Lipidomimetic Compounds Act as HIV-1 Entry Inhibitors by Altering Viral Membrane Structure
The envelope of Human Immunodeficiency Virus type 1 (HIV-1) consists of a liquid-ordered membrane enriched in raft lipids and containing the viral glycoproteins. Previous studies demonstrated that changes in viral membrane lipid composition affecting membrane structure or curvature can impair infect...
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Format: | Article |
Language: | English |
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Frontiers Media S.A.
2018-09-01
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Series: | Frontiers in Immunology |
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Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.01983/full |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jon Ander Nieto-Garai Bärbel Glass Carmen Bunn Matthias Giese Gary Jennings Beate Brankatschk Beate Brankatschk Sameer Agarwal Sameer Agarwal Kathleen Börner F. Xabier Contreras F. Xabier Contreras Hans-Joachim Knölker Hans-Joachim Knölker Claudia Zankl Claudia Zankl Kai Simons Cornelia Schroeder Cornelia Schroeder Cornelia Schroeder Maier Lorizate Hans-Georg Kräusslich |
spellingShingle |
Jon Ander Nieto-Garai Bärbel Glass Carmen Bunn Matthias Giese Gary Jennings Beate Brankatschk Beate Brankatschk Sameer Agarwal Sameer Agarwal Kathleen Börner F. Xabier Contreras F. Xabier Contreras Hans-Joachim Knölker Hans-Joachim Knölker Claudia Zankl Claudia Zankl Kai Simons Cornelia Schroeder Cornelia Schroeder Cornelia Schroeder Maier Lorizate Hans-Georg Kräusslich Lipidomimetic Compounds Act as HIV-1 Entry Inhibitors by Altering Viral Membrane Structure Frontiers in Immunology lipidomimetics HIV-1 envelope lipid raft modulation laurdan membrane order HIV fusion inhibitors |
author_facet |
Jon Ander Nieto-Garai Bärbel Glass Carmen Bunn Matthias Giese Gary Jennings Beate Brankatschk Beate Brankatschk Sameer Agarwal Sameer Agarwal Kathleen Börner F. Xabier Contreras F. Xabier Contreras Hans-Joachim Knölker Hans-Joachim Knölker Claudia Zankl Claudia Zankl Kai Simons Cornelia Schroeder Cornelia Schroeder Cornelia Schroeder Maier Lorizate Hans-Georg Kräusslich |
author_sort |
Jon Ander Nieto-Garai |
title |
Lipidomimetic Compounds Act as HIV-1 Entry Inhibitors by Altering Viral Membrane Structure |
title_short |
Lipidomimetic Compounds Act as HIV-1 Entry Inhibitors by Altering Viral Membrane Structure |
title_full |
Lipidomimetic Compounds Act as HIV-1 Entry Inhibitors by Altering Viral Membrane Structure |
title_fullStr |
Lipidomimetic Compounds Act as HIV-1 Entry Inhibitors by Altering Viral Membrane Structure |
title_full_unstemmed |
Lipidomimetic Compounds Act as HIV-1 Entry Inhibitors by Altering Viral Membrane Structure |
title_sort |
lipidomimetic compounds act as hiv-1 entry inhibitors by altering viral membrane structure |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2018-09-01 |
description |
The envelope of Human Immunodeficiency Virus type 1 (HIV-1) consists of a liquid-ordered membrane enriched in raft lipids and containing the viral glycoproteins. Previous studies demonstrated that changes in viral membrane lipid composition affecting membrane structure or curvature can impair infectivity. Here, we describe novel antiviral compounds that were identified by screening compound libraries based on raft lipid-like scaffolds. Three distinct molecular structures were chosen for mode-of-action studies, a sterol derivative (J391B), a sphingosine derivative (J582C) and a long aliphatic chain derivative (IBS70). All three target the viral membrane and inhibit virus infectivity at the stage of fusion without perturbing virus stability or affecting virion-associated envelope glycoproteins. Their effect did not depend on the expressed envelope glycoproteins or a specific entry route, being equally strong in HIV pseudotypes carrying VSV-G or MLV-Env glycoproteins. Labeling with laurdan, a reporter of membrane order, revealed different membrane structure alterations upon compound treatment of HIV-1, which correlated with loss of infectivity. J582C and IBS70 decreased membrane order in distinctive ways, whereas J391B increased membrane order. The compounds' effects on membrane order were reproduced in liposomes generated from extracted HIV lipids and thus independent both of virion proteins and of membrane leaflet asymmetry. Remarkably, increase of membrane order by J391B required phosphatidylserine, a lipid enriched in the HIV envelope. Counterintuitively, mixtures of two compounds with opposite effects on membrane order, J582C and J391B, did not neutralize each other but synergistically inhibited HIV infection. Thus, altering membrane order, which can occur by different mechanisms, constitutes a novel antiviral mode of action that may be of general relevance for enveloped viruses and difficult to overcome by resistance development. |
