Wellcome Centre Human Genetics, University of Oxford, Oxford, United Kingdom.
MRC-University of Glasgow Centre for Virus Research, Sir Michael Stoker Building, Glasgow, United Kingdom.
Elife. 2019 Sep 3;8:e42463. doi: 10.7554/eLife.42463.
Hepatitis C virus (HCV) is a highly variable pathogen that frequently establishes chronic infection. This genetic variability is affected by the adaptive immune response but the contribution of other host factors is unclear. Here, we examined the role played by interferon lambda-4 (IFN-λ4) on HCV diversity; IFN-λ4 plays a crucial role in spontaneous clearance or establishment of chronicity following acute infection. We performed viral genome-wide association studies using human and viral data from 485 patients of white ancestry infected with HCV genotype 3a. We demonstrate that combinations of host genetic variants, which determine IFN-λ4 protein production and activity, influence amino acid variation across the viral polyprotein - not restricted to specific viral proteins or HLA restricted epitopes - and modulate viral load. We also observed an association with viral di-nucleotide proportions. These results support a direct role for IFN-λ4 in exerting selective pressure across the viral genome, possibly by a novel mechanism.
丙型肝炎病毒 (HCV) 是一种高度变异的病原体，常导致慢性感染。这种遗传变异性受适应性免疫反应的影响，但其他宿主因素的贡献尚不清楚。在这里，我们研究了干扰素 lambda-4 (IFN-λ4) 在 HCV 多样性中所起的作用；IFN-λ4 在急性感染后自发清除或建立慢性感染中起着至关重要的作用。我们使用来自 485 名白人 HCV 基因型 3a 感染患者的人类和病毒数据进行了病毒全基因组关联研究。我们证明，决定 IFN-λ4 蛋白产生和活性的宿主遗传变异组合会影响病毒多蛋白中的氨基酸变异 - 不仅限于特定的病毒蛋白或 HLA 限制的表位 - 并调节病毒载量。我们还观察到与病毒二核苷酸比例的关联。这些结果支持 IFN-λ4 通过一种新的机制在整个病毒基因组上发挥选择压力的直接作用。
