HIV Subtype Influences HLA- B*07: 02-Associated HIV Disease Outcome
HIV Subtype Influences HLA- B*07: 02-Associated HIV Disease Outcome
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DOI：
10.1089/aid.2013.0197
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发表时间：
2014-05-01
影响因子：
1.5
通讯作者：
Goulder, Philip
中科院分区：
文献类型：
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作者：
Kloverpris, Henrik N.;Adland, Emily;Goulder, Philip
MHC 编码区域内的遗传多态性对人类基因组中 HIV 疾病进展的影响最为强烈，并为 HIV 免疫控制机制提供了重要线索。对与疾病快速进展相关的 HLA 等位基因进行的分析很少。 HLA-B*07:02 是一种 HLA I 类分子，在全球大多数人群中普遍存在，之前一直被认为与 B 分支感染的加速疾病进展有关。本研究调查了 HLA-B*07:02 与 C 分支感染中的高病毒设定点无关的观察结果。我们检验了这样的假设：这种与疾病结果相关的进化枝特异性差异可能与 CD8(+) T 细胞表位的不同靶向有关。我们观察到，与感染 B 进化枝感染的个体相比，感染 HLA-B*07:02 的 C 进化枝感染个体靶向范围更广的 Gag 表位，并且达到更高的量级。特别是，新的 p17-Gag（Gag22-30，RPGGKKHYM）表位针对超过 50% 的 HLA-B*07:02 阳性 C 分支感染个体，但该表位的分支特异性差异导致 B 分支感染中的非免疫原性。在研究的 16 个研究中，只有 C 分支 p24-Gag GL9 (Gag355-363，GPSHKARVL) 表位特异性 CD8(+) T 细胞反应与低病毒设定值相关。尽管该表位也是 B 分支感染中的目标，但逃逸突变体 S357S 在 B 分支感染中的出现频率高于 C 分支感染中的频率（HLA-B*07:02 阴性受试者中为 70%，而 HLA-B*07:02 阴性受试者中为 43%）。这些数据支持早期的研究表明，无论表达的特定HLA分子如何，Gag特异性CD8（+）T细胞反应的广度增加可能有助于改善HIV免疫控制。
Genetic polymorphisms within the MHC encoding region have the strongest impact on HIV disease progression of any in the human genome and provide important clues to the mechanisms of HIV immune control. Few analyses have been undertaken of HLA alleles associated with rapid disease progression. HLA-B*07:02 is an HLA class I molecule that is prevalent in most populations worldwide and that has previously been consistently linked to accelerated disease progression in B-clade infection. This study investigates the observation that HLA-B*07:02 is not associated with a high viral setpoint in C-clade infection. We examine the hypothesis that this clade-specific difference in association with disease outcome may be related to distinct targeting of CD8(+) T cell epitopes. We observed that C-clade-infected individuals with HLA-B*07:02 target a broader range of Gag epitopes, and to higher magnitudes, than do individuals infected with B-clade infection. In particular, a novel p17-Gag (Gag22-30, RPGGKKHYM) epitope is targeted in >50% of HLA-B*07:02-positive C-clade-infected individuals but clade-specific differences in this epitope result in nonimmunogenicity in B-clade infection. Only the C-clade p24-Gag GL9 (Gag355-363, GPSHKARVL) epitope-specific CD8(+) T cell response out of 16 studied was associated with a low viral setpoint. Although this epitope was also targeted in B-clade infection, the escape mutant S357S is present at higher frequency in B-clade infection than in C-clade infection (70% versus 43% in HLA-B*07:02-negative subjects). These data support earlier studies suggesting that increased breadth of the Gag-specific CD8(+) T cell response may contribute to improved HIV immune control irrespective of the particular HLA molecules expressed.