Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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 2.5ā€‰Ć… 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 CD4ā€“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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Overall structure.
Figure 2: Structure of core gp120.
Figure 4: Neutralizing antibody 17bā€“gp120 interface.
Figure 3: CD4ā€“gp120 interactions.
Figure 5: Diagram of gp120 initiation of fusion.

Similar content being viewed by others

References

  1. Barre-Sinoussi, F. et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immunodeficiency syndrome (AIDS). Science 220, 868ā€“871 (1983).

    ArticleĀ  ADSĀ  CASĀ  Google ScholarĀ 

  2. Gallo, R. C. et al. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science 224, 500ā€“503 (1984).

    ArticleĀ  ADSĀ  CASĀ  Google ScholarĀ 

  3. Kowalski, M. L. et al. Functional regions of the envelope glycoprotein of human immunodeficiency virus type 1. Science 237, 1351ā€“1355 (1987).

    ArticleĀ  ADSĀ  CASĀ  Google ScholarĀ 

  4. Lu, M., Blackow, S. & Kim, P. Atrimeric structural domain of the HIV-1 transmembrane glycoprotein. Nature Struct. Biol. 2, 1075ā€“1082 (1995).

    ArticleĀ  CASĀ  Google ScholarĀ 

  5. Starcich, B. R. et al. Identification and characterization of conserved and variable regions of the envelope gene HTLV-III/LAV, the retrovirus of AIDS. Cell 45, 637ā€“648 (1986).

    ArticleĀ  CASĀ  Google ScholarĀ 

  6. Leonard, C. K. et al. Assignment of intrachain disulfide bonds and characterization of potential glycosylation sites of the type 1 recombinant immunodeficiency virus envelope glycoprotein (gp120) expressed in Chinese hamster ovary cell. J. Biol. Chem. 265, 10373ā€“10382 (1990).

    CASĀ  Google ScholarĀ 

  7. Profy, A. T. et al. Epitopes recognized by the neutralizing antibodies of an HIV-1-infected individual. J. Immunol. 144, 4641ā€“4647 (1990).

    CASĀ  Google ScholarĀ 

  8. Ryu, S.-E. et al. Crystal structure of an HIV-binding recombinant fragment of human CD4. Nature 348, 419ā€“426 (1990).

    ArticleĀ  ADSĀ  CASĀ  Google ScholarĀ 

  9. Wang, J. H. et al. Atomic structure of a fragment of human CD4 containing two immunoglobulin-like domains. Nature 348, 411ā€“418 (1990).

    ArticleĀ  ADSĀ  CASĀ  Google ScholarĀ 

  10. Wu, H., Kwong, P. D. & Hendrickson, W. A. Dimeric association and segmental variability in the structure of human CD4. Nature 387, 527ā€“530 (1997).

    ArticleĀ  ADSĀ  CASĀ  Google ScholarĀ 

  11. Moebius, U., Clayton, L., Abraham, S., Harrison, S. & Reinhertz, E. The human immunodeficiency virus gp120 binding site of CD4: Delineation by quantitative equilibrium and kinetic binding studies of mutants in conjunction with a high-resolution CD4 atomic structure. J. Exp. Med. 176, 507ā€“517 (1992).

    ArticleĀ  CASĀ  Google ScholarĀ 

  12. Sweet, R. W., Truneh, A. & Hendrickson, W. A. CD4: its structure, role in immune function and AIDS pathogenesis, and potential as a pharmacologicla target. Curr. Opin. Biotech. 2, 622ā€“633 (1991).

    ArticleĀ  CASĀ  Google ScholarĀ 

  13. Olshevsky, U. et al. Identification of individual HIV-1 gp120 amino acids important for CD4 receptor binding. J. Virol. 64((1990)).

  14. Cordonnier, A., Montagnier, L. & Emerman, M. Single amino-acid changes in HIV envelope affect viral tropism and receptor binding. Nature 340, 571ā€“574 (1989).

    ArticleĀ  ADSĀ  CASĀ  Google ScholarĀ 

  15. Moore, J. P. Coreceptors: implications for HIV pathogenesis and therapy. Science 276, 51ā€“52 (1997).

    ArticleĀ  CASĀ  Google ScholarĀ 

  16. Feng, F., Broder, C. C., Kennedy, P. E. & Berger, E. A. HIV-1-entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272, 872ā€“877 (1996).

