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Cell. 2019 Jul 25;178(3):567-584.e19. doi: 10.1016/j.cell.2019.06.030.

Antibody Lineages with Vaccine-Induced Antigen-Binding Hotspots Develop Broad HIV Neutralization.

Author information

1
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
2
Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA.
3
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY 10027, USA; Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
4
Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98195, USA; Molecular and Cellular Biology PhD Program, University of Washington, Seattle, WA 98195, USA; Division of Human Biology and Epidemiology Program, Seattle, WA 98195, USA.
5
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY 10027, USA.
6
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm 17177, Sweden.
7
National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY 10027, USA.
8
Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
9
Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
10
NIH Intramural Sequencing Center, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
11
Division of Human Biology and Epidemiology Program, Seattle, WA 98195, USA.
12
Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98195, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA.
13
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
14
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. Electronic address: pdkwong@nih.gov.
15
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. Electronic address: jmascola@nih.gov.

Abstract

The vaccine-mediated elicitation of antibodies (Abs) capable of neutralizing diverse HIV-1 strains has been a long-standing goal. To understand how broadly neutralizing antibodies (bNAbs) can be elicited, we identified, characterized, and tracked five neutralizing Ab lineages targeting the HIV-1-fusion peptide (FP) in vaccinated macaques over time. Genetic and structural analyses revealed two of these lineages to belong to a reproducible class capable of neutralizing up to 59% of 208 diverse viral strains. B cell analysis indicated each of the five lineages to have been initiated and expanded by FP-carrier priming, with envelope (Env)-trimer boosts inducing cross-reactive neutralization. These Abs had binding-energy hotspots focused on FP, whereas several FP-directed Abs induced by immunization with Env trimer-only were less FP-focused and less broadly neutralizing. Priming with a conserved subregion, such as FP, can thus induce Abs with binding-energy hotspots coincident with the target subregion and capable of broad neutralization.

KEYWORDS:

B cell ontogeny; HIV-1 vaccine; broadly neutralizing antibody; fusion peptide; immune monitoring; interaction hotspot; multidonor antibody class

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