SIVcol Nef counteracts SERINC5 by promoting its proteasomal degradation but does not efficiently enhance HIV-1 replication in human CD4+ T cells and lymphoid tissue
| Autor: | Frank Kirchhoff, Dominik Hotter, Daniel Sauter, Martine Peeters, Christine Goffinet, Oliver T. Fackler, Konstantin M. J. Sparrer, Zhong Yao, Birthe Trautz, Ahidjo Ayouba, Bengisu Akbil, Thomas Zillinger, Igor Stagljar, Christina M. Stürzel, Swetha Ananth, Vânia Passos, Dorota Kmiec |
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| Přispěvatelé: | Institute of Molecular Virology [Ulm, Allemagne], Universitätsklinikum Ulm - University Hospital of Ulm, Department of Infectious Diseases, Integrative Virology [Heidelberg, Allemagne], Center for Integrative Infectious Diseases Research [Heidelberg, Allemagne] (CIID), Heidelberg University Hospital [Heidelberg]-Heidelberg University Hospital [Heidelberg], German Center for Infection Research, Partner Site Heidelberg [Allemagne] (DZIF), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Donnelly Centre [Toronto, ON, Canada], University of Toronto, Department of Biochemistry [University of Toronto], Department of Molecular Genetics [Toronto], Institute of Virology [Hannover], Hannover Medical School [Hannover] (MHH), Institute of Clinical Chemistry and Clinical Pharmacology [Bonn, Allemagne], University of Bonn, This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG, European Project: 323035,EC:FP7:ERC,ERC-2012-ADG_20120314,ANTI-VIROME(2013), Bodescot, Myriam, A combined evolutionary and proteomics approach to the discovery, induction and application of antiviral immunity factors - ANTI-VIROME - - EC:FP7:ERC2013-04-01 - 2018-03-31 - 323035 - VALID, Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Universität Bonn = University of Bonn, Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université Montpellier 1 (UM1) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
RNA viruses CD4-Positive T-Lymphocytes viruses Xenopus Monkeys Pathology and Laboratory Medicine Virus Replication Gene Products nef Virions White Blood Cells Database and Informatics Methods Jurkat Cells Immunodeficiency Viruses Animal Cells [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases Medicine and Health Sciences lcsh:QH301-705.5 Cells Cultured Infectivity Mammals T Cells CD28 Eukaryota virus diseases Transfection 3. Good health Cell biology medicine.anatomical_structure Infectious Diseases Medical Microbiology Viral Pathogens Viruses Vertebrates [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases [SDV.IMM]Life Sciences [q-bio]/Immunology Simian Immunodeficiency Virus Pathogens Cellular Types Sequence Analysis Research Article Primates lcsh:Immunologic diseases. Allergy Proteasome Endopeptidase Complex Infectious Disease Control [SDV.IMM] Life Sciences [q-bio]/Immunology Bioinformatics Lymphoid Tissue T cell Immune Cells Immunology Biology Viral Structure Colobus Research and Analysis Methods Microbiology 03 medical and health sciences Sequence Motif Analysis Virology Retroviruses Old World monkeys Genetics medicine Animals Humans Molecular Biology Microbial Pathogens Blood Cells Lentivirus Organisms Actin remodeling Biology and Life Sciences HIV Membrane Proteins Cell Biology biology.organism_classification Viral Replication 030104 developmental biology HEK293 Cells Viral replication lcsh:Biology (General) Amniotes Proteolysis Tetherin HIV-1 Parasitology lcsh:RC581-607 |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Public Library of Science, 2018, 14 (8), pp.e1007269. ⟨10.1371/journal.ppat.1007269⟩ PLoS Pathogens, 2018, 14 (8), pp.e1007269. ⟨10.1371/journal.ppat.1007269⟩ PLoS Pathogens, Vol 14, Iss 8, p e1007269 (2018) |
| ISSN: | 1553-7366 1553-7374 |
| Popis: | SERINC5 is a host restriction factor that impairs infectivity of HIV-1 and other primate lentiviruses and is counteracted by the viral accessory protein Nef. However, the importance of SERINC5 antagonism for viral replication and cytopathicity remained unclear. Here, we show that the Nef protein of the highly divergent SIVcol lineage infecting mantled guerezas (Colobus guereza) is a potent antagonist of SERINC5, although it lacks the CD4, CD3 and CD28 down-modulation activities exerted by other primate lentiviral Nefs. In addition, SIVcol Nefs decrease CXCR4 cell surface expression, suppress TCR-induced actin remodeling, and counteract Colobus but not human tetherin. Unlike HIV-1 Nef proteins, SIVcol Nef induces efficient proteasomal degradation of SERINC5 and counteracts orthologs from highly divergent vertebrate species, such as Xenopus frogs and zebrafish. A single Y86F mutation disrupts SERINC5 and tetherin antagonism but not CXCR4 down-modulation by SIVcol Nef, while mutation of a C-proximal di-leucine motif has the opposite effect. Unexpectedly, the Y86F change in SIVcol Nef had little if any effect on viral replication and CD4+ T cell depletion in preactivated human CD4+ T cells and in ex vivo infected lymphoid tissue. However, SIVcol Nef increased virion infectivity up to 10-fold and moderately increased viral replication in resting peripheral blood mononuclear cells (PBMCs) that were first infected with HIV-1 and activated three or six days later. In conclusion, SIVcol Nef lacks several activities that are conserved in other primate lentiviruses and utilizes a distinct proteasome-dependent mechanism to counteract SERINC5. Our finding that evolutionarily distinct SIVcol Nefs show potent anti-SERINC5 activity supports a relevant role of SERINC5 antagonism for viral fitness in vivo. Our results further suggest this Nef function is particularly important for virion infectivity under conditions of limited CD4+ T cell activation. Author summary The accessory protein Nef promotes primate lentiviral replication and enhances the pathogenicity of HIV-1 by mechanisms of immune evasion and enhancing viral infectivity and replication. Here, we show that the evolutionarily most isolated primate lentivirus SIVcol lacks several otherwise conserved Nef functions. Nevertheless, SIVcol Nef potently antagonizes SERINC5, a recently discovered inhibitor of viral infectivity, by down-modulating it from the cell surface and inducing its proteasomal degradation. We identified Y86 in SIVcol Nef as a key determinant of SERINC5 antagonism. Efficient counteraction of SERINC5 did not increase HIV-1 replication in preactivated CD4+ T cells and in ex vivo infected lymphoid tissue but had modest enhancing effects when resting PBMCs were first infected and activated six days later. Evolution of high anti-SERINC5 activity by SIVcol Nef supports a relevant role of this antagonism in vivo, for instance by enhancing virion infectivity under conditions of limited T cell activation. |
| Databáze: | OpenAIRE |
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