Monocyte chemotactic protein-2 activates CCR5 and blocks CD4/CCR5-mediated HIV-1 entry/replication
Monocyte chemotactic protein-2 activates CCR5 and blocks CD4/CCR5-mediated HIV-1 entry/replication
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DOI：
10.1074/jbc.273.8.4289
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发表时间：
1998-02-20
影响因子：
4.8
通讯作者：
Wang, JM
中科院分区：
文献类型：
--
作者：
Gong, WH;Howard, OMZ;Wang, JM
人类免疫缺陷病毒I型(HIV-1)细胞类型的趋向性由趋化因子受体的使用决定：T细胞系嗜性病毒使用CXCR4，而嗜单核细胞病毒主要使用CCR5作为融合辅助受体。CC趋化因子巨噬细胞炎性蛋白-1α(MIP-1α)、巨噬细胞炎性蛋白-1β(MIP-1β)和RANTES(受激活调节的正常T细胞表达和分泌)抑制CD4/CCR5介导的HIV-1细胞融合，MCP-2也是CC趋化因子亚家族的成员，具有与CCR-1和CCR2B等至少两种受体相互作用的能力。为了进一步研究MCP-2与白细胞的结合特性，我们观察到MCP-2而不是MCP-1有效地与MIP-1β竞争与单核细胞的结合，提示MCP-2可能与CCR5相互作用，正如预测的那样，MCP-2竞争抑制MIP-1β与稳定转染CCR5的HEK293细胞(CCR5/293细胞)的结合。MCP-2还与CCR5/293细胞结合并诱导其趋化，其效力与MIP-1β相当。共聚焦显微镜显示，MCP-2可引起CCR5/293细胞CCR5显著内化，且呈剂量依赖关系。此外，MCP-2还能抑制HIV-1ADA在共表达CD4的CCR5/293细胞中的进入/复制。这些结果表明，MCP-2以CCR5作为其功能受体之一，是HIV-1的另一种有效的天然抑制剂。
Human immunodeficiency virus, type I (HIV-1) cell-type tropism is dictated by chemokine receptor usage: T-cell line tropic viruses use CXCR4, whereas monocyte tropic viruses primarily use CCR5 as fusion coreceptors. CC chemokines macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, and RANTES (regulated on activation normal T cell expressed and secreted) inhibit CD4/CCR5-mediated HIV-1 cell fusion, MCP-2 is also a member of the CC chemokine subfamily and has the capacity to interact with at least two receptors including CCR-1 and CCR2B. In an effort to further characterize the binding properties of MCP-2 on leukocytes, we observed that MCP-2, but not MCP-1, effectively competed with MIP-1 beta for binding to monocytes, suggesting that MCP-2 may interact with CCR5, As predicted, MCP-2 competitively inhibited MIP-1 beta binding to HEK293 cells stably transfected with CCR5 (CCR5/293 cells). MCP-2 also bound to and induced chemotaxis of CCR5/293 cells with a potency comparable with that of MIP-1 beta. Confocal microscopy indicates that MCP-2 caused remarkable and dose-dependent internalization of CCR5 in CCR5/ 293 cells. Furthermore, MCP-2 inhibited the entry/replication of HIV-1ADA in CCR5/293 cells coexpressing CD4. These results indicated that MCP-2 uses CCR5 as one of its functional receptors and is an additional potent natural inhibitor of HIV-1.