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Targeting the Late Stage of HIV-1 Entry for Antibody-Dependent Cellular Cytotoxicity: Structural Basis for Env Epitopes in the C11 Region.

Authors
  • Tolbert, William D1
  • Gohain, Neelakshi1
  • Alsahafi, Nirmin2
  • Van, Verna1
  • Orlandi, Chiara3
  • Ding, Shilei4
  • Martin, Loïc5
  • Finzi, Andrés6
  • Lewis, George K3
  • Ray, Krishanu7
  • Pazgier, Marzena8
  • 1 Division of Vaccine Research, Institute of Human Virology, Baltimore, MD, USA; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 725 West Lombard Street, Baltimore, MD 21201, USA.
  • 2 Centre de Recherche du CHUM, Université de Montréal, Montreal, QC, Canada; CEA, Joliot, Service d'Ingénierie Moléculaire des Protéines, 91191 Gif-sur-Yvette, France. , (Canada)
  • 3 Division of Vaccine Research, Institute of Human Virology, Baltimore, MD, USA; Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA.
  • 4 Centre de Recherche du CHUM, Université de Montréal, Montreal, QC, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada. , (Canada)
  • 5 CEA, Joliot, Service d'Ingénierie Moléculaire des Protéines, 91191 Gif-sur-Yvette, France. , (France)
  • 6 Centre de Recherche du CHUM, Université de Montréal, Montreal, QC, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada. , (Canada)
  • 7 Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 725 West Lombard Street, Baltimore, MD 21201, USA.
  • 8 Division of Vaccine Research, Institute of Human Virology, Baltimore, MD, USA; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 725 West Lombard Street, Baltimore, MD 21201, USA. Electronic address: [email protected]
Type
Published Article
Journal
Structure
Publisher
Elsevier
Publication Date
Nov 07, 2017
Volume
25
Issue
11
Identifiers
DOI: 10.1016/j.str.2017.09.009
PMID: 29056481
Source
Medline
Keywords
License
Unknown

Abstract

Antibodies can have an impact on HIV-1 infection in multiple ways, including antibody-dependent cellular cytotoxicity (ADCC), a correlate of protection observed in the RV144 vaccine trial. One of the most potent ADCC-inducing epitopes on HIV-1 Env is recognized by the C11 antibody. Here, we present the crystal structure, at 2.9 Å resolution, of the C11-like antibody N12-i3, in a quaternary complex with the HIV-1 gp120, a CD4-mimicking peptide M48U1, and an A32-like antibody, N5-i5. Antibody N12-i3 recognizes an epitope centered on the N-terminal "eighth strand" of a critical β sandwich, which our analysis indicates to be emblematic of a late-entry state, after the gp120 detachment. In prior entry states, this sandwich comprises only seven strands, with the eighth strand instead pairing with a portion of the gp120 C terminus. The conformational gymnastics of HIV-1 gp120 thus includes altered β-strand pairing, possibly to reduce immunogenicity, although nevertheless still recognized by the human immune system.

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