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首页> 外文期刊>AIDS Research and Human Retroviruses >Targeting of a CD8 T Cell Env Epitope Presented by HLA-B*5802 Is Associated with Markers of HIV Disease Progression and Lack of Selection Pressure
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Targeting of a CD8 T Cell Env Epitope Presented by HLA-B*5802 Is Associated with Markers of HIV Disease Progression and Lack of Selection Pressure

机译：HLA-B * 5802呈现的CD8 T细胞Env表位的靶向与HIV疾病进展和缺乏选择压力的标志相关

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摘要

In HIV-infected persons, certain HLA class I alleles are associated with effective control of viremia, while others are associated with rapid disease progression. Among the most divergent clinical outcomes are the relatively good prognosis in HLA-B*5801 expressing persons and poor prognosis with HLA-B*5802. These two alleles differ by only three amino acids in regions involved in HLA-peptide recognition. This study evaluated a cohort of over 1000 persons with chronic HIV clade C virus infection to determine whether clinical outcome differences associated with B*5801 (n = 93) and B*5802 ( n = 259) expression are associated with differences in HIV-1-specific CD8 + T cell responses. The overall breadth and magnitude of HIV-1-specific CD8+ T cell responses were lower in persons expressing B*5802, and epitope presentation by B*5802 contributed significantly less to the overall response as compared to B*5801-restricted CD8 + T cells. Moreover, viral load in B*5802-positive persons was higher and CD4 cell counts lower when this allele contributed to the overall CD8 + T cell response, which was detected exclusively through a single epitope in Env. In addition, persons heterozygous for B*5802 compared to persons homozygous for other HLA-B alleles had significantly higher viral loads. Viral sequencing revealed strong selection pressure mediated through B*5801-restricted responses but not through B*5802. These data indicate that minor differences in HLA sequence can have a major impact on epitope recognition, and that selective targeting of Env through HLA-B*5802 is at least ineffectual if not actively adverse in the containment of viremia. These results provide experimental evidence that not all epitope-specific responses contribute to immune containment, a better understanding of which is essential to shed light on mechanisms involved in HIV disease progression.
机译：在HIV感染者中，某些HLA I类等位基因与病毒血症的有效控制有关，而另一些与疾病的快速发展有关。在最分歧的临床结果中，HLA-B * 5801表达者的预后相对较好，HLA-B * 5802的预后较差。这两个等位基因在HLA肽识别所涉及的区域仅相差三个氨基酸。这项研究评估了超过1000人的慢性HIV进化枝C病毒感染人群，以确定与B * 5801（n = 93）和B * 5802（n = 259）表达相关的临床结局差异是否与HIV-1的差异相关特异的CD8 + T细胞反应。与B * 5801限制的CD8 + T细胞相比，表达B * 5802的人的HIV-1特异性CD8 + T细胞应答的总体广度和强度较低，并且B * 5802的表位呈递对总体应答的贡献显着降低。而且，当等位基因有助于总体CD8 + T细胞反应时，B * 5802阳性患者的病毒载量较高，而CD4细胞计数较低，这只能通过Env中的单个表位检测到。此外，与其他HLA-B等位基因纯合子相比，B * 5802杂合子人的病毒载量明显更高。病毒测序显示强大的选择压力是通过B * 5801限制性反应介导的，而不是通过B * 5802介导的。这些数据表明，HLA序列的微小差异可能会对表位的识别产生重大影响，并且通过HLA-B * 5802选择性靶向Env至少对病毒血症的控制没有作用，即使这种作用不是积极的。这些结果提供了实验证据，表明并非所有表位特异性反应都有助于免疫抑制，对此的更好理解对于阐明参与HIV疾病进展的机制至关重要。

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