Cushing Anna, Kamali Amanda, Winters Mark, Hopmans Erik S, Bell John M, Grimes Susan M, Xia Li C, Zhang Nancy R, Moss Ronald B, Holodniy Mark, Ji Hanlee P
Stanford Genome Technology Center, Stanford University, Palo Alto, CA, 94304, United States.
Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, United States.
Sci Rep. 2015 Nov 5;5:16178. doi: 10.1038/srep16178.
Influenza remains a significant cause of disease mortality. The ongoing threat of influenza infection is partly attributable to the emergence of new mutations in the influenza genome. Among the influenza viral gene products, the hemagglutinin (HA) glycoprotein plays a critical role in influenza pathogenesis, is the target for vaccines and accumulates new mutations that may alter the efficacy of immunization. To study the emergence of HA mutations during the course of infection, we employed a deep-targeted sequencing method. We used samples from 17 patients with active H1N1 or H3N2 influenza infections. These patients were not treated with antivirals. In addition, we had samples from five patients who were analyzed longitudinally. Thus, we determined the quantitative changes in the fractional representation of HA mutations during the course of infection. Across individuals in the study, a series of novel HA mutations directly altered the HA coding sequence were identified. Serial viral sampling revealed HA mutations that either were stable, expanded or were reduced in representation during the course of the infection. Overall, we demonstrated the emergence of unique mutations specific to an infected individual and temporal genetic variation during infection.
流感仍然是导致疾病死亡的一个重要原因。流感感染的持续威胁部分归因于流感病毒基因组中新突变的出现。在流感病毒基因产物中，血凝素（HA）糖蛋白在流感发病机制中起关键作用，是疫苗的靶点，并且会积累可能改变免疫效果的新突变。为了研究感染过程中HA突变的出现情况，我们采用了深度靶向测序方法。我们使用了17例患有活动性H1N1或H3N2流感感染患者的样本。这些患者未接受抗病毒治疗。此外，我们还有来自5例进行纵向分析患者的样本。因此，我们确定了感染过程中HA突变分数表示的定量变化。在该研究的个体中，鉴定出一系列直接改变HA编码序列的新型HA突变。连续病毒采样显示，在感染过程中，HA突变要么稳定，要么在数量上增加或减少。总体而言，我们证明了感染个体特异性独特突变的出现以及感染期间的时间性基因变异。