topic |
lipidomimetics HIV-1 envelope lipid raft modulation laurdan membrane order HIV fusion inhibitors |
url |
https://www.frontiersin.org/article/10.3389/fimmu.2018.01983/full |
work_keys_str_mv |
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doaj-fd4444ee06e94b2faeeb9a3b8b7837312020-11-25T01:08:07ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-09-01910.3389/fimmu.2018.01983402042Lipidomimetic Compounds Act as HIV-1 Entry Inhibitors by Altering Viral Membrane StructureJon Ander Nieto-Garai0Bärbel Glass1Carmen Bunn2Matthias Giese3Gary Jennings4Beate Brankatschk5Beate Brankatschk6Sameer Agarwal7Sameer Agarwal8Kathleen Börner9F. Xabier Contreras10F. Xabier Contreras11Hans-Joachim Knölker12Hans-Joachim Knölker13Claudia Zankl14Claudia Zankl15Kai Simons16Cornelia Schroeder17Cornelia Schroeder18Cornelia Schroeder19Maier Lorizate20Hans-Georg Kräusslich21Departamento de Bioquímica y Biología Molecular, Instituto Biofisika (CSIC, UPV/EHU), Universidad del País Vasco, Bilbao, SpainDepartment of Infectious Diseases, Virology, Universitätsklinikum Heidelberg, Heidelberg, GermanyJADO Technologies, Dresden, GermanyJADO Technologies, Dresden, GermanyJADO Technologies, Dresden, GermanyJADO Technologies, Dresden, GermanyMembrane Biochemistry Group, Paul-Langerhans-Institute Dresden, Helmholtz Zentrum München at the University Hospital and Faculty of Medicine Carl Gustav Carus, Dresden, GermanyJADO Technologies, Dresden, GermanyDepartment of Chemistry, Technische Universität Dresden, Dresden, GermanyDepartment of Infectious Diseases, Virology, Universitätsklinikum Heidelberg, Heidelberg, GermanyDepartamento de Bioquímica y Biología Molecular, Instituto Biofisika (CSIC, UPV/EHU), Universidad del País Vasco, Bilbao, SpainIkerbasque, Basque Foundation for Science, Bilbao, SpainJADO Technologies, Dresden, GermanyDepartment of Chemistry, Technische Universität Dresden, Dresden, GermanyJADO Technologies, Dresden, GermanyDepartment of Chemistry, Technische Universität Dresden, Dresden, GermanyMax Planck Institute of Molecular Cell Biology and Genetics, Dresden, GermanyJADO Technologies, Dresden, GermanyMax Planck Institute of Molecular Cell Biology and Genetics, Dresden, GermanyDepartment of Anatomy, Medical Faculty Carl-Gustav-Carus, Technische Universität Dresden, Dresden, GermanyDepartamento de Bioquímica y Biología Molecular, Instituto Biofisika (CSIC, UPV/EHU), Universidad del País Vasco, Bilbao, SpainDepartment of Infectious Diseases, Virology, Universitätsklinikum Heidelberg, Heidelberg, GermanyThe envelope of Human Immunodeficiency Virus type 1 (HIV-1) consists of a liquid-ordered membrane enriched in raft lipids and containing the viral glycoproteins. Previous studies demonstrated that changes in viral membrane lipid composition affecting membrane structure or curvature can impair infectivity. Here, we describe novel antiviral compounds that were identified by screening compound libraries based on raft lipid-like scaffolds. Three distinct molecular structures were chosen for mode-of-action studies, a sterol derivative (J391B), a sphingosine derivative (J582C) and a long aliphatic chain derivative (IBS70). All three target the viral membrane and inhibit virus infectivity at the stage of fusion without perturbing virus stability or affecting virion-associated envelope glycoproteins. Their effect did not depend on the expressed envelope glycoproteins or a specific entry route, being equally strong in HIV pseudotypes carrying VSV-G or MLV-Env glycoproteins. Labeling with laurdan, a reporter of membrane order, revealed different membrane structure alterations upon compound treatment of HIV-1, which correlated with loss of infectivity. J582C and IBS70 decreased membrane order in distinctive ways, whereas J391B increased membrane order. The compounds' effects on membrane order were reproduced in liposomes generated from extracted HIV lipids and thus independent both of virion proteins and of membrane leaflet asymmetry. Remarkably, increase of membrane order by J391B required phosphatidylserine, a lipid enriched in the HIV envelope. Counterintuitively, mixtures of two compounds with opposite effects on membrane order, J582C and J391B, did not neutralize each other but synergistically inhibited HIV infection. Thus, altering membrane order, which can occur by different mechanisms, constitutes a novel antiviral mode of action that may be of general relevance for enveloped viruses and difficult to overcome by resistance development.https://www.frontiersin.org/article/10.3389/fimmu.2018.01983/fulllipidomimeticsHIV-1 envelopelipid raft modulationlaurdanmembrane orderHIV fusion inhibitors |