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 Anp32A and Anp32B genes. We note that variant rs182096718 in Anp32B 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.

中文翻译：

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ANP32B 中的一种天然变体会损害流感病毒在人类细胞中的复制

病毒需要宿主因素来支持其复制，而这些因素的遗传变异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，这些蛋白参与了具有复制能力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Anp32A和Anp32B基因中天然存在的单核苷酸变体 (SNV) 。我们注意到 Anp32B 中的变体rs182096718发现的频率高于任一基因中的其他变体。该 SNV 导致 ANP32B 中的 D130A 取代，与野生型 ANP32B 相比，它对 FluPol 活性的支持能力较差，并以较低的亲和力结合 FluPol。有趣的是，ANP32B-D130A 对野生型 ANP32B 产生显性负面影响，并干扰功能冗余的旁系同源物 ANP32A。FluPol 活性和病毒复制在表达野生型 ANP32A 和突变型 ANP32B-D130A 的 CRISPR 编辑细胞中减弱。我们提出了一个模型，其中 D130A 突变会损害 FluPol 二聚体的形成，从而导致复制受损。我们认为 rs182096718 的纯合子和杂合子携带者可能对流感病毒具有一定的遗传保护作用。