Effects of host restriction factors and the HTLV-1 subtype on susceptibility to HTLV-1-associated myelopathy/tropical spastic paraparesis.
Effects of host restriction factors and the HTLV-1 subtype on susceptibility to HTLV-1-associated myelopathy/tropical spastic paraparesis.
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DOI：
10.1186/s12977-017-0350-9
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发表时间：
2017-04-19
期刊：
影响因子：
3.3
通讯作者：
Takashima H
中科院分区：
文献类型：
--
作者：
Nozuma S;Matsuura E;Kodama D;Tashiro Y;Matsuzaki T;Kubota R;Izumo S;Takashima H
虽然人类嗜T淋巴细胞病毒1型（HTLV-1）感染是HTLV-1相关性脊髓病/热带痉挛性下肢轻瘫（HAM/TSP）发生的先决条件，但HAM/TSP中特异性前病毒突变尚未报道。在这项研究中，我们通过分析HAM/TSP患者（包括家族性病例）的HTLV-1前病毒的全序列来检查这些患者是否具有HTLV-1的疾病特异性基因组变异。此外，我们研究了宿主限制性因子赋予抗逆转录病毒活性的遗传变异，以确定哪些突变可能与HAM/TSP的耐药或易感性相关。受试者包括30例家族性HAM/TSP（f-HAM/TSP）患者，92例散发性HAM/TSP（s-HAM/TSP）患者和89例无症状HTLV-1携带者（AC）。在所有211个样本中，37个样本（18%）被归类为跨大陆亚型，174个样本（82%）被归类为日本亚型。三组中，f-HAM/TSP、s-HAM/TSP和ACs的跨洲亚型分别占33%、23%和7%。f-HAM/TSP（p < 0.001）和s-HAM/TSP（p < 0.001）中横贯大陆亚型的频率均显著高于AC。HTLV-1序列的50个突变在HAM/TSP患者中的发生率显著高于AC，然而，它们仅常见于横贯大陆的亚型。在这些突变中，10个常见的突变引起的HTLV-1序列的氨基酸变化是特定的跨大陆亚型。我们检查了宿主限制因子，并在HAM/TSP患者中检测到TRIM 5 α的罕见变异。TRIM 5 α 136 Q患者的前病毒载量（PVL）低于136 R患者（354 vs. 654拷贝/104 PBMC，p = 0.003）。TRIM 5 α 304 L变体患者的PVL显著高于304 H变体患者（1669 vs. 595拷贝/104 PBMC，p = 0.025）。我们没有发现任何HAM/TSP特异性宿主限制性因子突变。横贯大陆亚型对HAM/TSP易感，尤其是家族性病例。引起HTLV-1基因氨基酸变化的10种常见突变是横贯大陆亚型特有的。TRIM 5 α多态性与PVL相关，表明TRIM 5 α可能与HTLV-1复制有关。本文的在线版本（doi：10.1186/s12977-017-0350-9）包含补充材料，可供授权用户使用。
Although human T-lymphotropic virus type 1 (HTLV-1) infection is a prerequisite for the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), specific provirus mutations in HAM/TSP have not yet been reported. In this study, we examined whether HAM/TSP patients had the disease-specific genomic variants of HTLV-1 by analyzing entire sequences of HTLV-1 proviruses in these patients, including familial cases. In addition, we investigated the genetic variants of host restriction factors conferring antiretroviral activity to determine which mutations may be related to resistance or susceptibility to HAM/TSP. The subjects included 30 patients with familial HAM/TSP (f-HAM/TSP), 92 patients with sporadic HAM/TSP (s-HAM/TSP), and 89 asymptomatic HTLV-1 carriers (ACs). In all 211 samples, 37 samples (18%) were classified into transcontinental subtype and 174 samples (82%) were classified as Japanese subtype. Among three groups, the percentage of transcontinental subtype in f-HAM/TSP, s-HAM/TSP and ACs was 33, 23 and 7%, respectively. The frequency of transcontinental subtype was significantly higher in both f-HAM/TSP (p < 0.001) and s-HAM/TSP (p < 0.001) than in ACs. Fifty mutations in HTLV-1 sequences were significantly more frequent in HAM/TSP patients than in ACs, however, they were common only in transcontinental subtype. Among these mutations, ten common mutations causing amino acid changes in the HTLV-1 sequences were specific to the transcontinental subtype. We examined host restriction factors, and detected a rare variant in TRIM5α in HAM/TSP patients. The patients with TRIM5α 136Q showed lower proviral loads (PVLs) than those with 136R (354 vs. 654 copies/104 PBMC, p = 0.003). The patients with the 304L variant of TRIM5α had significantly higher PVLs than those with 304H (1669 vs. 595 copies/104 PBMC, p = 0.025). We could not find any HAM/TSP-specific mutations of host restriction factors. Transcontinental subtype is susceptible to HAM/TSP, especially in familial cases. Ten common mutations causing amino acid changes in the HTLV-1 gene were specific to the transcontinental subtype. TRIM5α polymorphisms were associated with PVLs, indicating that TRIM5α could be implicated in HTLV-1 replication. The online version of this article (doi:10.1186/s12977-017-0350-9) contains supplementary material, which is available to authorized users.