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Blocking of HIV-1 Infection by Targeting CD4 to Nonraft Membrane Domains

Human immunodeficiency virus (HIV)-1 infection depends on multiple lateral interactions between the viral envelope and host cell receptors. Previous studies have suggested that these interactions are possible because HIV-1 receptors CD4, CXCR4, and CCR5 partition in cholesterol-enriched membrane raf...

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Autores principales: del Real, Gustavo, Jiménez-Baranda, Sonia, Lacalle, Rosa Ana, Mira, Emilia, Lucas, Pilar, Gómez-Moutón, Concepción, Carrera, Ana C., Martínez-A., Carlos, Mañes, Santos
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2002
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193941/
https://www.ncbi.nlm.nih.gov/pubmed/12163558
http://dx.doi.org/10.1084/jem.20020308
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author del Real, Gustavo
Jiménez-Baranda, Sonia
Lacalle, Rosa Ana
Mira, Emilia
Lucas, Pilar
Gómez-Moutón, Concepción
Carrera, Ana C.
Martínez-A., Carlos
Mañes, Santos
author_facet del Real, Gustavo
Jiménez-Baranda, Sonia
Lacalle, Rosa Ana
Mira, Emilia
Lucas, Pilar
Gómez-Moutón, Concepción
Carrera, Ana C.
Martínez-A., Carlos
Mañes, Santos
author_sort del Real, Gustavo
collection PubMed
description Human immunodeficiency virus (HIV)-1 infection depends on multiple lateral interactions between the viral envelope and host cell receptors. Previous studies have suggested that these interactions are possible because HIV-1 receptors CD4, CXCR4, and CCR5 partition in cholesterol-enriched membrane raft domains. We generated CD4 partitioning mutants by substituting or deleting CD4 transmembrane and cytoplasmic domains and the CD4 ectodomain was unaltered. We report that all CD4 mutants that retain raft partitioning mediate HIV-1 entry and CD4-induced Lck activation independently of their transmembrane and cytoplasmic domains. Conversely, CD4 ectodomain targeting to a nonraft membrane fraction results in a CD4 receptor with severely diminished capacity to mediate Lck activation or HIV-1 entry, although this mutant binds gp120 as well as CD4wt. In addition, the nonraft CD4 mutant inhibits HIV-1 X4 and R5 entry in a CD4(+) cell line. These results not only indicate that HIV-1 exploits host membrane raft domains as cell entry sites, but also suggest new strategies for preventing HIV-1 infection.
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spelling pubmed-21939412008-04-11 Blocking of HIV-1 Infection by Targeting CD4 to Nonraft Membrane Domains del Real, Gustavo Jiménez-Baranda, Sonia Lacalle, Rosa Ana Mira, Emilia Lucas, Pilar Gómez-Moutón, Concepción Carrera, Ana C. Martínez-A., Carlos Mañes, Santos J Exp Med Article Human immunodeficiency virus (HIV)-1 infection depends on multiple lateral interactions between the viral envelope and host cell receptors. Previous studies have suggested that these interactions are possible because HIV-1 receptors CD4, CXCR4, and CCR5 partition in cholesterol-enriched membrane raft domains. We generated CD4 partitioning mutants by substituting or deleting CD4 transmembrane and cytoplasmic domains and the CD4 ectodomain was unaltered. We report that all CD4 mutants that retain raft partitioning mediate HIV-1 entry and CD4-induced Lck activation independently of their transmembrane and cytoplasmic domains. Conversely, CD4 ectodomain targeting to a nonraft membrane fraction results in a CD4 receptor with severely diminished capacity to mediate Lck activation or HIV-1 entry, although this mutant binds gp120 as well as CD4wt. In addition, the nonraft CD4 mutant inhibits HIV-1 X4 and R5 entry in a CD4(+) cell line. These results not only indicate that HIV-1 exploits host membrane raft domains as cell entry sites, but also suggest new strategies for preventing HIV-1 infection. The Rockefeller University Press 2002-08-05 /pmc/articles/PMC2193941/ /pubmed/12163558 http://dx.doi.org/10.1084/jem.20020308 Text en Copyright © 2002, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
del Real, Gustavo
Jiménez-Baranda, Sonia
Lacalle, Rosa Ana
Mira, Emilia
Lucas, Pilar
Gómez-Moutón, Concepción
Carrera, Ana C.
Martínez-A., Carlos
Mañes, Santos
Blocking of HIV-1 Infection by Targeting CD4 to Nonraft Membrane Domains
title Blocking of HIV-1 Infection by Targeting CD4 to Nonraft Membrane Domains
title_full Blocking of HIV-1 Infection by Targeting CD4 to Nonraft Membrane Domains
title_fullStr Blocking of HIV-1 Infection by Targeting CD4 to Nonraft Membrane Domains
title_full_unstemmed Blocking of HIV-1 Infection by Targeting CD4 to Nonraft Membrane Domains
title_short Blocking of HIV-1 Infection by Targeting CD4 to Nonraft Membrane Domains
title_sort blocking of hiv-1 infection by targeting cd4 to nonraft membrane domains
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193941/
https://www.ncbi.nlm.nih.gov/pubmed/12163558
http://dx.doi.org/10.1084/jem.20020308
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