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Structural basis for germline antibody recognition of HIV-1 immunogens

Scharf, Louise and West, Anthony P. , Jr. and Sievers, Stuart A. and Chen, Courtney and Jiang, Siduo and Gao, Han and Gray, Matthew D. and McGuire, Andrew T. and Scheid, Johannes F. and Nussenzweig, Michel C. and Stamatatos, Leonidas and Bjorkman, Pamela J. (2016) Structural basis for germline antibody recognition of HIV-1 immunogens. eLife, 5 . Art. No. e13783. ISSN 2050-084X. PMCID PMC4811768.

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Efforts to elicit broadly neutralizing antibodies (bNAbs) against HIV-1 require understanding germline bNAb recognition of HIV-1 envelope glycoprotein (Env). The VRC01-class bNAb family derived from the VH1-2*02 germline allele arose in multiple HIV-1–infected donors, yet targets the CD4-binding site on Env with common interactions. Modified forms of the 426c Env that activate germline-reverted B cell receptors are candidate immunogens for eliciting VRC01-class bNAbs. We present structures of germline-reverted VRC01-class bNAbs alone and complexed with 426c-based gp120 immunogens. Germline bNAb–426c gp120 complexes showed preservation of VRC01-class signature residues and gp120 contacts, but detectably different binding modes compared to mature bNAb-gp120 complexes. Unlike typical antibody-antigen interactions, VRC01–class germline antibodies exhibited preformed antigen-binding conformations for recognizing immunogens. Affinity maturation introduced substitutions increasing induced-fit recognition and electropositivity, potentially to accommodate negatively-charged complex-type N-glycans on gp120. These results provide general principles relevant to the unusual evolution of VRC01–class bNAbs and guidelines for structure-based immunogen design.

Item Type:Article
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URLURL TypeDescription file CentralArticle
Nussenzweig, Michel C.0000-0003-0592-8564
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2016 Scharf et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Received: 14 December 2015; Accepted: 05 March 2016; Published: 21 March 2016. We thank the Caltech Protein Expression Center for producing antibody and gp120 proteins, generation of suspension-adapted HEK293-S cells and use of the Biacore T200. Operations at the Stanford Synchrotron Radiation Lightsource are supported by the US Department of Energy and the National Institutes of Health. MCN is a Howard Hughes Medical Institute investigator. This research was supported by the National Institute Of Allergy And Infectious Diseases of the National Institutes of Health Grant HIVRAD P01 AI100148 (PJB and MCN); (the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health), Collaboration for AIDS Vaccine Discovery grants from The Bill and Melinda Gates Foundation (grant IDs 1040753 to PJB and 1124068 to MCN), the American Cancer Society (Grant PF-13-076-01-MPC to LS), and the California HIV/AIDS Research Program (CHRP grant F12-CT-214 to SAS). Author contributions: LSc, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article; APW, Analysis and interpretation of data, Drafting or revising the article; SAS, CC, SJ, Acquisition of data, Analysis and interpretation of data; HG, Acquisition of data, Contributed unpublished essential data or reagents; MDG, JFS, Contributed unpublished essential data or reagents; ATM, MCN, LSt, Drafting or revising the article, Contributed unpublished essential data or reagents; PJB, Conception and design, Analysis and interpretation of data, Drafting or revising the article. Competing interests: MCN: Reviewing editor, eLife. The other authors declare that no competing interests exist.
Funding AgencyGrant Number
Department of Energy (DOE)UNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
National Institute of Allergy and Infectious Diseases (NIAID)AI100148
Bill and Melinda Gates Foundation1040753
Bill and Melinda Gates Foundation1124068
American Cancer SocietyPF-13-076-01-MPC
California HIV/AIDS Research ProgramF12-CT-214
PubMed Central ID:PMC4811768
Record Number:CaltechAUTHORS:20160328-112605894
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:65709
Deposited By: Tony Diaz
Deposited On:28 Mar 2016 23:57
Last Modified:05 Dec 2019 21:44

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