    ArticleĀ  ADSĀ  CASĀ  Google ScholarĀ 

  17. Speck, R. F. et al. Selective employment of chemokine receptors as human immunodeficiency virus type 1 coreceptors determined by individual amino acids in the envelope V3 loop. J. Virol. 71, 7136ā€“7139 (1997).

    CASĀ  Google ScholarĀ 

  18. Thali, M. et al. Characterization of conserved human immunodeficiency virus type 1 (HIV-1) gp120 neutralization epitopes exposed upon gp120-CD4 binding. J. Virol. 67, 3978ā€“3988 (1993).

    CASĀ  Google ScholarĀ 

  19. Sattentau, Q. J., Moore, J. P., Vignaux, F., Traincard, F. & Poignard, P. Conformational changes induced in the envelope glycoproteins of human and simian immunodeficiency virus by soluble receptor binding. J. Virol. 64, 7383ā€“7383 (1993).

    Google ScholarĀ 

  20. Wu, L. et al. CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR5. Nature 384, 179ā€“183 (1996).

    ArticleĀ  ADSĀ  CASĀ  Google ScholarĀ 

  21. Moore, J. P., McKeating, J. A., Weiss, R. A. & Sattentau, Q. J. Dissociation of gp120 from HIV-1 virions induced by soluble CD4. Science 250, 1139ā€“1142 (1990).

    ArticleĀ  ADSĀ  CASĀ  Google ScholarĀ 

  22. Bullough, P. A., Hughson, F. M., Skehel, J. J. & Wiley, D. C. Structure of influenza haemagglutinin at the pH of membrane fusion. Nature 371, 37ā€“43 (1994).

    ArticleĀ  ADSĀ  CASĀ  Google ScholarĀ 

  23. Fass, D. et al. Structure of a murine leukemia virus receptor-binding glycoprotein at 2.0 ƅngstrƶm resolution. Science 277, 1662ā€“1666 (1997).

    ArticleĀ  CASĀ  Google ScholarĀ 

  24. Wyatt, R. et al. The antigenic structure of the HIV gp120 envelope glycoprotein. Nature 393, 705ā€“711 (1998).

    ArticleĀ  ADSĀ  CASĀ  Google ScholarĀ 

  25. Kwong, P. D. et al. Quantitative probability analysis and variational crystallization of gp120, the exterior envelope glycoprotein of the human immunodeficiency virus type 1 (HIV-1). J. Biol. Chem. (submitted).

  26. Binley, J. M. et al. Analysis of the interaction of antibodies with a conserved, enzymatically deglycosylated core of the HIV-1 gp120 envelope glycoprotein. AIDS Res. Hum. Retrovir. 14, 191ā€“198 (1997).

    ArticleĀ  Google ScholarĀ 

  27. Leesong, M., Hederson, B. S., Gillig, J. R., Schwab, J. M. & Smith, J. L. Structure of a dehydratase-isomerase from the bacterial pathway for biosynthesis of unsaturated fatty acids: two catalytic activities in one active site. Structure 4, 253ā€“264 (1996).

    ArticleĀ  CASĀ  Google ScholarĀ 

  28. Cedergren-Zeppezauer, E. S., Larsson, G., Nyman, P. O., Dauter, Z. & Wilson, K. S. Crystal structure of a dUTPase. Nature 355, 740ā€“743 (1992).

    ArticleĀ  ADSĀ  CASĀ  Google ScholarĀ 

  29. Ryu, S.-E., Truneh, A., Sweet, R. W. & Hendrickson, W. A. Structures of an HIV and MHC binding fragment from human CD4 as refined in two crystal lattices. Structure 2, 59ā€“74 (1994).

    ArticleĀ  CASĀ  Google ScholarĀ 

  30. Rizzuto, C. et al. Aconserved HIV gp120 glycoprotein structure involved in chemokine receptor binding. Science (in the press).

  31. Dragic, T. et al. Amino-terminal substitutions in the CCR5 coreceptor impair gp120 binding and human immunodeficiency type 1 entry. J. Virol. 72, 279ā€“285 (1998).

    CASĀ  Google ScholarĀ 

  32. Farzan, M. et al. Atryosine-rich region in the N-terminus of CCR5 is important for human immunodeficiency virus type 1 entry and mediates an association between gp120 and CCR5. J. Virol. 72, 1160ā€“1164 (1998).

    CASĀ  Google ScholarĀ 

  33. Wyatt, R. et al. Analysis of the interaction of the human immunodeficiency virus type 1 gp120 envelope glycoprotein with the gp41 transmembrane glycoprotein. J. Virol. 71, 9722ā€“9731 (1997).

