Systems Biology Approaches Reveal a Specific Interferon-Inducible Signature in HTLV-1 Associated Myelopathy

Sonja Tattermusch,Matthew P Berry,Finlay W Mcnab,Charles R M Bangham,Jason A Skinner,Damien Chaussabel,Graham P Taylor,Jacques Banchereau,Anne O'Garra,Susan R Ross

doi:10.1371/journal.ppat.1002480

Abstract

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that persists lifelong in the host. In ∼4% of infected people, HTLV-1 causes a chronic disabling neuroinflammatory disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The pathogenesis of HAM/TSP is unknown and treatment remains ineffective. We used gene expression microarrays followed by flow cytometric and functional assays to investigate global changes in blood transcriptional profiles of HTLV-1-infected and seronegative individuals. We found that perturbations of the p53 signaling pathway were a hallmark of HTLV-1 infection. In contrast, a subset of interferon (IFN)-stimulated genes was over-expressed in patients with HAM/TSP but not in asymptomatic HTLV-1 carriers or patients with the clinically similar disease multiple sclerosis. The IFN-inducible signature was present in all circulating leukocytes and its intensity correlated with the clinical severity of HAM/TSP. Leukocytes from patients with HAM/TSP were primed to respond strongly to stimulation with exogenous IFN. However, while type I IFN suppressed expression of the HTLV-1 structural protein Gag it failed to suppress the highly immunogenic viral transcriptional transactivator Tax. We conclude that over-expression of a subset of IFN-stimulated genes in chronic HTLV-1 infection does not constitute an efficient host response but instead contributes to the development of HAM/TSP.

Highlights

Human T-lymphotropic virus type 1 (HTLV-1) is an exogenous retrovirus that is widespread in the tropics and subtropics [1,2]
Infection with the Human T Lymphotropic virus is widespread in the tropics and subtropics, where it causes a chronic disabling disease of the nervous system abbreviated as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP)
We compared the frequencies of cell populations and gene expression profiles from diseased and asymptomatic HTLV-1 carriers to identify abnormalities in biological pathways that cause HAM/TSP

Summary

Introduction

HTLV-1 is an exogenous retrovirus that is widespread in the tropics and subtropics [1,2]. Chronic infection is characterised by a strong humoral and cellular immune response against the virus [3]. Whilst the majority of HTLV-1 carriers efficiently control the infection and remain clinically asymptomatic lifelong, some 1–4% develop a neurodegenerative inflammatory disorder known as HAM/TSP [1]. Patients present with multiple sclerosis-like symptoms including progressive spastic paraparesis, sensory loss and disturbances of bladder or bowel function [1,5]. The sequence and nature of the events that lead to the observed neuronal damage in HAM/TSP are not known and because of the lack of a suitable animal model a direct investigation of pathogenic mechanisms is not possible. Clinical management of HAM/TSP is unsatisfactory and current treatment remains only palliative

Objectives

Results

Discussion

Conclusion