Cytotoxic T lymphocytes and viral mutations in HTLV-I-associated myelopathy

HTLV-I 相关脊髓病中的细胞毒性 T 淋巴细胞和病毒突变

• 批准号: 14570610
• 负责人: KUBOTA Ryuji
• 金额: $ 1.98万
• 依托单位: Kagoshima University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570610/
• 关键词: HTLV-I; HTLV-I-associated myelopathy; cytotoxic T lymphocyte; mutant virus; viral evolution; 非同義置換; HTLV-I関連脊髄症(HAM)

Patients with HTLV-I-associated myelopathy(HAM)have high proviral load despite vigorous cytotoxic T lymphocytes(CTL)responses to the virus.To elucidate whether HTLV-I-speciflc CTL eliminate HTLV-I in vivo in patients with HAM and whether a mutant virus emerges and predominates during the time course in the patients, we performed a longitudinal analysis of HTLV-I proviral load, frequency and degeneracy of HTLV-I Tax specific CTL, viral sequence, and frequency of mutant virus-specific CTL in three patients with HAM.Frequency and degeneracy of CTL paralleled with the proviral load in the patients.Positive pressures were detected in 3 out of 6 sequences associated with the known CTL epitopes by analyzing synonymous and non-synonymous substitutions of viral sequences.The rate of naturally occurring mutant virus ranged from 0 to 20% in each patient, however, no mutant virus accumulated during the time course even if the virus was not recognized by the CTL. These data suggest that CTL in fact eliminate HTLV-J in vivo and that no escape variant of HTLV-I predominates during the time course.This implies that these CTL epitopes can be targets for vaccine development.

尽管细胞毒性 T 淋巴细胞 (CTL) 对病毒有强烈反应，但 HTLV-I 相关性脊髓病 (HAM) 患者仍具有较高的前病毒载量。突变病毒在患者体内出现并占主导地位，我们对 HTLV-I 前病毒载量、频率和简并性进行了纵向分析HTLV-I Tax 特异性 CTL、病毒序列以及三名 HAM 患者中突变病毒特异性 CTL 的频率。CTL 的频率和简并性与患者中的原病毒载量平行。在与 HAM 相关的 6 个序列中的 3 个中检测到正压力通过分析病毒序列的同义和非同义替换，找出已知的CTL表位。每个患者中自然发生突变病毒的比例为0%至20%，但没有突变病毒即使病毒未被 CTL 识别，病毒也会在这段时间内积累。这些数据表明，CTL 实际上在体内消除了 HTLV-J，并且在此期间没有 HTLV-I 的逃逸变体占主导地位。这意味着这些 CTL 表位可以作为疫苗开发的目标。

项目成果

Mitsuhiro Osame et al.: "Physiopathology and treatment of HAM"Nippon Naika Gakkai Zasshi.. 92(9). 65-74 (2003)

Mitsuhiro Osame 等：“HAM 的病理生理学和治疗”Nippon Naika Gakkai Zasshi.. 92(9)。

Mineki Saito et al.: "Decreased human T lymphotropic virus type I(HTLV-I)provirus load and alteration in T cell phenotype after interferon-alpha therapy for HTLV-I-associated myelopahty/tropical spastic paraparesis."J Infect Dis.. 189(1). 29-40 (2004)

Mineki Saito 等人：“在干扰素-α 治疗 HTLV-I 相关脊髓病/热带痉挛性截瘫后，人类 T 淋巴细胞病毒 I 型 (HTLV-I) 原病毒载量下降，T 细胞表型发生改变。”J Infect Dis..

Ryuji Kubota et al.: "Selected cytotoxic T lymphocytes with high specificity for HTLV-I in cerebrospinal fluid from a HAM/TSP patient."J Neurovirol.. 8(1). 53-57 (2002)

Ryuji Kubota 等人：“在 HAM/TSP 患者的脑脊液中选择对 HTLV-I 具有高度特异性的细胞毒性 T 淋巴细胞。”J Neurovirol.. 8(1)。

Ryuji Kubota: "Degenerate specificity of HTLV-I-specific CD8+ T cells during viral relplication in patients with HTLV-I-associated myelopathy (HAM/TSP)."Blood. 101(8). 3074-3081 (2003)

Ryuji Kubota：“HTLV-I 相关脊髓病 (HAM/TSP) 患者病毒复制过程中 HTLV-I 特异性 CD8 T 细胞的退化特异性。”血液。

Ryuji Kubota: "Degenerate specificity of HTLV-I-specific CD8+ T cells during viral replication in patients with HTLV-I-associated myelopathy (HAM/TSP)."Blood. 101(8). 3074-3081 (2003)

Ryuji Kubota：“HTLV-I 相关脊髓病 (HAM/TSP) 患者病毒复制过程中 HTLV-I 特异性 CD8 T 细胞的退化特异性。”血液。