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。