HIV-1 Envelope Glycoproteins Proteolytic Cleavage Protects Infected Cells from ADCC Mediated by Plasma from Infected Individuals

The HIV-1 envelope glycoprotein (Env) is synthesized in the endoplasmic reticulum as a trimeric gp160 precursor, which requires proteolytic cleavage by a cellular furin protease to mediate virus-cell fusion. Env is conformationally flexible but controls its transition from the unbound “closed” confo...

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Autores principales: Jérémie Prévost, Halima Medjahed, Dani Vézina, Hung-Ching Chen, Beatrice H. Hahn, Amos B. Smith, Andrés Finzi
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Publicado: MDPI AG 2021
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Acceso en línea:https://doaj.org/article/f9a7cfc38dc346768a1d29923cc3a948
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spelling oai:doaj.org-article:f9a7cfc38dc346768a1d29923cc3a9482021-11-25T19:13:38ZHIV-1 Envelope Glycoproteins Proteolytic Cleavage Protects Infected Cells from ADCC Mediated by Plasma from Infected Individuals10.3390/v131122361999-4915https://doaj.org/article/f9a7cfc38dc346768a1d29923cc3a9482021-11-01T00:00:00Zhttps://www.mdpi.com/1999-4915/13/11/2236https://doaj.org/toc/1999-4915The HIV-1 envelope glycoprotein (Env) is synthesized in the endoplasmic reticulum as a trimeric gp160 precursor, which requires proteolytic cleavage by a cellular furin protease to mediate virus-cell fusion. Env is conformationally flexible but controls its transition from the unbound “closed” conformation (State 1) to downstream CD4-bound conformations (States 2/3), which are required for fusion. In particular, HIV-1 has evolved several mechanisms that reduce the premature “opening” of Env which exposes highly conserved epitopes recognized by non-neutralizing antibodies (nnAbs) capable of mediating antibody-dependent cellular cytotoxicity (ADCC). Env cleavage decreases its conformational transitions favoring the adoption of the “closed” conformation. Here we altered the gp160 furin cleavage site to impair Env cleavage and to examine its impact on ADCC responses mediated by plasma from HIV-1-infected individuals. We found that infected primary CD4+ T cells expressing uncleaved, but not wildtype, Env are efficiently recognized by nnAbs and become highly susceptible to ADCC responses mediated by plasma from HIV-1-infected individuals. Thus, HIV-1 limits the exposure of uncleaved Env at the surface of HIV-1-infected cells at least in part to escape ADCC responses.Jérémie PrévostHalima MedjahedDani VézinaHung-Ching ChenBeatrice H. HahnAmos B. SmithAndrés FinziMDPI AGarticleHIV-1Env glycoproteinfurin cleavage siteCD4 mimeticsTemsavirnnAbsMicrobiologyQR1-502ENViruses, Vol 13, Iss 2236, p 2236 (2021)
institution DOAJ
collection DOAJ
language EN
topic HIV-1
Env glycoprotein
furin cleavage site
CD4 mimetics
Temsavir
nnAbs
Microbiology
QR1-502
spellingShingle HIV-1
Env glycoprotein
furin cleavage site
CD4 mimetics
Temsavir
nnAbs
Microbiology
QR1-502
Jérémie Prévost
Halima Medjahed
Dani Vézina
Hung-Ching Chen
Beatrice H. Hahn
Amos B. Smith
Andrés Finzi
HIV-1 Envelope Glycoproteins Proteolytic Cleavage Protects Infected Cells from ADCC Mediated by Plasma from Infected Individuals
description The HIV-1 envelope glycoprotein (Env) is synthesized in the endoplasmic reticulum as a trimeric gp160 precursor, which requires proteolytic cleavage by a cellular furin protease to mediate virus-cell fusion. Env is conformationally flexible but controls its transition from the unbound “closed” conformation (State 1) to downstream CD4-bound conformations (States 2/3), which are required for fusion. In particular, HIV-1 has evolved several mechanisms that reduce the premature “opening” of Env which exposes highly conserved epitopes recognized by non-neutralizing antibodies (nnAbs) capable of mediating antibody-dependent cellular cytotoxicity (ADCC). Env cleavage decreases its conformational transitions favoring the adoption of the “closed” conformation. Here we altered the gp160 furin cleavage site to impair Env cleavage and to examine its impact on ADCC responses mediated by plasma from HIV-1-infected individuals. We found that infected primary CD4+ T cells expressing uncleaved, but not wildtype, Env are efficiently recognized by nnAbs and become highly susceptible to ADCC responses mediated by plasma from HIV-1-infected individuals. Thus, HIV-1 limits the exposure of uncleaved Env at the surface of HIV-1-infected cells at least in part to escape ADCC responses.
format article
author Jérémie Prévost
Halima Medjahed
Dani Vézina
Hung-Ching Chen
Beatrice H. Hahn
Amos B. Smith
Andrés Finzi
author_facet Jérémie Prévost
Halima Medjahed
Dani Vézina
Hung-Ching Chen
Beatrice H. Hahn
Amos B. Smith
Andrés Finzi
author_sort Jérémie Prévost
title HIV-1 Envelope Glycoproteins Proteolytic Cleavage Protects Infected Cells from ADCC Mediated by Plasma from Infected Individuals
title_short HIV-1 Envelope Glycoproteins Proteolytic Cleavage Protects Infected Cells from ADCC Mediated by Plasma from Infected Individuals
title_full HIV-1 Envelope Glycoproteins Proteolytic Cleavage Protects Infected Cells from ADCC Mediated by Plasma from Infected Individuals
title_fullStr HIV-1 Envelope Glycoproteins Proteolytic Cleavage Protects Infected Cells from ADCC Mediated by Plasma from Infected Individuals
title_full_unstemmed HIV-1 Envelope Glycoproteins Proteolytic Cleavage Protects Infected Cells from ADCC Mediated by Plasma from Infected Individuals
title_sort hiv-1 envelope glycoproteins proteolytic cleavage protects infected cells from adcc mediated by plasma from infected individuals
publisher MDPI AG
publishDate 2021
url https://doaj.org/article/f9a7cfc38dc346768a1d29923cc3a948
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