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Nat Commun. 2017 Oct 19;8(1):1049. doi: 10.1038/s41467-017-01119-w.

The β20-β21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions.

Author information

1
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, 02215, USA. alon_herschhorn@dfci.harvard.edu.
2
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, 02115, USA. alon_herschhorn@dfci.harvard.edu.
3
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, 02215, USA.
4
Department of Chemical and Biological Engineering, Drexel University, Philadelphia, Pennsylvania, 19104, USA.
5
Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, 06536, USA.
6
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA.
7
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, 20892, USA.
8
Department of Biology, Johns Hopkins University, Baltimore, Maryland, 21218, USA.
9
Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, New York, 10065, USA.
10
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, 02215, USA. joseph_sodroski@dfci.harvard.edu.
11
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, 02115, USA. joseph_sodroski@dfci.harvard.edu.
12
Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, 02115, USA. joseph_sodroski@dfci.harvard.edu.

Abstract

The entry of HIV-1 into target cells is mediated by the viral envelope glycoproteins (Env). Binding to the CD4 receptor triggers a cascade of conformational changes in distant domains that move Env from a functionally "closed" State 1 to more "open" conformations, but the molecular mechanisms underlying allosteric regulation of these transitions are still elusive. Here, we develop chemical probes that block CD4-induced conformational changes in Env and use them to identify a potential control switch for Env structural rearrangements. We identify the gp120 β20-β21 element as a major regulator of Env transitions. Several amino acid changes in the β20-β21 base lead to open Env conformations, recapitulating the structural changes induced by CD4 binding. These HIV-1 mutants require less CD4 to infect cells and are relatively resistant to State 1-preferring broadly neutralizing antibodies. These data provide insights into the molecular mechanism and vulnerability of HIV-1 entry.

PMID:
29051495
PMCID:
PMC5648922
DOI:
10.1038/s41467-017-01119-w
[Indexed for MEDLINE]
Free PMC Article

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