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Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody

Nature volume 393, pages 648–659 (1998)Cite this article

Abstract

The entry of human immunodeficiency virus (HIV) into cells requires the sequential interaction of the viral exterior envelope glycoprotein, gp120, with the CD4 glycoprotein and a chemokine receptor on the cell surface. These interactions initiate a fusion of the viral and cellular membranes. Although gpl20 can elicit virus-neutralizing antibodies, HIV eludes the immune system. We have solved the X-ray crystal structure at 2.5 Å resolution of an HIV-1 gp120 core complexed with a two-domain fragment of human CD4 and an antigen-binding fragment of a neutralizing antibody that blocks chemokine-receptor binding. The structure reveals a cavity-laden CD4–gp120 interface, a conserved binding site for the chemokine receptor, evidence for a conformational change upon CD4 binding, the nature of a CD4-induced antibody epitope, and specific mechanisms for immune evasion. Our results provide a framework for understanding the complex biology of HIV entry into cells and should guide efforts to intervene.

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Figure 1: Overall structure.
Figure 2: Structure of core gp120.
Figure 4: Neutralizing antibody 17b–gp120 interface.
Figure 3: CD4–gp120 interactions.
Figure 5: Diagram of gp120 initiation of fusion.

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Acknowledgements

We thank M. Doyle for microcalorimetry results, C. Kokolis and the SSCC group at SmithKline Beecham for assistance with gp120 proteins, C. Lusty for suggestions on crosslinking, C.Ogata for beamline assistance, A.-S. Yang for automated structural alignment, and past and present members of W.A.H.'s group, especially D. Fremont for help with programs, E. Martinez-Hackert for help with figures, L. Shapiro for discussion, J. Williams for sequence alignments, and H. Wu for analysis of CD4 movement. Beamline X4A at the National Synchrotron Light Source, a Department of Energy facility, is supported by the Howard Hughes Medical Institute. This work was made possible by gifts from the late William McCarty-Cooper, from the G. Harold and Leila Y. Mathers Foundation, from the Friends 10, and from Douglas and Judi Krupp. Support was provided by the Aaron Diamond Foundation, the American Foundation for AIDS Research, the Howard Hughes Medical Institute, and the NIH.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, 10032, New York, USA

    Peter D. Kwong & Wayne A. Hendrickson

  2. Department of Cancer Immunology and AIDS, Department of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Harvard School of Public Health, Boston, 02115, Massachusetts, USA

    Richard Wyatt & Joseph Sodroski

  3. Department of Pediatrics, Tulane University Medical Center, 1430 Tulane Avenue, New Orleans, 70112, Louisiana, USA

    James Robinson

  4. Department of Immunology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, 19406, Pennsylvania, USA

    Raymond W. Sweet

  5. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, 02115, Massachusetts, USA

    Joseph Sodroski

  6. Howard Hughes Medical Institute, Columbia University, New York, 10032, New York, USA

    Wayne A. Hendrickson

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  1. Peter D. Kwong
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Correspondence to Wayne A. Hendrickson.

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Kwong, P., Wyatt, R., Robinson, J. et al. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393, 648–659 (1998). https://doi.org/10.1038/31405

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