    CASĀ  Google ScholarĀ 

  34. Helseth, E., Olshevsky, U., Furman, C. & Sodroski, J. Human immunodeficiency virus type 1 gp120 envelope glycoprotein regions important for association with the gp41 transmembrane glycoprotein. J. Virol. 65, 2119ā€“2123 (1991).

    CASĀ  Google ScholarĀ 

  35. Wilson, I. A., Skehel, J. J. & Wiley, D. C. Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3ā€‰Ć… resolution. Nature 289, 366ā€“373 (1981).

    ArticleĀ  ADSĀ  CASĀ  Google ScholarĀ 

  36. Wyatt, R. et al. Involvement of the V1/V2 variable loop structure in the exposure of human immunodeficiency virus type 1 gp120 epitopes induced by receptor binding. J. Virol. 69, 5723ā€“5733 (1995).

    CASĀ  Google ScholarĀ 

  37. Rost, B., Sander, C. & Schneider, R. PHD ā€” an automated mail server for protein secondary structure prediction. Comput. Appl. Biosci. 10, 53ā€“60 (1994).

    CASĀ  Google ScholarĀ 

  38. Wyatt, R. et al. Functional and immunologic characterization of human immunodeficiency virus type 1 envelope glycoproteins containing deletions of the major variable regions. J. Virol. 67, 4557ā€“4565 (1993).

    CASĀ  Google ScholarĀ 

  39. Wu, H. et al. Kinetic and structural analysis of mutant CD4 receptors that are defective in HIV gp120 binding. Proc. Natl Acad. Sci. USA 93, 15030ā€“15035 (1996).

    ArticleĀ  ADSĀ  CASĀ  Google ScholarĀ 

  40. Chan, D. C., Fass, D., Berger, J. M. & Kim, P. S. Core structure of gp41 from the HIV envelope glycoprotein. Cell 89, 263ā€“273 (1997).

    ArticleĀ  CASĀ  Google ScholarĀ 

  41. Weissenhorn, W., Dessen, A., Harrison, S. C., Skehel, J. J. & Wiley, D. C. Atomic structure of the ectodomain from HIV-1 gp41. Nature 387, 426ā€“430 (1997).

    ArticleĀ  ADSĀ  CASĀ  Google ScholarĀ 

  42. Dumonceaux, J. et al. Spontaneous mutations in the env gene of the human immunodeficiency virus type 1 NDK isolate are associated with a CD4-independent entry phenotype. J. Virol. 72, 519ā€“519 (1998).

    Google ScholarĀ 

  43. Moir, S., Perreault, J. & Poulin, L. Postbinding events mediated by human immunodeficiency virus type 1 are sensitive to modifications in the D4-transmembrane linked region of CD4. J. Virol. 70, 8019ā€“8028 (1996).

    CASĀ  Google ScholarĀ 

  44. Kohlstaadt, L. A., Wang, J., Friedman, J. M., Rice, P. A. & Steitz, T. A. Crystal structure at 3.5ā€‰Ć… resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 256, 1783ā€“1790 (1992).

    ArticleĀ  ADSĀ  Google ScholarĀ 

  45. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Meth. Enymol. 276, 307ā€“326 (1997).

    ArticleĀ  CASĀ  Google ScholarĀ 

  46. Brunger, A. T. XPLOR Version 3.1 manual (Yale University, New Haven, (1993)).

    Google ScholarĀ 

  47. Jones, T. A., Zou, J. Y., Cowan, S. W. & Kjeldgaard, M. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr. A 47, 110ā€“119 (1991).

    ArticleĀ  Google ScholarĀ 

  48. Zhu, X. et al. Structural analysis of substrate binding by the molecular chaperone DnaK. Science 272, 1606ā€“1614 (1996).

    ArticleĀ  ADSĀ  CASĀ  Google ScholarĀ 

  49. Carson, M. Ribbons 2.0. J. Appl. Crystallogr. 24, 958ā€“961 (1991).

    ArticleĀ  Google ScholarĀ 

  50. Nicholls, A., Sharp, K. A. & Honig, B. Protein folding and association: insight from the interfacial and thermodynamic properties of hydrocarbons. Proteins Struct. Funct. Genet. 11, 281ā€“296 (1991).

    ArticleĀ  CASĀ  Google ScholarĀ 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Wayne A. Hendrickson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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, 648ā€“659 (1998). https://doi.org/10.1038/31405

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/31405

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter ā€” what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing