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Virus-like Particles Identify an HIV V1V2 Apex-Binding Neutralizing Antibody that Lacks a Protruding Loop

Cale EM 1 , Gorman J 1 , Radakovich NA 1 , Crooks ET 2 , Osawa K 2 , Tong T 3 Show all authors , Li J 1 , Nagarajan R 4 , Ozorowski G 5 , Ambrozak DR 1 , Asokan M 1 , Bailer RT 1 , Bennici AK 1 , Chen X 1 , Doria-Rose NA 1 , Druz A 1 , Feng Y 6 , Joyce MG 1 , Louder MK 1 , O'Dell S 1 , Oliver C 1 , Pancera M 1 , Connors M 7 , Hope TJ 8 , Kepler TB 9 , Wyatt RT 6 , Ward AB 5 , Georgiev IS 10 , Kwong PD 11 , Mascola JR 12 , Binley JM 13

Affiliations 

  • 1 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
  • 2 San Diego Biomedical Research Institute, San Diego, CA 92121, USA
  • 3 Sunway University, School of Science and Technology, Department of Biological Sciences, Jalan Universiti, Bandar Sunway, 47500 Selangor Darul Ehsan, Malaysia
  • 4 Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
  • 5 Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
  • 6 Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
  • 7 HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
  • 8 Department of Cell and Molecular Biology, Feinberg Medical School, Northwestern University, Chicago, IL 60611, USA
  • 9 Boston University Department of Microbiology, Boston, MA 02118, USA
  • 10 Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
  • 11 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: pdkwong@nih.gov
  • 12 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: jmascola@nih.gov
  • 13 San Diego Biomedical Research Institute, San Diego, CA 92121, USA. Electronic address: jbinley@sdbri.org
Immunity, 2017 05 16;46(5):777-791.e10.
PMID: 28514685 DOI: 10.1016/j.immuni.2017.04.011

Abstract

Most HIV-1-specific neutralizing antibodies isolated to date exhibit unusual characteristics that complicate their elicitation. Neutralizing antibodies that target the V1V2 apex of the HIV-1 envelope (Env) trimer feature unusually long protruding loops, which enable them to penetrate the HIV-1 glycan shield. As antibodies with loops of requisite length are created through uncommon recombination events, an alternative mode of apex binding has been sought. Here, we isolated a lineage of Env apex-directed neutralizing antibodies, N90-VRC38.01-11, by using virus-like particles and conformationally stabilized Env trimers as B cell probes. A crystal structure of N90-VRC38.01 with a scaffolded V1V2 revealed a binding mode involving side-chain-to-side-chain interactions that reduced the distance the antibody loop must traverse the glycan shield, thereby facilitating V1V2 binding via a non-protruding loop. The N90-VRC38 lineage thus identifies a solution for V1V2-apex binding that provides a more conventional B cell pathway for vaccine design.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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