HLA Heterozygote Advantage against HIV-1 Is Driven by Quantitative and Qualitative Differences in HLA Allele-Specific Peptide Presentation
HLA Heterozygote Advantage against HIV-1 Is Driven by Quantitative and Qualitative Differences in HLA Allele-Specific Peptide Presentation
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DOI：
10.1093/molbev/msz249
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发表时间：
2020-03-01
影响因子：
10.7
通讯作者：
Lenz, Tobias L.
中科院分区：
文献类型：
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作者：
Arora, Jatin;Pierini, Federica;Lenz, Tobias L.
病原体介导的平衡选择被认为是宿主免疫遗传多样性的关键驱动力。人类平衡选择的一个标志是人类白细胞抗原（HLA）基因的杂合子优势，从而改善HIV-1控制。然而，观察到的杂合子优势的实际机制仍然是难以捉摸的。HLA杂合子可以向免疫细胞呈递更广泛的抗原性病毒肽，可能导致更有效的细胞毒性T细胞应答。或者，杂合性可能只是增加了携带最具保护性的HLA等位基因的机会，因为已知单个HLA等位基因在与HIV-1控制的相关性方面存在显著差异。在这里，我们使用了来自6,311名HIV-1感染者的数据，以探索肽呈递的定量和定性方面在HLA杂合子抗HIV优势中的相对贡献。通过筛选整个HIV-1蛋白质组，我们观察到杂合子个体表现出由其HLA I类等位基因呈递的更广泛的HIV-1肽。此外，病毒载量与个体HLA变体结合的HIV-1肽库的宽度呈负相关，特别是在HLA-B。这表明HLA-B的杂合子优势至少部分由定量肽呈递介导。我们还观察到HLA-B杂合个体中HIV-1序列的多样性更高，这表明HLA杂合性的进化压力更大。然而，HLA杂合子也更可能携带某些HLA等位基因，包括高度保护性的HLA-B * 57：01变体，表明HLA杂合子优势最终来自抗原呈递中定量和定性效应的组合。
Pathogen-mediated balancing selection is regarded as a key driver of host immunogenetic diversity. A hallmark for balancing selection in humans is the heterozygote advantage at genes of the human leukocyte antigen (HLA), resulting in improved HIV-1 control. However, the actual mechanism of the observed heterozygote advantage is still elusive. HLA heterozygotes may present a broader array of antigenic viral peptides to immune cells, possibly resulting in a more efficient cytotoxic T-cell response. Alternatively, heterozygosity may simply increase the chance to carry the most protective HLA alleles, as individual HLA alleles are known to differ substantially in their association with HIV-1 control. Here, we used data from 6,311 HIV-1-infected individuals to explore the relative contribution of quantitative and qualitative aspects of peptide presentation in HLA heterozygote advantage against HIV. Screening the entire HIV-1 proteome, we observed that heterozygous individuals exhibited a broader array of HIV-1 peptides presented by their HLA class I alleles. In addition, viral load was negatively correlated with the breadth of the HIV-1 peptide repertoire bound by an individuals HLA variants, particularly at HLA-B. This suggests that heterozygote advantage at HLA-B is at least in part mediated by quantitative peptide presentation. We also observed higher HIV-1 sequence diversity among HLA-B heterozygous individuals, suggesting stronger evolutionary pressure from HLA heterozygosity. However, HLA heterozygotes were also more likely to carry certain HLA alleles, including the highly protective HLA-B*57:01 variant, indicating that HLA heterozygote advantage ultimately results from a combination of quantitative and qualitative effects in antigen presentation.