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Structural Basis of Immune Evasion at the Site of CD4 Attachment on HIV-1 gp 120

机译：HIV-1 gp 120上CD4附着部位的免疫逃逸的结构基础

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摘要

The site on HIV-1 gp120 that binds to the CD4 receptor is vulnerable to antibodies. However, most antibodies that interact with this site cannot neutralize HIV-1. To understand the basis of this resistance, we determined co-crystal structures for two poorly neutralizing, CD4-binding site (CD4BS) antibodies, F105 and bl3, in complexes with gpl20. Both antibodies exhibited approach angles to gp120 similar to those of CD4 and a rare, broadly neutralizing CD4BS antibody, b12. Slight differences in recognition, however, resulted in substantial differences in F105- and b13-bound conformations relative to b12-bound gp120. Modeling and binding experiments revealed these conformations to be poorly compatible with the viral spike. This incompatibility, the consequence of slight differences in CD4BS recognition, renders HIV-1 resistant to all but the most accurately targeted antibodies.
机译：HIV-1 gp120上与CD4受体结合的位点易受抗体影响。但是，与该位点相互作用的大多数抗体不能中和HIV-1。为了理解这种抗性的基础，我们确定了与gp120结合的两种中和性差的CD4结合位点（CD4BS）抗体F105和bl3的共晶体结构。两种抗体对gp120的接近角均与CD4相似，而罕见的，广泛中和的CD4BS抗体b12。然而，在识别上的细微差异导致F105和b13结合的构象相对于b12结合的gp120有实质性的差异。建模和结合实验表明，这些构象与病毒峰的相容性很差。这种不相容性是CD4BS识别稍有差异的结果，使HIV-1对除最精确靶向的抗体以外的所有抗体具有抗性。

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  • 来源
    《Science》 |2009年第5956期|1123-1127|共5页
  • 作者

    Lei Chen; Young Do Kwon; Tongqing Zhou; Xueling Wu; Sijy ODell; Lisa Cavacini; Ann J. Hessell; Marie Pancera; Min Tang; Ling Xu; Zhi-Yong Yang; Mei-Yun Zhang; James Arthos; Dennis R. Burton; Dimiter S. Dimitrov; Gary J. Nabel; Marshall R. Posner; Joseph Sodroski; Richard Wyatt; John R. Mascola; Peter D. Kwong;

  • 作者单位

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA;

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA;

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA;

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA;

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA;

    Head and Neck Oncology Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA;

    Departments of Immunology and Microbial Science and International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA;

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA;

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA;

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA;

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA;

    Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA;

    Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA;

    Departments of Immunology and Microbial Science and International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA 02114, USA;

    Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA;

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA;

    Head and Neck Oncology Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA;

    Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA;

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA;

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA;

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA;

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