HTLV-1 Evades Type I Interferon Antiviral Signaling by Inducing the Suppressor of Cytokine Signaling 1 (SOCS1)

PLoS Pathogens

Eduardo Hernandez¹  Stéphane Olindo¹  Mirdad Kazanji¹  John Hiscott²  Rafick-Pierre Sékaly³  Meztli Arguello³  Peter Wilkinson³  Gérard Panelatti⁴  Renée Douville⁴  Stéphanie Olière⁴  Agnès Lézin⁴  Thi Lien-Anh Nguyen⁴  Raymond Césaire⁵ 

[1] Departments of Microbiology and Medicine, McGill University, Montreal, Quebec, Canada;Laboratoire d'Immunologie, Centre de Recherche du Centre Hospitalier de l'Université de Montréal Saint-Luc, Montréal, Quebec, Canada;Laboratoire de Virologie-Immunologie, Service de Neurologie and JE2503, Université des Antilles et de la Guyane, Centre Hospitalier Universitaire de Fort-de-France, Fort-de-France, Martinique;Molecular Oncology Group, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada;Unité de Rétrovirologie, Centre International de Recherches Médicales de Franceville (CIRMF), Franceville, Gabon

关键词: HTLV-1;    Gene expression;    T cells;    RNA extraction;    Interferons;    Viral gene expression;    Immunoblotting;    Polymerase chain reaction;   

DOI  :  10.1371/journal.ppat.1001177

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of Adult T cell Leukemia (ATL) and the neurological disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the majority of HTLV-1–infected individuals remain asymptomatic carriers (AC) during their lifetime, 2–5% will develop either ATL or HAM/TSP, but never both. To better understand the gene expression changes in HTLV-1-associated diseases, we examined the mRNA profiles of CD4+ T cells isolated from 7 ATL, 12 HAM/TSP, 11 AC and 8 non-infected controls. Using genomic approaches followed by bioinformatic analysis, we identified gene expression pattern characteristic of HTLV-1 infected individuals and particular disease states. Of particular interest, the suppressor of cytokine signaling 1—SOCS1—was upregulated in HAM/TSP and AC patients but not in ATL. Moreover, SOCS1 was positively correlated with the expression of HTLV-1 mRNA in HAM/TSP patient samples. In primary PBMCs transfected with a HTLV-1 proviral clone and in HTLV-1-transformed MT-2 cells, HTLV-1 replication correlated with induction of SOCS1 and inhibition of IFN-α/β and IFN-stimulated gene expression. Targeting SOCS1 with siRNA restored type I IFN production and reduced HTLV-1 replication in MT-2 cells. Conversely, exogenous expression of SOCS1 resulted in enhanced HTLV-1 mRNA synthesis. In addition to inhibiting signaling downstream of the IFN receptor, SOCS1 inhibited IFN-β production by targeting IRF3 for ubiquitination and proteasomal degradation. These observations identify a novel SOCS1 driven mechanism of evasion of the type I IFN antiviral response against HTLV-1.

【 授权许可】

CC BY