Distinct HIV-1 escape patterns selected by cytotoxic T cells with identical epitope specificity.
Distinct HIV-1 escape patterns selected by cytotoxic T cells with identical epitope specificity.
复制标题
具有相同表位特异性的细胞毒性 T 细胞选择不同的 HIV-1 逃逸模式。
DOI：
10.1128/jvi.02572-12
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发表时间：
2013
影响因子：
5.4
通讯作者：
Fuk
中科院分区：
文献类型：
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作者：
Yagita,Yuichi;Kuse,Nozomi;Kuroki,Kimiko;Gatanaga,Hiroyuki;Carlson,JonathanM;Chikata,Takayuki;Brumme,ZabrinaL;Murakoshi,Hayato;Akahoshi,Tomohiro;Pfeifer,Nico;Mallal,Simon;John,Mina;Ose,Toyoyuki;Matsubara,Haruki;Kanda,Ryo;Fuk
Pol 283 -8特异性、HLA-B*51：01限制性、细胞毒性T细胞（CTL）在HIV-1感染的长期控制中起关键作用。然而，这些CTL选择逆转录酶（RT）I135 X逃逸突变，这可能是积累在循环HIV-1序列。我们研究了通过对相同表位特异但受HLA-B*52：01限制的CTL对I135 X突变的选择。我们发现，Pol 283 -8特异性，HLA-B*52：01限制性CTL主要在慢性HIV-1感染者中引起。这些CTL具有很强的抑制野生型HIV-1复制的能力，尽管这种能力弱于HLA-B*51：01限制性CTL。HLA-B*52：01-Pol 283 -8肽复合物的晶体结构提供了明确的证据，表明HLA-B*52：01与HLA-B*51：01类似地呈递肽，确保了两个等位基因交叉呈递该表位。群体水平分析显示，在日本人和主要是高加索人的队列中，HLA-B*51：01与I135 T突变体有很强的关联，而HLA-B*52：01与几种I135 X突变体的关联相对较弱。体外病毒抑制试验表明，HLA-B*52：01限制性CTL不能抑制I135 X突变体病毒的复制，表明CTL对这些突变体病毒具有选择性。这些结果表明，I135 X突变体选择的不同模式可能是由于这两种CTL在抑制HIV-1复制的能力方面的差异造成的。
Pol283-8-specific, HLA-B*51:01-restricted, cytotoxic T cells (CTLs) play a critical role in the long-term control of HIV-1 infection. However, these CTLs select for the reverse transcriptase (RT) I135X escape mutation, which may be accumulating in circulating HIV-1 sequences. We investigated the selection of the I135X mutation by CTLs specific for the same epitope but restricted by HLA-B*52:01. We found that Pol283-8-specific, HLA-B*52:01-restricted CTLs were elicited predominantly in chronically HIV-1-infected individuals. These CTLs had a strong ability to suppress the replication of wild-type HIV-1, though this ability was weaker than that of HLA-B*51:01-restricted CTLs. The crystal structure of the HLA-B*52:01-Pol283-8 peptide complex provided clear evidence that HLA-B*52:01 presents the peptide similarly to HLA-B*51:01, ensuring the cross-presentation of this epitope by both alleles. Population level analyses revealed a strong association of HLA-B*51:01 with the I135T mutant and a relatively weaker association of HLA-B*52:01 with several I135X mutants in both Japanese and predominantly Caucasian cohorts. Anin vitroviral suppression assay revealed that the HLA-B*52:01-restricted CTLs failed to suppress the replication of the I135X mutant viruses, indicating the selection of these mutants by the CTLs. These results suggest that the different pattern of I135X mutant selection may have resulted from the difference between these two CTLs in the ability to suppress HIV-1 replication.