Influenza A virus (IAV) is a human respiratory pathogen that causes yearly global epidemics, as well as sporadic pandemics due to human adaptation of pathogenic strains. Efficient replication of IAV in different species is, in part, dictated by its ability to exploit the genetic environment of the host cell. To investigate IAV tropism in human cells, we evaluated the replication of IAV strains in a diverse subset of epithelial cell lines. HeLa cells were refractory to the growth of human H1N1 and H3N2 viruses and low-pathogenic avian influenza (LPAI) viruses. Interestingly, a human isolate of the highly pathogenic avian influenza (HPAI) H5N1 virus successfully propagated in HeLa cells to levels comparable to those in a human lung cell line. Heterokaryon cells generated by fusion of HeLa and permissive cells supported H1N1 virus growth, suggesting the absence of a host factor(s) required for the replication of H1N1, but not H5N1, viruses in HeLa cells. The absence of this factor(s) was mapped to reduced nuclear import, replication, and translation, as well as deficient viral budding. Using reassortant H1N1:H5N1 viruses, we found that the combined introduction of nucleoprotein (NP) and hemagglutinin (HA) from an H5N1 virus was necessary and sufficient to enable H1N1 virus growth. Overall, this study suggests that the absence of one or more cellular factors in HeLa cells results in abortive replication of H1N1, H3N2, and LPAI viruses, which can be circumvented upon the introduction of H5N1 virus NP and HA. Further understanding of the molecular basis of this restriction will provide important insights into the virus-host interactions that underlie IAV pathogenesis and tropism.IMPORTANCE Many zoonotic avian influenza A viruses have successfully crossed the species barrier and caused mild to life-threatening disease in humans. While human-to-human transmission is limited, there is a risk that these zoonotic viruses may acquire adaptive mutations enabling them to propagate efficiently and cause devastating human pandemics. Therefore, it is important to identify viral determinants that provide these viruses with a replicative advantage in human cells. Here, we tested the growth of influenza A virus in a subset of human cell lines and found that abortive replication of H1N1 viruses in HeLa cells can be circumvented upon the introduction of H5N1 virus HA and NP. Overall, this work leverages the genetic diversity of multiple human cell lines to highlight viral determinants that could contribute to H5N1 virus pathogenesis and tropism.

中文翻译：

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H5N1甲型流感病毒中的病毒决定因素使HeLa细胞能够产生感染。

甲型流感病毒（IAV）是一种人类呼吸道病原体，会导致每年的全球流行病以及由于人类对病原体的适应而导致的零星大流行。IAV在不同物种中的有效复制部分取决于其利用宿主细胞遗传环境的能力。为了研究人细胞中IAV的向性，我们评估了IAV株在上皮细胞系的不同子集中的复制。HeLa细胞对人类H1N1和H3N2病毒以及低致病性禽流感（LPAI）病毒的生长具有抵抗力。有趣的是，人类高致病性禽流感（HPAI）H5N1病毒分离株在HeLa细胞中成功繁殖，其水平可与人肺细胞系中的水平相提并论。HeLa与允许细胞融合产生的异核细胞支持H1N1病毒的生长，提示在HeLa细胞中不存在复制H1N1病毒（而非H5N1病毒）所需的宿主因子。不存在该因素的原因是核输入，复制和翻译减少以及病毒出芽不足。使用重配的H1N1：H5N1病毒，我们发现从H5N1病毒中联合引入核蛋白（NP）和血凝素（HA）是必要且足以使H1N1病毒生长。总的来说，这项研究表明，HeLa细胞中缺乏一种或多种细胞因子会导致H1N1，H3N2和LPAI病毒的流产复制，而在引入H5N1病毒NP和HA时可以避免这种复制。对该限制的分子基础的进一步了解将提供对IAV发病机理和向性基础的病毒-宿主相互作用的重要见解。重要信息许多人畜共患的甲型禽​​流感病毒已成功越过物种壁垒，并在人类中引起了轻度甚至危及生命的疾病。尽管人与人之间的传播受到限制，但这些人畜共患病毒可能会获得适应性突变，从而使其能够有效传播并造成毁灭性的人类大流行，这是有风险的。因此，重要的是确定使这些病毒在人细胞中具有复制优势的病毒决定簇。在这里，我们测试了人类细胞系亚型中A型流感病毒的生长情况，发现在引入H5N1病毒HA和NP后，可以规避HeLa细胞中H1N1病毒的流产复制。总体，