Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses.
Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses.
复制标题
HIV-1 GAG中的簇突变是逃避HLA-B27限制的细胞毒性T淋巴细胞反应所必需的。
DOI：
10.1084/jem.193.3.375
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发表时间：
2001-02-05
影响因子：
15.3
通讯作者：
Phillips, R E
中科院分区：
文献类型：
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作者：
Kelleher, A D;Long, C;Holmes, E C;Allen, R L;Wilson, J;Conlon, C;Workman, C;Shaunak, S;Olson, K;Goulder, P;Brander, C;Ogg, G;Sullivan, J S;Dyer, W;Jones, I;McMichael, A J;Rowland-Jones, S;Phillips, R E
携带人类组织相容性白细胞抗原（HLA）-B27的患者对HIV-1的免疫应答特征在于对p24 gag（氨基酸263-272，KRWIILGLNK）中表位的免疫显性应答。在HIV-1 gag残基264处用赖氨酸（K）或甘氨酸（G）取代精氨酸（R）（R264 K和R264 G）导致与HLA-B27结合较差的表位。我们在4名携带HLA-B27的患者中检测到R264 K突变。在这些患者中，有3例突变发生较晚，与疾病进展一致。在另一种情况下，它发生在1年内的感染，并与合胞体诱导表型的病毒。在每种情况下，R264 K与残基268处的亮氨酸至甲硫氨酸的变化紧密相关。在失去对该表位的细胞毒性T淋巴细胞（CTL）应答后，在存在高病毒载量的情况下，观察到回复到野生型序列。在第五例患者中，当HIV-1疾病进展时检测到R264 G突变。其发生与残基260处谷氨酸突变为天冬氨酸有关。系统发育分析表明，这些取代出现在自然选择，而不是遗传漂变或连锁。CTL逃逸病毒的生长需要高病毒载量和额外的，可能是补偿性的，gag蛋白突变。
The immune response to HIV-1 in patients who carry human histocompatibility leukocyte antigen (HLA)-B27 is characterized by an immunodominant response to an epitope in p24 gag (amino acids 263–272, KRWIILGLNK). Substitution of lysine (K) or glycine (G) for arginine (R) at HIV-1 gag residue 264 (R264K and R264G) results in epitopes that bind to HLA-B27 poorly. We have detected a R264K mutation in four patients carrying HLA-B27. In three of these patients the mutation occurred late, coinciding with disease progression. In another it occurred within 1 yr of infection and was associated with a virus of syncytium-inducing phenotype. In each case, R264K was tightly associated with a leucine to methionine change at residue 268. After the loss of the cytotoxic T lymphocyte (CTL) response to this epitope and in the presence of high viral load, reversion to wild-type sequence was observed. In a fifth patient, a R264G mutation was detected when HIV-1 disease progressed. Its occurrence was associated with a glutamic acid to aspartic acid mutation at residue 260. Phylogenetic analyses indicated that these substitutions emerged under natural selection rather than by genetic drift or linkage. Outgrowth of CTL escape viruses required high viral loads and additional, possibly compensatory, mutations in the gag protein.