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TitleInitiation of HIV neutralizing B cell lineages with sequential envelope immunizations.
Journal, issue, pagesNat Commun, Vol. 8, Issue 1, Page 1732, Year 2017
Publish dateNov 23, 2017
AuthorsWilton 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 /
PubMed AbstractA 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 ...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 EnvB 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.
External linksNat Commun / PubMed:29170366 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.75 - 28.1 Å
Structure data

EMDB-9401:
CH505 SOSIP.664 trimer in complex with DH522.2 Fab
Method: EM (single particle) / Resolution: 28.1 Å

PDB-5ukn:
Structure of unliganded anti-gp120 CD4bs antibody DH522UCA Fab
Method: X-RAY DIFFRACTION / Resolution: 1.75 Å

PDB-5uko:
Structure of unliganded anti-gp120 CD4bs antibody DH522IA Fab
Method: X-RAY DIFFRACTION / Resolution: 2.3 Å

PDB-5ukp:
Structure of unliganded anti-gp120 CD4bs antibody DH522.1 Fab
Method: X-RAY DIFFRACTION / Resolution: 2.0 Å

PDB-5ukq:
Structure of unliganded anti-gp120 CD4bs antibody DH522.2 Fab
Method: X-RAY DIFFRACTION / Resolution: 2.1 Å

PDB-5ukr:
Structure of unliganded anti-gp120 CD4bs antibody DH522.2 Fab in complex with a gp120 core
Method: X-RAY DIFFRACTION / Resolution: 2.712 Å

Chemicals

ChemComp-CL:
Unknown entry / Chloride

ChemComp-HOH:
WATER / Water

ChemComp-GOL:
GLYCEROL / Glycerol

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • Homo sapiens (human)
  • human immunodeficiency virus 1
  • macaca mulatta (Rhesus monkey)
KeywordsIMMUNE SYSTEM / HIV gp120 / HIV gp120 immune system

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