Year: 2017
Type: article
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.
Source: Nature Communications
Authors: 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, Laurent Verkoczy
Institutions: Duke University, Duke Medical Center, Boston Children's Hospital, Harvard University, Jinan University, Boston University, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Vaccine Research Center, Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University, Infectious Disease Research Institute, GlaxoSmithKline (Belgium)
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G1756342139, G2123841078, G2177238625, G2986651025, G3056361687, Defining parameters to induce breadth in knockin mice expressing HIV bnAb precursors, HIV-1 vaccine-elicited antibodies target envelope glycans, G5267713852, G572720644, Data commons for 'omic, microscopy and analysis core facilities, G7397782118, G7811065844, G8650374520, G9000100583, G9000127136, G9000129325, Providence/Boston Center for AIDS Research (CFAR), Center for AIDS Research, G926065654, G957283583
OpenAlex ID: W2768887307