Format

Send to

Choose Destination
Cell Host Microbe. 2019 Apr 10;25(4):578-587.e5. doi: 10.1016/j.chom.2019.03.002.

An Asymmetric Opening of HIV-1 Envelope Mediates Antibody-Dependent Cellular Cytotoxicity.

Author information

1
Centre de Recherche du CHUM, Montreal, QC, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
2
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, USA.
3
Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia.
4
Centre de Recherche du CHUM, Montreal, QC, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC, Canada.
5
Infectious Diseases Division, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
6
Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY, USA.
7
Centre de Recherche du CHUM, Montreal, QC, Canada.
8
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323, USA.
9
Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06536, USA.
10
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
11
Centre de Recherche du CHUM, Montreal, QC, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC, Canada; Department of Medicine, Université de Montréal, Montreal, QC, Canada; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
12
Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia. Electronic address: isabelle.rouiller@unimelb.edu.au.
13
Centre de Recherche du CHUM, Montreal, QC, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC, Canada. Electronic address: andres.finzi@umontreal.ca.
14
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, USA. Electronic address: james.munro@tufts.edu.

Abstract

The HIV-1 envelope glycoprotein (Env) (gp120-gp41)3 is the target for neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC). HIV-1 Env is flexible, sampling different conformational states. Before engaging CD4, Env adopts a closed conformation (State 1) that is largely antibody resistant. CD4 binding induces an intermediate state (State 2), followed by an open conformation (State 3) that is susceptible to engagement by antibodies that recognize otherwise occluded epitopes. We investigate conformational changes in Env that induce ADCC in the presence of a small-molecule CD4-mimetic compound (CD4mc). We uncover an asymmetric Env conformation (State 2A) recognized by antibodies targeting the conserved gp120 inner domain and mediating ADCC. Sera from HIV+ individuals contain these antibodies, which can stabilize Env State 2A in combination with CD4mc. Additionally, triggering State 2A on HIV-infected primary CD4+ T cells exposes epitopes that induce ADCC. Strategies that induce this Env conformation may represent approaches to fight HIV-1 infection.

KEYWORDS:

17b; A32; ADCC; CD4i Abs; HIV-1; State 2A; cryo-EM; envelope glycoproteins; smFRET

PMID:
30974085
DOI:
10.1016/j.chom.2019.03.002

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center