HIV-1 infection through the CCR5 receptor is blocked by receptor dimerization

被引:127
作者
Vila-Coro, AJ [1 ]
Mellado, M [1 ]
de Ana, AM [1 ]
Lucas, P [1 ]
del Real, G [1 ]
Martinez, C [1 ]
Rodriguez-Frade, JM [1 ]
机构
[1] Univ Autonoma Madrid, Ctr Nacl Biotecnol, Dept Immunol & Oncol, E-28049 Madrid, Spain
关键词
AIDS; chemokine; chemokine receptor;
D O I
10.1073/pnas.050457797
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The identification of the chemokine receptors as receptors for HIV-1 has boosted interest in these molecules, raising expectations for the development of new strategies to prevent HIV-1 infection. The discovery that chemokines block HIV-1 replication has focused attention on identifying their mechanism of action. Previous studies concluded that this inhibitory effect may be mediated by steric hindrance or by receptor down-regulation. We have identified a CCR5 receptor-specific mAb that neither competes with the chemokine for binding nor triggers signaling, as measured by Ca2+ influx or chemotaxis. The antibody neither triggers receptor down-regulation nor interferes with the R5 JRFL viral strain gp120 binding to CCR5, but blocks HIV-1 replication in both in vitro assays using peripheral blood mononuclear cells as HIV-1 targets, as well as in vivo using human peripheral blood mononuclear cell-reconstituted SCID (severe combined immunodeficient) mice. Our evidence shows that the anti-CCR5 mAb efficiently prevents HIV-1 infection by inducing receptor dimerization. Chemokine receptor dimerization also is induced by chemokines and is required for their anti-HIV-1 activity. In addition to providing a molecular mechanism through which chemokines black HIV-1 infection, these results illustrate the prospects for developing new tools that possess HIV-1 suppressor activity, but lack the undesired inflammatory side effects of the chemokines.
引用
收藏
页码:3388 / 3393
页数:6
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