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Immunization for HIV-1 Broadly Neutralizing Antibodies in Human Ig Knockin Mice

Dosenovic, Pia and von Boehmer, Lotta and Escolano, Amelia and Jardine, Joseph and Freund, Natalia T. and Gitlin, Alexander D. and McGuire, Andrew T. and Kulp, Daniel W. and Oliveira, Thiago and Scharf, Louise and Pietzsch, John and Gray, Matthew D. and Cupo, Albert and van Gils, Marit J. and Yao, Kai-Hui and Liu, Cassie and Gazumyan, Anna and Seaman, Michael S. and Bjorkman, Pamela J. and Sanders, Rogier W. and Moore, John P. and Stamatatos, Leonidas and Schief, William R. and Nussenzweig, Michel C. (2015) Immunization for HIV-1 Broadly Neutralizing Antibodies in Human Ig Knockin Mice. Cell, 161 (7). pp. 1505-1515. ISSN 0092-8674. PMCID PMC4604566.

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A subset of individuals infected with HIV-1 develops broadly neutralizing antibodies (bNAbs) that can prevent infection, but it has not yet been possible to elicit these antibodies by immunization. To systematically explore how immunization might be tailored to produce them, we generated mice expressing the predicted germline or mature heavy chains of a potent bNAb to the CD4 binding site (CD4bs) on the HIV-1 envelope glycoprotein (Env). Immunogens specifically designed to activate B cells bearing germline antibodies are required to initiate immune responses, but they do not elicit bNAbs. In contrast, native-like Env trimers fail to activate B cells expressing germline antibodies but elicit bNAbs by selecting for a restricted group of light chains bearing specific somatic mutations that enhance neutralizing activity. The data suggest that vaccination to elicit anti-HIV-1 antibodies will require immunization with a succession of related immunogens.

Item Type:Article
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URLURL TypeDescription CentralArticle
Freund, Natalia T.0000-0002-5386-502X
Bjorkman, Pamela J.0000-0002-2277-3990
Nussenzweig, Michel C.0000-0003-0592-8564
Additional Information:© 2015 Elsevier Inc. Received May 11, 2015; Revised May 29, 2015; Accepted May 29, 2015; Published June 18, 2015. We thank Chingwen Yang, Dorjee Shola, and Rada Norinsky for their contribution in the generation of the knockin mice; Thomas Eisenreich, David Bosque, and Susan Hinklein for assistance with the mice; Klara Velinzon and Neena Thomas for assistance with single-cell FACS sorting; Zoran Jankovic for laboratory support; Alex Robles for technical assistance with the HIV-1 TZMbl neutralization assays; and Anthony West for advice regarding the selection of the HIV-1 virus panels. This work was supported by grants from NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) UM1 AI100663 (M.C.N., W.R.S., and R.W.S.), Bill and Melinda Gates Foundation grant OPP1033115(M.C.N.),NIH grant AI037526 (M.C.N.), the International AIDS Vaccine Initiative Neutralizing Antibody Consortium and Center (W.R.S.), and by BMGF CAVD funding for the IAVI NAC Center (W.R.S.). This work was also supported by NIH grant U19 AI109632 (M.C.N. and L.S.), HIVRAD/P01 AI094419-01 (L.S.), HIVRAD/P01 AI082362 (J.P.M. and R.W.S.), HIVRAD/P01 AI100148 (P.J.B. and M.C.N.), Bill and Melinda Gates Foundation grant 1032144 (M.S.S.), and the Aids Fonds Netherlands, grant 2012041 (M.J.v.G.). P.D. is supported by an international postdoctoral fellowship from the Swedish Research Council. L.v.B. is supported by The Rockefeller University Center for Clinical and Translational SciencegrantUL1TR000043/KL2TR000151fromtheNational Center for Advancing Translational Sciences (NCATS). A.D.G. is supported by MSTP grant T32GM07739 to the Weill Cornell/ Rockefeller/ Sloan-Kettering Tri-Institutional MD-PhD Program. A.M. is supported by a Canadian Institutes of Health Research Fellowship. R.W.S. is a recipient of a Vidi grant from the Netherlands Organization for Scientific Research (NWO) and a Starting Investigator Grant from the European Research Council (ERC-StG-2011–280829-SHEV). M.C.N. and P.J.B. are Howard Hughes Medical Institute Investigators.
Funding AgencyGrant Number
NIHUM1 AI100663
Bill and Melinda Gates FoundationOPP1033115
International AIDS Vaccine InitiativeUNSPECIFIED
Collaboration for AIDS Vaccine Discovery (CAVD)UNSPECIFIED
NIHU19 AI109632
NIHHIVRAD/P01 AI094419-01
Bill and Melinda Gates Foundation1032144
Aids Fonds Netherlands2012041
Swedish Research CouncilUNSPECIFIED
National Center for Advancing Translational Sciences (NCATS)UL1TR000043/KL2TR000151
NIH Predoctoral FellowshipT32GM07739
Canadian Institutes of Health Research (CIHR)UNSPECIFIED
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)UNSPECIFIED
European Research Council (ERC)ERC-StG-2011–280829-SHEV
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Issue or Number:7
PubMed Central ID:PMC4604566
Record Number:CaltechAUTHORS:20150701-123923449
Persistent URL:
Official Citation:Dosenovic, P., von Boehmer, L., Escolano, A., Jardine, J., Freund, Natalia T., Gitlin, Alexander D., . . . Nussenzweig, Michel C. (2015). Immunization for HIV-1 Broadly Neutralizing Antibodies in Human Ig Knockin Mice. Cell, 161(7), 1505-1515. doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:58736
Deposited By: Joanne McCole
Deposited On:06 Jul 2015 16:01
Last Modified:03 Oct 2019 08:39

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