• A Corrigendum to this article was published on 06 June 2017

This article has been updated


Binding of the gp120 envelope (Env) glycoprotein to the CD4 receptor is the first step in the HIV-1 infectious cycle. Although the CD4-binding site has been extensively characterized, the initial receptor interaction has been difficult to study because of major CD4-induced structural rearrangements. Here we used cryogenic electron microscopy (cryo-EM) to visualize the initial contact of CD4 with the HIV-1 Env trimer at 6.8-Å resolution. A single CD4 molecule is embraced by a quaternary HIV-1–Env surface formed by coalescence of the previously defined CD4-contact region with a second CD4-binding site (CD4-BS2) in the inner domain of a neighboring gp120 protomer. Disruption of CD4-BS2 destabilized CD4-trimer interaction and abrogated HIV-1 infectivity by preventing the acquisition of coreceptor-binding competence. A corresponding reduction in HIV-1 infectivity occurred after the mutation of CD4 residues that interact with CD4-BS2. Our results document the critical role of quaternary interactions in the initial HIV-Env-receptor contact, with implications for treatment and vaccine design.

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Change history

  • 27 April 2017

    In the version of this article initially published, funding information for B.C. and C.S.P. was missing NIH grant S10 OD019994-01. In addition, there was an incorrect comma in the introduction (after "glycoprotein" in the sentence "Upon binding to the primary cellular receptor, CD4, the external gp120 Env glycoprotein undergoes major conformational changes...") that has been removed. The errors have been corrected in the HTML and PDF versions of the article.


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We thank J.P. Moore and A. Cupo (Weill Medical College of Cornell University, New York, New York, USA) for providing plasmids for expression of the BG505 SOSIP.664 trimer and furin; M. Farzan (Scripps Research Institute, Jupiter, Florida, USA) for providing the plasmid to express human CD4-immunoglobulin; D.R. Burton (Scripps Research Institute, La Jolla, California, USA, and Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA), M. Connors (Laboratory of Immunoregulation, NIAID, NIH, Bethesda, Maryland, USA), J.R. Mascola (Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, USA), and J.E. Robinson (Tulane University School of Medicine, New Orleans, Louisiana, USA) for anti-gp120 mAbs; E. Berger (Laboratory of Viral Diseases, NIAID, NIG, Bethesda, Maryland, USA) for the full-length CD4 gene and the gene encoding gp160 from BG505-T332N and BaL; D. Ichikawa and Y. Lin for help in performing selected experiments; J. Arthos, E.A. Berger, and R. Cimbro for helpful discussion; P. Gangopadhyay for help with MATLAB and Origin; and the AIDS Reagent Program for providing the reagents indicated in the Online Methods. The GPU-enabled frame-alignment program we used was generously provided by Y. Cheng and X. Li. The cryo-EM work was done at the National Resource for Automated Molecular Microscopy based at the Simons Electron Microscopy Center, which is supported by grants from the NIH (GM103310 and S10 OD019994-01) and the Simons Foundation (349247) to B.C. and C.S.P. This research was supported by the Intramural Programs of the Vaccine Research Center and of the Division of Intramural Research, NIAID, NIH.

Author information

Author notes

    • Qingbo Liu
    •  & Priyamvada Acharya

    These authors contributed equally to this work.


  1. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.

    • Qingbo Liu
    • , Peng Zhang
    • , Christina Guzzo
    • , Jacky Lu
    • , Alice Kwon
    • , Deepali Gururani
    • , Huiyi Miao
    •  & Paolo Lusso
  2. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.

    • Priyamvada Acharya
    • , Tatsiana Bylund
    • , Gwo-Yu Chuang
    • , Aliaksandr Druz
    • , Tongqing Zhou
    •  & Peter D Kwong
  3. National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, New York, USA.

    • Priyamvada Acharya
    • , William J Rice
    • , Christoph Wigge
    • , Bridget Carragher
    •  & Clinton S Potter
  4. Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.

    • Michael A Dolan


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Q.L. and P.L. conceived the project and designed biological and virological studies; P.A., T.Z., and P.D.K. conceived and designed structural studies; Q.L., J.L., and D.G. mutagenized gp160 from different HIV-1 isolates and produced infectious pseudoparticles; Q.L., C.G., H.M., and A.K. carried out infectivity assays and antigenicity studies of surface-expressed Envs; Q.L., D.G., and P.Z. produced and purified mutants of SOSIP trimer and gp120 monomer; Q.L. characterized the purified proteins and performed immunogenicity studies and CD4-binding and CCR5-binding assays; A.D. expressed DS-SOSIP proteins for SPR and cryo-EM studies; Q.L. and P.A. purified CD4-BS2 mutants of DS-SOSIP trimer and performed SPR analysis of CD4 binding; P.A. purified DS-SOSIP, prepared the DS-SOSIP-CD4-PGT145 complex, and performed cryo-EM experiments, with W.J.R. and C.W. providing assistance with electron microscopy data collection; P.A., T.B., G.-Y.C., and T.Z. analyzed the structure; M.A.D. performed docking experiments and MD simulations; B.C., C.S.P., and P.D.K. supervised cryo-EM experiments and structural analyses; Q.L., P.A., P.D.K., and P.L. analyzed data and wrote the paper; and all coauthors read and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Paolo Lusso.

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