and protein expression. This induction is not a direct effect of the virus but appears to be due to a factor that is secreted into the cell culture medium by HCMV-infected cells. Additionally, HCMV acts to inhibit MCP-1 expression at the level of transcription during infection. This transcriptional repression occurs at early times postinfection (p.i.) and requires viral gene expression.