Structural mechanism of trimeric HIV-1 envelope glycoprotein activation.

HIV-1 infection begins with the binding of trimeric viral envelope glycoproteins (Env) to CD4 and a co-receptor on target T-cells. Understanding how these ligands influence the structure of Env is of fundamental interest for HIV vaccine development. Using cryo-electron microscopy, we describe the co...

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Autores principales:	Erin E H Tran, Mario J Borgnia, Oleg Kuybeda, David M Schauder, Alberto Bartesaghi, Gabriel A Frank, Guillermo Sapiro, Jacqueline L S Milne, Sriram Subramaniam
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/751ac1f8702e4987964ef6137c268483
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spelling	oai:doaj.org-article:751ac1f8702e4987964ef6137c2684832021-11-18T06:04:13ZStructural mechanism of trimeric HIV-1 envelope glycoprotein activation.1553-73661553-737410.1371/journal.ppat.1002797https://doaj.org/article/751ac1f8702e4987964ef6137c2684832012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22807678/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374HIV-1 infection begins with the binding of trimeric viral envelope glycoproteins (Env) to CD4 and a co-receptor on target T-cells. Understanding how these ligands influence the structure of Env is of fundamental interest for HIV vaccine development. Using cryo-electron microscopy, we describe the contrasting structural outcomes of trimeric Env binding to soluble CD4, to the broadly neutralizing, CD4-binding site antibodies VRC01, VRC03 and b12, or to the monoclonal antibody 17b, a co-receptor mimic. Binding of trimeric HIV-1 BaL Env to either soluble CD4 or 17b alone, is sufficient to trigger formation of the open quaternary conformation of Env. In contrast, VRC01 locks Env in the closed state, while b12 binding requires a partial opening in the quaternary structure of trimeric Env. Our results show that, despite general similarities in regions of the HIV-1 gp120 polypeptide that contact CD4, VRC01, VRC03 and b12, there are important differences in quaternary structures of the complexes these ligands form on native trimeric Env, and potentially explain differences in the neutralizing breadth and potency of antibodies with similar specificities. From cryo-electron microscopic analysis at ∼9 Å resolution of a cleaved, soluble version of trimeric Env, we show that a structural signature of the open Env conformation is a three-helix motif composed of α-helical segments derived from highly conserved, non-glycosylated N-terminal regions of the gp41 trimer. The three N-terminal gp41 helices in this novel, activated Env conformation are held apart by their interactions with the rest of Env, and are less compactly packed than in the post-fusion, six-helix bundle state. These findings suggest a new structural template for designing immunogens that can elicit antibodies targeting HIV at a vulnerable, pre-entry stage.Erin E H TranMario J BorgniaOleg KuybedaDavid M SchauderAlberto BartesaghiGabriel A FrankGuillermo SapiroJacqueline L S MilneSriram SubramaniamPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 8, Iss 7, p e1002797 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Erin E H Tran Mario J Borgnia Oleg Kuybeda David M Schauder Alberto Bartesaghi Gabriel A Frank Guillermo Sapiro Jacqueline L S Milne Sriram Subramaniam Structural mechanism of trimeric HIV-1 envelope glycoprotein activation.
description	HIV-1 infection begins with the binding of trimeric viral envelope glycoproteins (Env) to CD4 and a co-receptor on target T-cells. Understanding how these ligands influence the structure of Env is of fundamental interest for HIV vaccine development. Using cryo-electron microscopy, we describe the contrasting structural outcomes of trimeric Env binding to soluble CD4, to the broadly neutralizing, CD4-binding site antibodies VRC01, VRC03 and b12, or to the monoclonal antibody 17b, a co-receptor mimic. Binding of trimeric HIV-1 BaL Env to either soluble CD4 or 17b alone, is sufficient to trigger formation of the open quaternary conformation of Env. In contrast, VRC01 locks Env in the closed state, while b12 binding requires a partial opening in the quaternary structure of trimeric Env. Our results show that, despite general similarities in regions of the HIV-1 gp120 polypeptide that contact CD4, VRC01, VRC03 and b12, there are important differences in quaternary structures of the complexes these ligands form on native trimeric Env, and potentially explain differences in the neutralizing breadth and potency of antibodies with similar specificities. From cryo-electron microscopic analysis at ∼9 Å resolution of a cleaved, soluble version of trimeric Env, we show that a structural signature of the open Env conformation is a three-helix motif composed of α-helical segments derived from highly conserved, non-glycosylated N-terminal regions of the gp41 trimer. The three N-terminal gp41 helices in this novel, activated Env conformation are held apart by their interactions with the rest of Env, and are less compactly packed than in the post-fusion, six-helix bundle state. These findings suggest a new structural template for designing immunogens that can elicit antibodies targeting HIV at a vulnerable, pre-entry stage.
format	article
author	Erin E H Tran Mario J Borgnia Oleg Kuybeda David M Schauder Alberto Bartesaghi Gabriel A Frank Guillermo Sapiro Jacqueline L S Milne Sriram Subramaniam
author_facet	Erin E H Tran Mario J Borgnia Oleg Kuybeda David M Schauder Alberto Bartesaghi Gabriel A Frank Guillermo Sapiro Jacqueline L S Milne Sriram Subramaniam
author_sort	Erin E H Tran
title	Structural mechanism of trimeric HIV-1 envelope glycoprotein activation.
title_short	Structural mechanism of trimeric HIV-1 envelope glycoprotein activation.
title_full	Structural mechanism of trimeric HIV-1 envelope glycoprotein activation.
title_fullStr	Structural mechanism of trimeric HIV-1 envelope glycoprotein activation.
title_full_unstemmed	Structural mechanism of trimeric HIV-1 envelope glycoprotein activation.
title_sort	structural mechanism of trimeric hiv-1 envelope glycoprotein activation.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/751ac1f8702e4987964ef6137c268483
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Structural mechanism of trimeric HIV-1 envelope glycoprotein activation.

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