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

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.

人类T细胞嗜淋巴病毒1型（Human T-lymphotropic virus type 1, HTLV-1）是一种可在宿主体内终身持续感染的逆转录病毒。约4%的感染者会罹患人类T细胞嗜淋巴病毒1型相关脊髓病/热带痉挛性截瘫（HAM/TSP）——一种慢性致残性神经炎性疾病。目前HAM/TSP的发病机制尚不明确，且尚无有效的治疗方案。本研究采用基因表达微阵列（gene expression microarrays）联合流式细胞术与功能实验，对HTLV-1感染者与血清学阴性个体的血液转录组整体表达谱变化进行了分析。研究发现p53信号通路失调是HTLV-1感染的标志性分子特征。与之相反，干扰素（IFN）刺激基因的一个子集在HAM/TSP患者体内呈现过表达状态，但在无症状HTLV-1携带者或临床特征相似的多发性硬化症患者中并未出现该表达特征。该干扰素诱导特征谱存在于所有循环白细胞中，且其表达强度与HAM/TSP的临床严重程度呈显著正相关。HAM/TSP患者的外周血白细胞经外源性干扰素刺激后可产生强烈的应答反应。然而，尽管I型干扰素可抑制HTLV-1结构蛋白Gag的表达，却无法抑制免疫原性极强的病毒转录反式激活蛋白Tax的表达。综上，慢性HTLV-1感染中部分干扰素刺激基因的过表达并非有效的宿主防御应答，反而会促进HAM/TSP的发生与发展。