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Structure. 2017 Nov 7;25(11):1719-1731.e4. doi: 10.1016/j.str.2017.09.009. Epub 2017 Oct 19.

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

Author information

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.
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.
5
CEA, Joliot, Service d'Ingénierie Moléculaire des Protéines, 91191 Gif-sur-Yvette, 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.
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: mpazgier@ihv.umaryland.edu.

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.

KEYWORDS:

C11 epitope region; C11-like antibody; HIV-1 entry; N12-i3 antibody; antibody-dependent cellular cytotoxicity (ADCC); cluster A epitopes; crystal structure

PMID:
29056481
PMCID:
PMC5677539
DOI:
10.1016/j.str.2017.09.009
[Indexed for MEDLINE]
Free PMC Article

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