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Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies

McGuire, Andrew T. and Hoot, Sam and Dreyer, Anita M. and Lippy, Adriana and Stuart, Andrew and Cohen, Kristen W. and Jardine, Joseph and Menis, Sergey and Scheid, Johannes F. and West, Anthony P. and Schief, William R. and Stamatatos, Leonidas (2013) Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies. Journal of Experimental Medicine, 210 (4). pp. 655-663. ISSN 0022-1007. PMCID PMC3620356. doi:10.1084/jem.20122824.

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Broadly neutralizing antibodies (bnAbs) against HIV are believed to be a critical component of the protective responses elicited by an effective HIV vaccine. Neutralizing antibodies against the evolutionarily conserved CD4-binding site (CD4-BS) on the HIV envelope glycoprotein (Env) are capable of inhibiting infection of diverse HIV strains, and have been isolated from HIV-infected individuals. Despite the presence of anti–CD4-BS broadly neutralizing antibody (bnAb) epitopes on recombinant Env, Env immunization has so far failed to elicit such antibodies. Here, we show that Env immunogens fail to engage the germline-reverted forms of known bnAbs that target the CD4-BS. However, we found that the elimination of a conserved glycosylation site located in Loop D and two glycosylation sites located in variable region 5 of Env allows Env-binding to, and activation of, B cells expressing the germline-reverted BCRs of two potent broadly neutralizing antibodies, VRC01 and NIH45-46. Our results offer a possible explanation as to why Env immunogens have been ineffective in stimulating the production of such bNAbs. Importantly, they provide key information as to how such immunogens can be engineered to initiate the process of antibody-affinity maturation against one of the most conserved Env regions.

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Additional Information:© 2013 McGuire et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at Submitted: 20 December 2012. Accepted: 5 March 2013. We thank Zachary Caldwell, Sara Carbonetti, Anna Gazumyan, Jolene Glenn, Sam Danziger, and D. Noah Sather for technical support. This work was supported by National Institute of Allergy and Infectious Diseases/HIV Vaccine Research and Design grant P01AI081625 and R56 AI047708 (L. Stamatatos). We also acknowledge support by the J.B Pendleton Charitable Trust and by the University of Washington Center for AIDS Research, an NIH funded program (P30 AI027757). A.M. Dreyer was supported by the Swiss National Science Foundation (PBBSP3 144245). The authors declare no competing financial interests.
Funding AgencyGrant Number
NIHR56 AI047708
J. B. Pendleton Charitable TrustUNSPECIFIED
University of Washington Center for AIDS ResearchUNSPECIFIED
NIHP30 AI027757
Swiss National Science Foundation (SNSF)PBBSP3 144245
Issue or Number:4
PubMed Central ID:PMC3620356
Record Number:CaltechAUTHORS:20130510-092835018
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Official Citation:Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies Andrew T. McGuire, Sam Hoot, Anita M. Dreyer, Adriana Lippy, Andrew Stuart, Kristen W. Cohen, Joseph Jardine, Sergey Menis, Johannes F. Scheid, Anthony P. West, William R. Schief, and Leonidas Stamatatos 210:655-663. doi:10.1084/jem.20122824
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:38415
Deposited By: Ruth Sustaita
Deposited On:10 May 2013 20:05
Last Modified:09 Nov 2021 23:37

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