摘 要
病毒性疾病对全球公共卫生构成重大威胁，抗病毒药物的广泛应用在控制病毒传播和减轻疾病负担方面发挥了重要作用，但耐药性问题日益凸显。为深入理解抗病毒药物耐药性的产生机制，本研究聚焦于病毒基因组突变、宿主细胞微环境改变及二者相互作用对抗病毒药物敏感性的影响。通过整合多组学数据，结合体内外实验模型，系统分析了多种代表性病毒（如HIV、HBV等）在药物压力下的进化规律。结果表明，病毒关键靶点基因发生特异性突变是导致耐药的主要分子基础，这些突变可改变药物结合位点构象或影响病毒复制酶活性；同时发现宿主细胞因子表达谱变化能调控病毒生命周期，进而影响药物疗效。创新性地揭示了宿主-病毒互作网络中多个潜在耐药相关节点，并构建了预测耐药发生的数学模型，为临床合理用药提供理论依据。该研究不仅深化了对抗病毒药物耐药性分子机制的认识，还为开发新型抗病毒策略和优化治疗方案奠定了重要基础。
关键词：抗病毒药物耐药性；病毒基因组突变；宿主细胞微环境；药物敏感性；多组学分析
Abstract
Viral diseases pose a significant threat to global public health, and the widespread use of antiviral drugs has played a crucial role in controlling viral transmission and alleviating disease burden. However, drug resistance has become an increasingly prominent issue. To gain a deeper understanding of the mechanisms underlying antiviral drug resistance, this study focuses on the impact of viral genome mutations, alterations in the host cell microenvironment, and their interactions on drug sensitivity. By integrating multi-omics data and utilizing both in vitro and in vivo experimental models, we systematically analyzed the evolutionary patterns of representative viruses such as HIV and HBV under drug pressure. The results indicate that specific mutations in key viral target genes constitute the primary molecular basis for resistance, which can alter the conformation of drug-binding sites or affect viral replicase activity. Concurrently, changes in the ex pression profiles of host cell factors were found to modulate the viral life cycle, thereby influencing drug efficacy. Innovatively, this study revealed multiple potential resistance-related nodes within the host-virus interaction network and developed a mathematical model to predict the occurrence of resistance, providing a theoretical basis for rational clinical drug use. This research not only enhances our understanding of the molecular mechanisms of antiviral drug resistance but also lays an important foundation for developing novel antiviral strategies and optimizing treatment regimens.
Keywords：Antiviral Drug Resistance；Viral Genome Mutation；Host Cell Microenvironment；Drug Sensitivity；Multi-omics Analysis
目 录
摘 要 I
Abstract II
引 言 1
第一章 病毒基因变异与耐药性 2
1.1 病毒复制中的突变机制 2
1.2 基因多态性与药物敏感性 2
1.3 突变选择压力下的进化 3
第二章 药物靶点的适应性改变 4
2.1 靶点蛋白结构变化 4
2.2 药物结合位点修饰 4
2.3 靶点功能补偿机制 5
第三章 病毒代谢通路的重编程 6
3.1 代谢酶活性调控机制 6
3.2 代谢产物对药物影响 6
3.3 代谢网络的适应性调整 7
第四章 宿主因素对耐药性的影响 9
4.1 宿主免疫反应作用 9
4.2 宿主细胞转运蛋白 9
4.3 宿主微环境的影响 10
结 论 12
参考文献 13
致 谢 14
