Department of Infectious Disease, Faculty of Medicine, Imperial College London, UK.
Present address: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
J Gen Virol. 2021 Sep;102(9). doi: 10.1099/jgv.0.001664.
Viruses require host factors to support their replication, and genetic variation in such factors can affect susceptibility to infectious disease. Influenza virus replication in human cells relies on ANP32 proteins, which are involved in assembly of replication-competent dimeric influenza virus polymerase (FluPol) complexes. Here, we investigate naturally occurring single nucleotide variants (SNV) in the human and genes. We note that variant rs182096718 in is found at a higher frequency than other variants in either gene. This SNV results in a D130A substitution in ANP32B, which is less able to support FluPol activity than wild-type ANP32B and binds FluPol with lower affinity. Interestingly, ANP32B-D130A exerts a dominant negative effect over wild-type ANP32B and interferes with the functionally redundant paralogue ANP32A. FluPol activity and virus replication are attenuated in CRISPR-edited cells expressing wild-type ANP32A and mutant ANP32B-D130A. We propose a model in which the D130A mutation impairs FluPol dimer formation, thus resulting in compromised replication. We suggest that both homozygous and heterozygous carriers of rs182096718 may have some genetic protection against influenza viruses.
病毒需要宿主因子来支持其复制，而这些因子的遗传变异可能会影响对传染病的易感性。流感病毒在人类细胞中的复制依赖于 ANP32 蛋白，该蛋白参与复制有效的二聚体流感病毒聚合酶 (FluPol) 复合物的组装。在这里，我们研究了人类 和 基因中自然发生的单核苷酸变异 (SNV)。我们注意到 基因中的 rs182096718 变异比这两个基因中的其他变异更常见。该 SNV导致 ANP32B 中的 D130A 取代，其支持 FluPol 活性的能力低于野生型 ANP32B，并且与 FluPol 的结合亲和力较低。有趣的是，ANP32B-D130A 对野生型 ANP32B 产生显性负效应，并干扰功能冗余的同源物 ANP32A。在表达野生型 ANP32A 和突变型 ANP32B-D130A 的 CRISPR 编辑细胞中，FluPol 活性和病毒复制减弱。我们提出了一个模型，其中 D130A 突变会损害 FluPol 二聚体形成，从而导致复制受损。我们建议，rs182096718 的纯合子和杂合子携带者都可能对流感病毒有一定的遗传保护。
