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Title: Structures of HIV-1 Env V1V2 with broadly neutralizing antibodies reveal commonalities that enable vaccine design

Journal Article · · Nature Structural & Molecular Biology
DOI:https://doi.org/10.1038/nsmb.3144· OSTI ID:1238279
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  1. National Inst. of Health (NIH), Bethesda, MD (United States)
  2. Univ. of Washington, Seattle, WA (United States)
  3. National Inst. of Health (NIH), Bethesda, MD (United States); Univ. of Texas, Austin, TX (United States)
  4. Univ. of California, San Francisco, CA (United States)
  5. Univ. of Texas, Austin, TX (United States)
  6. National Human Genome Research Institute, NIH, Bethesda, MD (United States)
  7. Frederick National Lab. for Cancer Research, MD (United States)
  8. Duke Univ. Medical Center, Durham, NC (United States)
  9. National Inst. for Communicable Diseases of the National Health Lab. Service, Johannesburg (South Africa); Univ. of KwaZulu-Natal, Congella (South Africa)
  10. National Inst. for Communicable Diseases of the National Health Lab. Service, Johannesburg (South Africa); Univ. of the Witwatersrand, Johannesburg (South Africa); Univ. of KwaZulu-Natal, Congella (South Africa)
  11. National Inst. of Health (NIH), Bethesda, MD (United States); Columbia Univ., New York, NY (United States)
+ Show Author Affiliations

Broadly neutralizing antibodies (bNAbs) against HIV-1 Env V1V2 arise in multiple donors. However, atomic-level interactions had previously been determined only with antibodies from a single donor, thus making commonalities in recognition uncertain. Here we report the cocrystal structure of V1V2 with antibody CH03 from a second donor and model Env interactions of antibody CAP256-VRC26 from a third donor. These V1V2-directed bNAbs used strand-strand interactions between a protruding antibody loop and a V1V2 strand but differed in their N-glycan recognition. Ontogeny analysis indicated that protruding loops develop early, and glycan interactions mature over time. Altogether, the multidonor information suggested that V1V2-directed bNAbs form an 'extended class', for which we engineered ontogeny-specific antigens: Env trimers with chimeric V1V2s that interacted with inferred ancestor and intermediate antibodies. As a result, the ontogeny-based design of vaccine antigens described here may provide a general means for eliciting antibodies of a desired class.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); Frederick National Laboratory for Cancer Research; National Institutes of Health (NIH); Intramural Research Program of the Vaccine Research Center; U.S. National Inst. of Allergy and Infectious Diseases (NIAID); Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery; Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery
Grant/Contract Number:
W-31-109-Eng-38; HHSN261200800001E; 1U01-AI116086-01; R21-AI112389; OPP1033102; CHAVI-ID; UM1 AI100645
OSTI ID:
1238279
Journal Information:
Nature Structural & Molecular Biology, Vol. 23, Issue 1; ISSN 1545-9993
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 129 works
Citation information provided by
Web of Science

