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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Examination of the contributions of size and avidity to the neutralization mechanisms of the anti-HIV antibodies b12 and 4E10
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Examination of the contributions of size and avidity to the neutralization mechanisms of the anti-HIV antibodies b12 and 4E10

机译：检查大小和亲和力对抗HIV抗体b12和4E10的中和机制的贡献

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摘要

Monoclonal antibodies b12 and 4E10 are broadly neutralizing against a variety of strains of the human immunodeficiency virus type 1 (HIV-1). The epitope for b12 maps to the CD4-binding site in the gp120 subunit of HIV-1's trimeric gp120-gp41 envelope spike, whereas 4E10 recognizes the membrane-proximal external region (MPER) of gp41. Here, we constructed and compared a series of architectures for the b12 and 4E10 combining sites that differed in size, valency, and flexibility. In a comparative analysis of the ability of the b12 and 4E10 constructs to neutralize a panel of clade B HIV-1 strains, we observed that the ability of bivalent constructs to cross-link envelope spikes on the virion surface made a greater contribution to neutralization by b12 than by 4E10. Increased distance and flexibility between antibody combining sites correlated with enhanced neutralization for both antibodies, suggesting restricted mobility for the trimeric spikes embedded in the virion surface. The size of a construct did not appear to be correlated with neutralization potency for b12, but larger 4E10 constructs exhibited a steric occlusion effect, which we interpret as evidence for restricted access to its gp41 epitope. The combination of limited avidity and steric occlusion suggests a mechanism for evading neutralization by antibodies that target epitopes in the highly conserved MPER of gp41.
机译：单克隆抗体b12和4E10对多种人类免疫缺陷病毒1型（HIV-1）株具有广泛的中和作用。 b12的表位映射到HIV-1的三聚体gp120-gp41包膜突突的gp120亚基中的CD4结合位点，而4E10识别gp41的膜近端外部区域（MPER）。在这里，我们构建并比较了b12和4E10组合站点的一系列体系结构，这些站点的大小，价位和灵活性都不同。在对b12和4E10构建体中和一组进化枝B HIV-1菌株的能力的比较分析中，我们观察到二价构建体交联病毒体表面包膜尖峰的能力对中和作用的贡献更大。 b12比4E10高。抗体结合位点之间的距离和灵活性增加，与两种抗体的中和作用增强相关，表明嵌入在病毒粒子表面的三聚体刺突的活动性受到限制。构建体的大小似乎与b12的中和能力无关，但是较大的4E10构建体表现出空间闭塞效应，我们将其解释为对其gp41表位的限制进入的证据。有限的亲和力和空间闭塞的组合提示了一种机制，可通过靶向高度保守的gp41 MPER中表位的抗体中和。

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    Joshua S. Klein; Priyanthi N. P. Gnanapragasam; Rachel P. Galimidi; Christopher P. Foglesong; Anthony P. West; Jr.; Pamela J. Bjorkman;

  • 作者单位

    Graduate option in Biochemistry and Molecular Biophysics, California Institute of Technology, Pasadena, CA 91125;

    Graduate option in Division of Biology, California Institute of Technology, Pasadena, CA 91125;

    Graduate option in Division of Biology, California Institute of Technology, Pasadena, CA 91125;

    Graduate option in Division of Biology, California Institute of Technology, Pasadena, CA 91125;

    Graduate option in Division of Biology, California Institute of Technology, Pasadena, CA 91125;

    Graduate option in Division of Biology, California Institute of Technology, Pasadena, CA 91125 Graduate option in Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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