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Immunity. 2015 Dec 15;43(6):1053-63. doi: 10.1016/j.immuni.2015.11.007.

Affinity Maturation of a Potent Family of HIV Antibodies Is Primarily Focused on Accommodating or Avoiding Glycans.

Author information

1
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Scripps Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
2
Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, 1105 AZ, the Netherlands.
3
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
4
International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Scripps Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
5
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10065, USA.
6
Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, 1105 AZ, the Netherlands; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10065, USA.
7
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Scripps Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: wilson@scripps.edu.

Abstract

The high-mannose patch on the HIV-1 envelope (Env) glycoprotein is the epicenter for binding of the potent broadly neutralizing PGT121 family of antibodies, but strategies for generating such antibodies by vaccination have not been defined. We generated structures of inferred antibody intermediates by X-ray crystallography and electron microscopy to elucidate the molecular events that occurred during evolution of this family. Binding analyses revealed that affinity maturation was primarily focused on avoiding, accommodating, or binding the N137 glycan. The overall antibody approach angle to Env was defined very early in the maturation process, yet some variation evolved in the PGT121 family branches that led to differences in glycan specificities in their respective epitopes. Furthermore, we determined a crystal structure of the recombinant BG505 SOSIP.664 HIV-1 trimer with a PGT121 family member at 3.0 Å that, in concert with these antibody intermediate structures, provides insights to advance design of HIV vaccine candidates.

PMID:
26682982
PMCID:
PMC4692269
DOI:
10.1016/j.immuni.2015.11.007
[Indexed for MEDLINE]
Free PMC Article
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