Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations

Wilton B. Williams, Jinsong Zhang, Chuancang Jiang, Nathan I. Nicely, Daniela Fera, Kan Luo, M. Anthony Moody, Hua-Xin Liao, S. Munir Alam, Thomas B. Kepler, Akshaya Ramesh, Kevin Wiehe, James A. Holland, Todd Bradley, Nathan Vandergrift, Kevin O. Saunders, Robert Parks, Andrew Foulger, Shi-Mao Xia, Mattia Bonsignori, David C. Montefiori, Mark Louder, Amanda Eaton, Sampa Santra, Richard Scearce, Laura Sutherland, Amanda Newman, Hilary Bouton-Verville, Cindy Bowman, Howard Bomze, Feng Gao, Dawn J. Marshall, John F. Whitesides, Xiaoyan Nie, Garnett Kelsoe, Steven G. Reed, Christopher B. Fox, Kim Clary, Marguerite Koutsoukos, David Franco, John R. Mascola, Stephen C. Harrison, Barton F. Haynes () and Laurent Verkoczy ()
Additional contact information
Wilton B. Williams: Duke University School of Medicine
Jinsong Zhang: Duke University School of Medicine
Chuancang Jiang: Duke University School of Medicine
Nathan I. Nicely: Duke University School of Medicine
Daniela Fera: Boston Children’s Hospital and Harvard Medical School
Kan Luo: Duke University School of Medicine
M. Anthony Moody: Duke University School of Medicine
Hua-Xin Liao: Duke University School of Medicine
S. Munir Alam: Duke University School of Medicine
Thomas B. Kepler: Boston University School of Medicine
Akshaya Ramesh: Boston University School of Medicine
Kevin Wiehe: Duke University School of Medicine
James A. Holland: Duke University School of Medicine
Todd Bradley: Duke University School of Medicine
Nathan Vandergrift: Duke University School of Medicine
Kevin O. Saunders: Duke University School of Medicine
Robert Parks: Duke University School of Medicine
Andrew Foulger: Duke University School of Medicine
Shi-Mao Xia: Duke University School of Medicine
Mattia Bonsignori: Duke University School of Medicine
David C. Montefiori: Duke University School of Medicine
Mark Louder: National Institute of Health
Amanda Eaton: Duke University School of Medicine
Sampa Santra: Boston Children’s Hospital and Harvard Medical School
Richard Scearce: Duke University School of Medicine
Laura Sutherland: Duke University School of Medicine
Amanda Newman: Duke University School of Medicine
Hilary Bouton-Verville: Duke University School of Medicine
Cindy Bowman: Duke University School of Medicine
Howard Bomze: Duke University School of Medicine
Feng Gao: Duke University School of Medicine
Dawn J. Marshall: Duke University School of Medicine
John F. Whitesides: Duke University School of Medicine
Xiaoyan Nie: Duke University
Garnett Kelsoe: Duke University School of Medicine
Steven G. Reed: Infectious Disease Research Institute
Christopher B. Fox: Infectious Disease Research Institute
Kim Clary: Infectious Disease Research Institute
Marguerite Koutsoukos: GSK Vaccines
David Franco: GSK Vaccines
John R. Mascola: National Institute of Health
Stephen C. Harrison: Boston Children’s Hospital and Harvard Medical School
Barton F. Haynes: Duke University School of Medicine
Laurent Verkoczy: Duke University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-20

Abstract: Abstract A strategy for HIV-1 vaccine development is to define envelope (Env) evolution of broadly neutralizing antibodies (bnAbs) in infection and to recreate those events by vaccination. Here, we report host tolerance mechanisms that limit the development of CD4-binding site (CD4bs), HCDR3-binder bnAbs via sequential HIV-1 Env vaccination. Vaccine-induced macaque CD4bs antibodies neutralize 7% of HIV-1 strains, recognize open Env trimers, and accumulate relatively modest somatic mutations. In naive CD4bs, unmutated common ancestor knock-in mice Env+B cell clones develop anergy and partial deletion at the transitional to mature B cell stage, but become Env− upon receptor editing. In comparison with repetitive Env immunizations, sequential Env administration rescue anergic Env+ (non-edited) precursor B cells. Thus, stepwise immunization initiates CD4bs-bnAb responses, but immune tolerance mechanisms restrict their development, suggesting that sequential immunogen-based vaccine regimens will likely need to incorporate strategies to expand bnAb precursor pools.

Date: 2017
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DOI: 10.1038/s41467-017-01336-3

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