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

Abstract

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.

Functional Comparison of HBZ and the Related APH-2 Protein Provides Insight into Human T-Cell Leukemia Virus Type 1 Pathogenesis

“…However, other studies showed that Foxp3 expression in Tregs was stabilized by the cellular protein SOCS1 (60). The SOCS1 protein is upregulated by HTLV-1 infection, specifically, by Tax-1 (61,62). Previous observations suggested that ATL cells, which act phenotypically like Tregs, have high levels of expression of Foxp3 and maintain Tax expression (63).…”

Human T-Cell Leukemia/Lymphoma Virus Type 1 p30, but Not p12/p8, Counteracts Toll-Like Receptor 3 (TLR3) and TLR4 Signaling in Human Monocytes and Dendritic Cells

“…Although the mechanism is not fully understood, Hishizawa et al have shown that dendritic cells isolated from HTLV-1-infected individuals have an impaired ability to secrete type 1 IFN (16). In addition, it has been reported that the cellular protein SOCS, which inhibits STAT1 phosphorylation, inhibits intracellular signal transduction downstream of the IFN receptor, IFNAR1/2, in both ex vivo CD4 ϩ cells from HTLV-1-infected individuals and in vitro in HTLV-1-infected cells (50)(51)(52). Moreover, in HTLV-1-infected cells in vitro, the level of phosphorylation of Tyk2 and STAT2, two key molecules in the activation cascade of the IFN pathway, is decreased (53).…”

Human T-lymphotropic virus proteins and post-translational modification pathways

“…+ T cells from HAM/TSP and asymptomatic carriers, and correlates with viral replication [58] . In particular, SOCS-1 inhibits IFN expression and IFN-stimulated gene expression [58] .…”

“…In particular, SOCS-1 inhibits IFN expression and IFN-stimulated gene expression [58] . SOCS adaptors are bound to cullin-2 and -5 through elongin C and elongin B proteins to constitute ubiquitin ligase complexes [59] .…”