Identification of an unique CXCR4 epitope whose ligation inhibits infection by both CXCR4 and CCR5 tropic human immunodeficiency type-I viruses.
Identification of an unique CXCR4 epitope whose ligation inhibits infection by both CXCR4 and CCR5 tropic human immunodeficiency type-I viruses.
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DOI：
10.1186/1742-4690-8-84
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发表时间：
2011-10-22
期刊：
影响因子：
3.3
通讯作者：
Tanaka Y
中科院分区：
文献类型：
--
作者：
Adachi T;Tanaka R;Kodama A;Saito M;Takahashi Y;Ansari AA;Tanaka Y
针对 1 型人类免疫缺陷病毒 (HIV-1) 的趋化因子受体小化合物已被开发出来，并且正在研究用作抗 HIV-1 杀菌剂。此外，针对趋化因子受体的单克隆抗体 (mAb) 也被证明具有抗 HIV-1 活性。本研究的目的是利用体外激活的原代外周血单核细胞 (PBMC) 筛选一组三种抗 CXCR4 特异性单克隆抗体 (mAb) 阻断 HIV-1 感染的能力。使用抗 CD3 和抗 CD28 mAb 将来自正常供体的 PBMC 预激活 1 天，并用低剂量的 CCR5 向性 (R5)、CXCR4 向性 (X4) 或双向性 (X4R5) HIV-1 分离株感染等分试样，并在一组抗 CXCR4 mAb 存在的情况下培养。该小组包括针对 N 末端的克隆 A145 mAb、针对由细胞外环 (ECL)1 和 ECL2 组成的构象表位的 A120 mAb 以及针对 CXCR4 的 ECL3 的 A80 mAb。在这些 mAb 中，A120 mAb 显示出最有效的感染抑制作用，不仅通过 X4，而且令人惊讶地还通过 R5 和 X4R5 HIV-1。据推测，R5 HIV-1 的抑制作用是由于 A120 mAb 具有诱导 CCR5 结合 β 趋化因子 MIP-1α、MIP-1β 和/或 RANTES 水平的新能力，以及下调活化 CD4+ T 细胞上 CCR5 表达的能力。中和抗 MIP-1α mAb 显着逆转 A120 mAb 对 R5 HIV-1 感染的抑制作用。本文描述的数据已经鉴定了CXCR4的独特表位，其连接不仅直接抑制X4 HIV-1，而且还通过诱导更高水平的天然CCR5配体间接抑制R5 HIV-1感染。
Small chemical compounds which target chemokine receptors have been developed against human immunodeficiency virus type 1 (HIV-1) and are under investigation for use as anti-HIV-1 microbicides. In addition, monoclonal antibodies (mAbs) against chemokine receptors have also been shown to have anti-HIV-1 activities. The objective of the present study was to screen a panel of three anti-CXCR4 specific monoclonal antibodies (mAbs) for their ability to block the HIV-1 infection using in vitro activated primary peripheral blood mononuclear cells (PBMCs). PBMCs from normal donors were pre-activated with anti-CD3 and anti-CD28 mAbs for 1 day, and aliquots were infected with a low dose of CCR5-tropic (R5), CXCR4 tropic (X4) or dual tropic (X4R5) HIV-1 isolates and cultured in the presence of a panel of anti-CXCR4 mAbs. The panel included clones A145 mAb against the N-terminus, A120 mAb against a conformational epitope consisting of extracellular loops (ECL)1 and ECL2, and A80 mAb against ECL3 of CXCR4. Among these mAbs, the A120 mAb showed the most potent inhibition of infection, by not only X4 but surprisingly also R5 and X4R5 HIV-1. The inhibition of R5 HIV-1 was postulated to result from the novel ability of the A120 mAb to induce the levels of the CCR5-binding β-chemokines MIP-1α, MIP-1β and/or RANTES, and the down modulation of CCR5 expression on activated CD4+ T cells. Neutralizing anti-MIP-1α mAb significantly reversed the inhibitory effect of the A120 mAb on R5 HIV-1 infection. The data described herein have identified a unique epitope of CXCR4 whose ligation not only directly inhibits X4 HIV-1, but also indirectly inhibits R5 HIV-1 infection by inducing higher levels of natural CCR5 ligands.
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影响因子：
56.9
作者：
Feng, Y;Broder, CC;Berger, EA
通讯作者：
Berger, EA
HIV-1进入抑制剂：概述。
影响因子：
4.1
作者：
Kuritzkes DR
通讯作者：
Kuritzkes DR
DOI：
10.1126/science.1194396
发表时间：
2010-11-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Wu B;Chien EY;Mol CD;Fenalti G;Liu W;Katritch V;Abagyan R;Brooun A;Wells P;Bi FC;Hamel DJ;Kuhn P;Handel TM;Cherezov V;Stevens RC
通讯作者：
Stevens RC
DOI：
10.1073/pnas.0804286105
发表时间：
2008-07-22
影响因子：
11.1
作者：
Contento, Rita Lucia;Molon, Barbara;Viola, Antonella
通讯作者：
Viola, Antonella
影响因子：
5.4
作者：
Brelot, A;Heveker, N;Alizon, M
通讯作者：
Alizon, M