PDF(Pubmed)
Abstract：
The Gag280 mutation is associated with HLA-C*01:02 but not with HLA-B*52:01 in subtype A/E-infected individuals, whereas this mutation is associated with HLA-B*52:01 but not with HLA-C*01:02 in subtype B infections. Although it is known that the Gag280 mutant is selected by HLA-B*52:01-restricted GagRI8 (Gag275-282)-specific T cells in subtype B infections, it remains unknown why this Gag280 mutation is associated with HLA-C*01:02 rather than HLA-B*52:01 in subtype A/E infections. The subtype B and A/E viruses have different consensus sequence, with Thr and Val at Gag280, respectively. To clarify the effect of this difference in Gag280 consensus sequence, we investigated the role of HLA-C*01:02-restricted GagYI9 (Gag277-285)-specific T cells in selection of Gag280 mutations in subtype A/E-infected Vietnamese and subtype B-infected Japanese individuals. GagYI9-4V-specific T cells, which were frequently elicited in Vietnamese individuals infected with the consensus-type A/E virus, failed to recognize GagV280T mutant A/E virus-infected cells. GagYI9-4T mutant epitope-specific T cells, which were weakly elicited in individuals infected with the mutant A/E virus, had weak or no ability to recognize the mutant virus. These results account for the mechanism for selection and accumulation of GagV280T mutants in the case of subtype A/E infections. In contrast, HLA-C*01:02-restricted GagYI9-4T-specific T cells were weakly elicited in Japanese individuals infected with the subtype B virus, explaining why HLA-C*01:02-restricted Gag280 mutations are not accumulated in the case of a subtype B infection. The present study demonstrated that a difference in the Gag280 consensus sequence influenced the elicitation of the GagYI9-specific T cells involved in the accumulation of HLA-C*01:02-associated Gag280 mutations.IMPORTANCE HIV-1 mutations escaped from HIV-specific CD8+ T cells are mostly detected as HLA-associated mutations. A diversity of HLA-associated mutations is somewhat distinct to each race and region, since HLA allele distribution differs among them. A difference in the consensus sequence among HIV-1 subtypes may also influence the diversity of HLA-associated mutations. HLA-C*01:02-associated GagV280T and HLA-B*52:01-associated GagT280A/S mutations were previously identified in HIV-1 subtype A/E-infected and subtype B-infected individuals, respectively, though these subtype viruses have a different consensus sequence at Gag280. We demonstrated that the GagV280T mutant virus was selected by HLA-C*01:02-restricted GagYI9-4V-specific T cells in subtype A/E-infected Vietnamese but that HLA-C*01:02-restricted GagYI9-4T-specific T cells were weakly elicited in subtype B-infected Japanese. Together with our recent study which demonstrated the mechanism for the accumulation of HLA-B*52:01-associated mutations, we clarified the mechanism for the accumulation of different Gag280 mutations and the effect of the difference in the consensus sequence on the accumulation of escape mutations.
摘要：
在亚型A/E感染的个体中，Gag280突变与HLA-C*01:02相关，但与HLA-B*52:01无关。而在B型亚型感染中，该突变与HLA-B*52:01相关，但与HLA-C*01:02无关。尽管已知Gag280突变体是由HLA-B*52：01限制性GagRI8（Gag275-282）特异性T细胞在B型感染中选择的，在A/E亚型感染中,Gag280突变与HLA-C*01:02而非HLA-B*52:01相关的原因尚不清楚.B亚型和A/E亚型病毒具有不同的共有序列,Thr和Val分别位于Gag280。为了阐明Gag280共有序列中这种差异的影响，我们研究了HLA-C*01:02限制性GagYI9(Gag277-285)特异性T细胞在选择A/E亚型感染的越南人和B亚型感染的日本人的Gag280突变中的作用.GagYI9-4V特异性T细胞,经常在感染共识型A/E病毒的越南个体中引起，未能识别GagV280T突变型A/E病毒感染的细胞。GagYI9-4T突变表位特异性T细胞,在感染突变型A/E病毒的个体中弱诱导，具有弱的或没有能力识别突变病毒。这些结果解释了在亚型A/E感染的情况下GagV280T突变体的选择和积累的机制。相比之下,HLA-C*01：02限制性GagYI9-4T特异性T细胞在感染B型病毒的日本个体中弱诱导，解释为什么HLA-C*01:02限制性Gag280突变在B亚型感染的情况下没有积累。本研究表明，Gag280共有序列的差异影响了参与HLA-C*01：02相关Gag280突变积累的GagYI9特异性T细胞的激发。重要性从HIV特异性CD8+T细胞逃逸的HIV-1突变大多被检测为HLA相关突变。HLA相关突变的多样性在每个种族和地区都有所不同，因为HLA等位基因分布在它们之间不同。HIV-1亚型之间共有序列的差异也可能影响HLA相关突变的多样性。HLA-C*01:02相关的GagV280T和HLA-B*52:01相关的GagT280A/S突变先前在HIV-1亚型A/E感染和亚型B感染的个体中被鉴定,分别,尽管这些亚型病毒在Gag280上具有不同的共有序列。我们证明了GagV280T突变病毒是通过HLA-C*01：02限制性GagYI9-4V特异性T细胞在A/E亚型感染的越南人中选择的，但HLA-C*01：02限制性GagYI9-4T特异性T细胞在B型感染的日本人中弱诱导。加上我们最近的研究，证明了HLA-B*52:01相关突变的积累机制，我们阐明了不同Gag280突变积累的机制以及共有序列差异对逃逸突变积累的影响。
