Increased replicative fitness can lead to decreased drug sensitivity of hepatitis C virus.
Increased replicative fitness can lead to decreased drug sensitivity of hepatitis C virus.
复制标题
复制适应性的增强可导致丙型肝炎病毒的药物敏感性降低。
DOI：
10.1128/jvi.01860-14
复制
发表时间：
2014
影响因子：
5.4
通讯作者：
Perales,Celia
中科院分区：
文献类型：
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作者：
Sheldon,Julie;Beach,NathanM;Moreno,Elena;Gallego,Isabel;Piñeiro,David;Martínez-Salas,Encarnación;Gregori,Josep;Quer,Josep;Esteban,JuanIgnacio;Rice,CharlesM;Domingo,Esteban;Perales,Celia
丙型肝炎病毒（HCV）在人肝癌细胞中的传代导致人群对α干扰素（IFN-α）、特拉匹韦、达卡他韦、环孢素和利巴韦林显示出部分耐药性，尽管之前没有暴露于这些药物。在不存在和存在药物的情况下，病毒生产的突变谱分析和动力学表明，耐药性不是由于初始或传代群体的突变谱中存在耐药性突变，而是由于传代过程中获得的复制适应性增加。健身增加并没有改变宿主因素，导致关闭一般宿主细胞蛋白质合成和优先翻译的HCV RNA。这些结果表明，病毒复制健身是一种机制的多药耐药的HCV。重要的是，病毒的耐药通常是由于存在的氨基酸取代的蛋白质靶向药物。在目前的研究与丙型肝炎病毒，我们表明，高病毒复制健身可以赋予一般耐药表型的病毒。结果排除了耐药突变的基因组负责观察到的表型的可能性。复制适应性可能是多药耐药的决定因素，这一事实可能解释了为什么病毒对长期慢性HCV感染的药物治疗不太敏感，这有利于复制适应性的增加。
Passage of hepatitis C virus (HCV) in human hepatoma cells resulted in populations that displayed partial resistance to alpha interferon (IFN-α), telaprevir, daclatasvir, cyclosporine, and ribavirin, despite no prior exposure to these drugs. Mutant spectrum analyses and kinetics of virus production in the absence and presence of drugs indicate that resistance is not due to the presence of drug resistance mutations in the mutant spectrum of the initial or passaged populations but to increased replicative fitness acquired during passage. Fitness increases did not alter host factors that lead to shutoff of general host cell protein synthesis and preferential translation of HCV RNA. The results imply that viral replicative fitness is a mechanism of multidrug resistance in HCV.IMPORTANCEViral drug resistance is usually attributed to the presence of amino acid substitutions in the protein targeted by the drug. In the present study with HCV, we show that high viral replicative fitness can confer a general drug resistance phenotype to the virus. The results exclude the possibility that genomes with drug resistance mutations are responsible for the observed phenotype. The fact that replicative fitness can be a determinant of multidrug resistance may explain why the virus is less sensitive to drug treatments in prolonged chronic HCV infections that favor increases in replicative fitness.