Human Hepatitis B Viral Infection Outcomes Are Linked to Naturally Occurring Variants of HLA-DOA That Have Altered Function
Human Hepatitis B Viral Infection Outcomes Are Linked to Naturally Occurring Variants of HLA-DOA That Have Altered Function
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DOI：
10.4049/jimmunol.2000476
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发表时间：
2020-08-15
影响因子：
4.4
通讯作者：
Denzin, Lisa K.
中科院分区：
文献类型：
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作者：
Graves, Austin M.;Virdis, Francesca;Denzin, Lisa K.
MHC II类（MHCII）的HLA分子结合并呈递病原体衍生的肽用于CD 4 T细胞活化。MHCII在细胞内体中的肽负载由非经典MHCII分子HLA-DM（DM）和HLA-DO（DO）的相互作用控制。DM催化肽加载，而DO，一种MHCII底物模拟物，阻止DM与MHCII相互作用，导致改变的MHCII-肽库和增加的MHCII-CLIP。虽然编码DO的两个基因（DOA和DOB）被认为是非多态性的，但也有罕见的自然变异。我们先前的工作确定了改变DO功能的DOB变体。在这项研究中，我们表明，在DOA基因的自然变异也影响DO功能。使用1000个基因组计划数据库，我们发现，近似98%的个体表达典型的DOA*0101等位基因，其余的个体大多表达DOA*0102，我们发现这是一个获得性功能等位基因。对25种天然存在的DO α变体（包括常见等位基因）进行分析，鉴定出3种无效变体和1种调节DM活性的能力降低的变体和9种调节DM活性的能力增加的变体。出乎意料的是，几种变体产生降低的DO蛋白水平，但有效地抑制DM活性。最后，相关的单核苷酸多态性的分析，遗传连锁的DOA*0102共同等位基因，获得的功能变异，与人类肝炎B病毒的持久性。相反，我们发现DO α F114 L无效等位基因与病毒清除相关。总的来说，这些研究表明，人类DOA基因中发生的自然变异影响DO功能，并可能与病毒感染的特定结果有关。
HLA molecules of the MHC class II (MHCII) bind and present pathogen-derived peptides for CD4 T cell activation. Peptide loading of MHCII in the endosomes of cells is controlled by the interplay of the nonclassical MHCII molecules, HLA-DM (DM) and HLA-DO (DO). DM catalyzes peptide loading, whereas DO, an MHCII substrate mimic, prevents DM from interacting with MHCII, resulting in an altered MHCII-peptide repertoire and increased MHCII-CLIP. Although the two genes encoding DO (DOA and DOB) are considered nonpolymorphic, there are rare natural variants. Our previous work identified DOB variants that altered DO function. In this study, we show that natural variation in the DOA gene also impacts DO function. Using the 1000 Genomes Project database, we show that similar to 98% of individuals express the canonical DOA*0101 allele, and the remaining individuals mostly express DOA*0102, which we found was a gain-of-function allele. Analysis of 25 natural occurring DO alpha variants, which included the common alleles, identified three null variants and one variant with reduced and nine with increased ability to modulate DM activity. Unexpectedly, several of the variants produced reduced DO protein levels yet efficiently inhibited DM activity. Finally, analysis of associated single-nucleotide polymorphisms genetically linked the DOA*0102 common allele, a gain-of-function variant, with human hepatitis B viral persistence. In contrast, we found that the DO alpha F114L null allele was linked with viral clearance. Collectively, these studies show that natural variation occurring in the human DOA gene impacts DO function and can be linked to specific outcomes of viral infections.