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Common helical V1V2 conformations of HIV-1 Envelope expose the α4β7 binding site on intact virions journal October 2018
Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1 journal June 2018
Opening dynamics of HIV-1 gp120 upon receptor binding is dictated by a key hydrophobic core journal January 2019
Envelope residue 375 substitutions in simian–human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques journal May 2016
Cryo-EM structure of a CD4-bound open HIV-1 envelope trimer reveals structural rearrangements of the gp120 V1V2 loop journal October 2016
Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo journal August 2017
Detection and activation of HIV broadly neutralizing antibody precursor B cells using anti-idiotypes journal July 2019
Anti-idiotypic antibodies elicit anti-HIV-1–specific B cell responses journal July 2019
Towards conformational fidelity of a quaternary HIV-1 epitope: computational design and directed evolution of a minimal V1V2 antigen journal April 2018
Is It Possible to Develop a “Universal” Influenza Virus Vaccine?: Immunogenetic Considerations Underlying B-Cell Biology in the Development of a Pan-Subtype Influenza A Vaccine Targeting the Hemagglutinin Stem journal June 2017
Native-like Env trimers as a platform for HIV-1 vaccine design journal January 2017
Germline-targeting immunogens journal January 2017
Antibody-virus co-evolution in HIV infection: paths for HIV vaccine development journal January 2017
Production of complex viral glycoproteins in plants as vaccine immunogens journal July 2018
Priming HIV-1 broadly neutralizing antibody precursors in human Ig loci transgenic mice journal September 2016
Detection of Broadly Neutralizing Activity within the First Months of HIV-1 Infection journal March 2016
HIV-1 Envelope Glycoproteins from Diverse Clades Differentiate Antibody Responses and Durability among Vaccinees journal January 2018
Prime-Boost Immunizations with DNA, Modified Vaccinia Virus Ankara, and Protein-Based Vaccines Elicit Robust HIV-1 Tier 2 Neutralizing Antibodies against the CAP256 Superinfecting Virus journal February 2019
Development of broadly neutralizing antibodies in HIV-1 infected elite neutralizers journal September 2018
Glycan modifications to the gp120 immunogens used in the RV144 vaccine trial improve binding to broadly neutralizing antibodies journal April 2018
The adjuvant AlhydroGel elicits higher antibody titres than AddaVax when combined with HIV-1 subtype C gp140 from CAP256 journal December 2018
Phenotypic deficits in the HIV-1 envelope are associated with the maturation of a V2-directed broadly neutralizing antibody lineage journal January 2018
Glycoengineering HIV-1 Env creates ‘supercharged’ and ‘hybrid’ glycans to increase neutralizing antibody potency, breadth and saturation journal May 2018
Select gp120 V2 domain specific antibodies derived from HIV and SIV infection and vaccination inhibit gp120 binding to α4β7 journal August 2018
Somatic hypermutation to counter a globally rare viral immunotype drove off-track antibodies in the CAP256-VRC26 HIV-1 V2-directed bNAb lineage journal September 2019
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Phenotypic deficits in the HIV-1 envelope are associated with the maturation of a V2-directed broadly neutralizing antibody lineage text January 2018
Elicitation of Neutralizing Antibodies Targeting the V2 Apex of the HIV Envelope Trimer in a Wild-Type Animal Model journal January 2018
Completeness of HIV-1 Envelope Glycan Shield at Transmission Determines Neutralization Breadth journal October 2018
V2-Directed Vaccine-like Antibodies from HIV-1 Infection Identify an Additional K169-Binding Light Chain Motif with Broad ADCC Activity journal December 2018
The Chimpanzee SIV Envelope Trimer: Structure and Deployment as an HIV Vaccine Template journal May 2019
HIV-1 Neutralizing Antibody Signatures and Application to Epitope-Targeted Vaccine Design journal August 2019
HIV Envelope Glycoform Heterogeneity and Localized Diversity Govern the Initiation and Maturation of a V2 Apex Broadly Neutralizing Antibody Lineage journal November 2017
Promise and problems associated with the use of recombinant AAV for the delivery of anti-HIV antibodies journal January 2016
Antibodyomics: bioinformatics technologies for understanding B-cell immunity to HIV-1 journal January 2017
Identification and specificity of broadly neutralizing antibodies against HIV journal January 2017
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Prospecting for an HIV vaccine journal March 2017
Effect of Glycosylation on an Immunodominant Region in the V1V2 Variable Domain of the HIV-1 Envelope gp120 Protein journal October 2016
Boosting of HIV envelope CD4 binding site antibodies with long variable heavy third complementarity determining region in the randomized double blind RV305 HIV-1 vaccine trial journal February 2017
5′ Rapid Amplification of cDNA Ends and Illumina MiSeq Reveals B Cell Receptor Features in Healthy Adults, Adults With Chronic HIV-1 Infection, Cord Blood, and Humanized Mice journal March 2018
V2-Specific Antibodies in HIV-1 Vaccine Research and Natural Infection: Controllers or Surrogate Markers journal August 2019

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