Article abstract
Nature Immunology 8, 569 - 577 (2007)
Published online: 13 May 2007 | doi:10.1038/ni1470
Activation of the lectin DC-SIGN induces an immature dendritic cell phenotype triggering Rho-GTPase activity required for HIV-1 replication
Ashleigh Hodges1, Katherine Sharrocks1, Mariola Edelmann2, Dilair Baban3, Arnaud Moris4, Olivier Schwartz4, Hal Drakesmith5, Kay Davies3, Benedikt Kessler2, Andrew McMichael1 & Alison Simmons1
Abstract
DC-SIGN, a C-type lectin expressed on dendritic cells (DCs), can sequester human immunodeficiency virus (HIV) virions in multivesicular bodies. Here, using large-scale gene expression profiling and tyrosine-phosphorylated proteome analyses, we characterized signaling mediated by DC-SIGN after activation by either HIV or a DC-SIGN-specific antibody. Activation of DC-SIGN resulted in downregulation of genes encoding major histocompatibility complex class II, Jagged 1 and interferon-response molecules and upregulation of the gene encoding transcription factor ATF3. Phosphorylated proteome analysis showed that HIV- or antibody-stimulated DC-SIGN signaling was mediated by the Rho guanine nucleotide–exchange factor LARG and led to increased Rho-GTPase activity. Activation of LARG in DCs exposed to HIV was required for the formation of virus–T cell synapses. Thus, HIV sequestration by and stimulation of DC-SIGN helps HIV evade immune responses and spread to cells.
- Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
- The Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK.
- Medical Research Council Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.
- Groupe Virus et Immunité, Institut Pasteur, 75724 Paris, Cedex 15, France.
- Molecular Immunology Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
Correspondence to: Alison Simmons1 e-mail: asimmons@hammer.imm.ox.ac.uk
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