Chemokine sequestration by viral chemoreceptors as a novel viral escape strategy: withdrawal of chemokines from the environment of cytomegalovirus-infected cells.
Chemokine sequestration by viral chemoreceptors as a novel viral escape strategy: withdrawal of chemokines from the environment of cytomegalovirus-infected cells.
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DOI：
10.1084/jem.188.5.855
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发表时间：
1998-09-07
期刊：
影响因子：
--
通讯作者：
Michelson S
中科院分区：
文献类型：
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作者：
Bodaghi B;Jones TR;Zipeto D;Vita C;Sun L;Laurent L;Arenzana-Seisdedos F;Virelizier JL;Michelson S
人巨细胞病毒（HCMV）是一种β疱疹病毒，它已经开发出多种逃避免疫系统的方法，特别是下调主要组织相容性复合体I类重链的细胞表面表达。在这里，我们报告说，HCMV设计了另一种手段，以损害免疫监视机制。在没有转录抑制或细胞趋化因子受体CCR-1、CCR-3和CCR-5的多聚腺苷酸化RNA表达的情况下，HCMV感染的成纤维细胞中组成性产生的单核细胞趋化蛋白（MCP）-1和肿瘤坏死因子超诱导的RANTES（受激活调节，正常T细胞表达和分泌）的细胞外积累下调。竞争性结合实验表明，HCMV感染的细胞与RANTES、MCP-1、巨噬细胞炎性蛋白（MIP）-1β和MCP-3结合，但与未感染细胞中不表达的MIP-1α结合的受体相同，而与MCP-2结合的受体不同。HCMV编码与CC趋化因子受体具有同源性的三种蛋白：US 27、US 28和UL 33。用缺失US 28或US 27和US 28基因的HCMV突变体感染的细胞不能下调RANTES或MCP-1的细胞外积累。相比之下，用缺失US 27的突变体感染的细胞继续结合并下调这些趋化因子。趋化因子从培养基中的消耗至少部分是由于细胞外趋化因子的持续内化，因为外源性添加的生物素化的RANTES在HCMV感染的细胞中积累。因此，HCMV可以通过CC趋化因子的强烈隔离来改变感染细胞的趋化因子环境，主要由US 28编码的趋化因子受体的表达介导。
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-1α, 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.