Vpu Exploits the Cross-Talk between BST2 and the ILT7 Receptor to Suppress Anti-HIV-1 Responses by Plasmacytoid Dendritic Cells

Autor: Édouard A Côté, Nick Aschman, Winfried Weissenhorn, Johanne Mercier, Éric A. Cohen, Mariana G. Bego
Přispěvatelé: Thomas, Frank, Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID, Infrastructure Française pour la Biologie Structurale Intégrée - - FRISBI2010 - ANR-10-INBS-0005 - INBS - VALID, Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Partnership for Structural Biology Platforms, ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Jazyk: angličtina
Rok vydání: 2015
Předmět:
CD4-Positive T-Lymphocytes
lcsh:Immunologic diseases. Allergy
Viral protein
[SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Structural Biology [q-bio.BM]
Human Immunodeficiency Virus Proteins
Immunology
HIV Infections
Biology
GPI-Linked Proteins
medicine.disease_cause
Microbiology
Cell Line
Antigen
Antigens
CD
Interferon
Virology
Genetics
medicine
Humans
Viral Regulatory and Accessory Proteins
Receptors
Immunologic
Receptor
Molecular Biology
lcsh:QH301-705.5
Immune Evasion
Microscopy
Confocal
Innate immune system
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Structural Biology [q-bio.BM]
virus diseases
hemic and immune systems
Dendritic Cells
Receptor Cross-Talk
TLR7
Surface Plasmon Resonance
Flow Cytometry
Coculture Techniques
3. Good health
Cell biology
lcsh:Biology (General)
Cell culture
HIV-1
Tetherin
Parasitology
lcsh:RC581-607
Research Article
medicine.drug
Zdroj: PLoS Pathogens, Vol 11, Iss 7, p e1005024 (2015)
PLoS Pathogens
PLoS Pathogens, Public Library of Science, 2015, 11 (7), pp.e1005024
PLoS Pathogens, 2015, 11 (7), pp.e1005024
ISSN: 1553-7366
1553-7374
Popis: Plasmacytoid dendritic cells (pDCs) constitute a major source of type-I interferon (IFN-I) production during acute HIV infection. Their activation results primarily from TLR7-mediated sensing of HIV-infected cells. However, the interactions between HIV-infected T cells and pDCs that modulate this sensing process remain poorly understood. BST2/Tetherin is a restriction factor that inhibits HIV release by cross-linking virions onto infected cell surface. BST2 was also shown to engage the ILT7 pDC-specific inhibitory receptor and repress TLR7/9-mediated IFN-I production by activated pDCs. Here, we show that Vpu, the HIV-1 antagonist of BST2, suppresses TLR7-mediated IFN-I production by pDC through a mechanism that relies on the interaction of BST2 on HIV-producing cells with ILT7. Even though Vpu downregulates surface BST2 as a mean to counteract the restriction on HIV-1 release, we also find that the viral protein re-locates remaining BST2 molecules outside viral assembly sites where they are free to bind and activate ILT7 upon cell-to-cell contact. This study shows that through a targeted regulation of surface BST2, Vpu promotes HIV-1 release and limits pDC antiviral responses upon sensing of infected cells. This mechanism of innate immune evasion is likely to be important for an efficient early viral dissemination during acute infection.
Author Summary Plasmacytoid dendritic cells (pDCs) produce large quantities of type I interferon (IFN-I) upon stimulation by many viruses, including HIV. Their activation is very effective following cell contacts with HIV-1-infected CD4+ T cells. We investigated whether HIV-1 could regulate the antiviral responses of pDCs triggered upon sensing of infected cells. We show that HIV-1 suppresses the levels of IFN-I produced by pDCs through a process that requires expression of the Vpu accessory protein in virus-producing cells. A well-described role of Vpu is to promote efficient HIV-1 production by counteracting BST2, a host factor that entraps nascent viral particle at the cell surface. Apart from its antiviral activity, BST2 was reported to inhibit IFN-I production by pDCs through binding and activation of the ILT7 pDC-specific inhibitory receptor. Our results reveal that through a highly sophisticated targeted regulation of BST2 levels at the surface of infected cells, Vpu promotes HIV-1 release and limits IFN-I production by pDCs via the negative signaling exerted by the BST2-ILT7 pair. Overall, this study sheds light on a novel Vpu-BST2 interaction that allows HIV-1 to escape pDC antiviral responses. This modulation of pDC antiviral response by HIV Vpu may facilitate the initial viral expansion during acute infection.
Databáze: OpenAIRE
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