White Maria C, Steel John, Lowen Anice C
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA
J Virol. 2017 May 12;91(11). doi: 10.1128/JVI.00195-17. Print 2017 Jun 1.
Influenza A virus (IAV) RNA packaging signals serve to direct the incorporation of IAV gene segments into virus particles, and this process is thought to be mediated by segment-segment interactions. These packaging signals are segment and strain specific, and as such, they have the potential to impact reassortment outcomes between different IAV strains. Our study aimed to quantify the impact of packaging signal mismatch on IAV reassortment using the human seasonal influenza A/Panama/2007/99 (H3N2) and pandemic influenza A/Netherlands/602/2009 (H1N1) viruses. Focusing on the three most divergent segments, we constructed pairs of viruses that encoded identical proteins but differed in the packaging signal regions on a single segment. We then evaluated the frequency with which segments carrying homologous versus heterologous packaging signals were incorporated into reassortant progeny viruses. We found that, when segment 4 (HA) of coinfecting parental viruses was modified, there was a significant preference for the segment containing matched packaging signals relative to the background of the virus. This preference was apparent even when the homologous HA constituted a minority of the HA segment population available in the cell for packaging. Conversely, when segment 6 (NA) or segment 8 (NS) carried modified packaging signals, there was no significant preference for homologous packaging signals. These data suggest that movement of NA and NS segments between the human H3N2 and H1N1 lineages is unlikely to be restricted by packaging signal mismatch, while movement of the HA segment would be more constrained. Our results indicate that the importance of packaging signals in IAV reassortment is segment dependent. Influenza A viruses (IAVs) can exchange genes through reassortment. This process contributes to both the highly diverse population of IAVs found in nature and the formation of novel epidemic and pandemic IAV strains. Our study sought to determine the extent to which IAV packaging signal divergence impacts reassortment between seasonal IAVs. Our knowledge in this area is lacking, and insight into the factors that influence IAV reassortment will inform and strengthen ongoing public health efforts to anticipate the emergence of new viruses. We found that the packaging signals on the HA segment, but not the NA or NS segments, restricted IAV reassortment. Thus, the packaging signals of the HA segment could be an important factor in determining the likelihood that two IAV strains of public health interest will undergo reassortment.
甲型流感病毒（IAV）的RNA包装信号用于指导IAV基因片段掺入病毒颗粒，并且这一过程被认为是由片段间相互作用介导的。这些包装信号具有片段和毒株特异性，因此，它们有可能影响不同IAV毒株之间的重配结果。我们的研究旨在使用人类季节性甲型流感病毒A/巴拿马/2007/99（H3N2）和大流行性甲型流感病毒A/荷兰/602/2009（H1N1）来量化包装信号不匹配对IAV重配的影响。聚焦于三个差异最大的片段，我们构建了成对的病毒，这些病毒编码相同的蛋白质，但在单个片段的包装信号区域存在差异。然后，我们评估了携带同源与异源包装信号的片段掺入重配子代病毒中的频率。我们发现，当共感染的亲代病毒的片段4（HA）被修饰时，相对于病毒背景，含有匹配包装信号的片段存在显著偏好。即使同源HA在细胞中可用于包装的HA片段群体中占少数，这种偏好也很明显。相反，当片段6（NA）或片段8（NS）携带修饰的包装信号时，对同源包装信号没有显著偏好。这些数据表明，NA和NS片段在人类H3N2和H1N1谱系之间的移动不太可能受到包装信号不匹配的限制，而HA片段的移动将受到更多限制。我们的结果表明，包装信号在IAV重配中的重要性是片段依赖性的。甲型流感病毒（IAVs）可以通过重配交换基因。这一过程既导致了自然界中发现的高度多样化的IAV群体，也促成了新型流行和大流行IAV毒株的形成。我们的研究旨在确定IAV包装信号差异在多大程度上影响季节性IAV之间的重配。我们在这一领域的知识尚缺，而深入了解影响IAV重配的因素将为正在进行的公共卫生工作提供信息并加强其力度，以预测新病毒的出现。我们发现，HA片段上的包装信号而非NA或NS片段上的包装信号限制了IAV重配。因此，HA片段的包装信号可能是决定两种具有公共卫生意义的IAV毒株进行重配可能性的一个重要因素。
