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

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, Michael S. Seaman, William R. Schief, Roland K. Strong, Michel C. Nussenzweig and Leonidas Stamatatos ()
Additional contact information
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
Roland K. Strong: Fred Hutchinson Cancer Research Center
Michel C. Nussenzweig: Laboratory of Molecular Immunology
Leonidas Stamatatos: Fred Hutchinson Cancer Research Center

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10618

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