流感病毒的抗原变异和耐药性产生是其生存至关重要的两种手段。面对来自免疫系统与药物的双重压力，两者需要相互协同才能使病毒获取更大的生存优势。然而目前很少有人研究两者的关系。在本项目中，我们将以人流感H1N1和H3N2病毒为模型，通过计算和实验相结合的策略来研究病毒的抗原变异和神经氨酸酶抑制剂耐药性之间的关联及其分子机理。具体来说，我们将从病毒的表面蛋白血凝素(HA)和神经氨酸酶(NA)的基因序列出发，为每株病毒构建共进化网络；通过分析网络中节点、边和模块的差异与病毒抗原变异和耐药性变化的关联，并整合网络结构信息，确定出对该病毒抗原变异和耐药性变化具有显著影响的位点和位点间相互作用；最后通过血凝抑制实验和NA功能实验来证实关键位点的作用。本项目的实施将不仅有利于加深对于流感病毒适应性机制的理解，具有重要的理论意义，同时也对流感病毒的疫苗设计与抗流感药物的使用提供指导。

Antigenic drift and production of drug-resistant variants are two key factors for continual epidemics of influenza viruses. Their collaboration is necessary for the virus to survive the double challenges of antibody pressure and antiviral drugs. Lots of efforts have been devoted to clarify their respective mechanisms, however, little attention has been focused on their relationship. Here, we propose a new strategy of combining computational analyses and experimental efforts to investigate the relationship between antigenic variation and neuraminidase inhibitor (NAI) resistance for human influenza A(H1N1) and A(H3N2) viruses. Firstly, a nucleotide co-occurrence network would be constructed for each influenza virus based on the nucleotide sequences of hemagglutinin (HA) and neuraminidase (NA). Then, the correlation between the changes of network elements, including the nodes, edges and modules, and variation of antigenicity or NAI resistance would be conducted, which could identify the sites and site interactions contributing significantly to antigenic variation or NAI resistance. Finally, the HA and NA inhibition experiments would be used to confirm the contribution of sites or site interactions to antigenic variation or NAI resistance. This work could not only help to clarify the mechanisms underlying the association between antigenic variation and drug resistance, but also help for influenza vaccine design and drug usage.