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Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice

Author

Listed:
  • Andrew T. McGuire

    (Fred Hutchinson Cancer Research Center)

  • Matthew D. Gray

    (Fred Hutchinson Cancer Research Center)

  • Pia Dosenovic

    (Laboratory of Molecular Immunology)

  • Alexander D. Gitlin

    (Laboratory of Molecular Immunology)

  • Natalia T. Freund

    (Laboratory of Molecular Immunology)

  • John Petersen

    (Fred Hutchinson Cancer Research Center)

  • Colin Correnti

    (Fred Hutchinson Cancer Research Center)

  • William Johnsen

    (Fred Hutchinson Cancer Research Center)

  • Robert Kegel

    (Fred Hutchinson Cancer Research Center)

  • Andrew B. Stuart

    (Fred Hutchinson Cancer Research Center)

  • Jolene Glenn

    (Fred Hutchinson Cancer Research Center)

  • Michael S. Seaman

    (Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center)

  • William R. Schief

    (The Scripps Research Institute
    IAVI Neutralizing Antibody Center, The Scripps Research Institute
    Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute
    Ragon Institute of MGH, MIT, and Harvard)

  • Roland K. Strong

    (Fred Hutchinson Cancer Research Center)

  • Michel C. Nussenzweig

    (Laboratory of Molecular Immunology
    Howard Hughes Medical Institute, The Rockefeller University)

  • Leonidas Stamatatos

    (Fred Hutchinson Cancer Research Center
    University of Washington)

Abstract

VRC01-class broadly neutralizing HIV-1 antibodies protect animals from experimental infection and could contribute to an effective vaccine response. Their predicted germline forms (gl) bind Env inefficiently, which may explain why they are not elicited by HIV-1 Env-immunization. Here we show that an optimized Env immunogen can engage multiple glVRC01-class antibodies. Furthermore, this immunogen activates naive B cells expressing the human germline heavy chain of 3BNC60, paired with endogenous mouse light chains in vivo. To address whether it activates B cells expressing the fully humanized gl3BNC60 B-cell receptor (BCR), we immunized mice carrying both the heavy and light chains of gl3BNC60. B cells expressing this BCR display an autoreactive phenotype and fail to respond efficiently to soluble forms of the optimized immunogen, unless it is highly multimerized. Thus, specifically designed Env immunogens can activate naive B cells expressing human BCRs corresponding to precursors of broadly neutralizing HIV-1 antibodies even when the B cells display an autoreactive phenotype.

Suggested Citation

  • Andrew T. McGuire & Matthew D. Gray & Pia Dosenovic & Alexander D. Gitlin & Natalia T. Freund & John Petersen & Colin Correnti & William Johnsen & Robert Kegel & Andrew B. Stuart & Jolene Glenn & Mich, 2016. "Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice," Nature Communications, Nature, vol. 7(1), pages 1-10, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10618
    DOI: 10.1038/ncomms10618
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    Cited by:

    1. Wen-Han Yu & Peng Zhao & Monia Draghi & Claudia Arevalo & Christina B Karsten & Todd J Suscovich & Bronwyn Gunn & Hendrik Streeck & Abraham L Brass & Michael Tiemeyer & Michael Seaman & John R Mascola, 2018. "Exploiting glycan topography for computational design of Env glycoprotein antigenicity," PLOS Computational Biology, Public Library of Science, vol. 14(4), pages 1-28, April.
    2. Kim-Marie A. Dam & Christopher O. Barnes & Harry B. Gristick & Till Schoofs & Priyanthi N. P. Gnanapragasam & Michel C. Nussenzweig & Pamela J. Bjorkman, 2022. "HIV-1 CD4-binding site germline antibody–Env structures inform vaccine design," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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