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

Alon Herschhorn (), Christopher Gu, Francesca Moraca, Xiaochu Ma, Mark Farrell, Amos B. Smith, Marie Pancera, Peter D. Kwong, Arne Schön, Ernesto Freire, Cameron Abrams, Scott C. Blanchard, Walther Mothes and Joseph G. Sodroski ()
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Alon Herschhorn: Dana-Farber Cancer Institute
Christopher Gu: Dana-Farber Cancer Institute
Francesca Moraca: Drexel University
Xiaochu Ma: Yale University School of Medicine
Mark Farrell: University of Pennsylvania
Amos B. Smith: University of Pennsylvania
Marie Pancera: National Institutes of Health
Peter D. Kwong: National Institutes of Health
Arne Schön: Johns Hopkins University
Ernesto Freire: Johns Hopkins University
Cameron Abrams: Drexel University
Scott C. Blanchard: Weill Cornell Medical College of Cornell University
Walther Mothes: Yale University School of Medicine
Joseph G. Sodroski: Dana-Farber Cancer Institute

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01119-w

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