Combination chemotherapy, a potential strategy for reducing the emergence of drug-resistant influenza A variants
Combination chemotherapy, a potential strategy for reducing the emergence of drug-resistant influenza A variants
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DOI：
10.1016/j.antiviral.2006.01.012
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发表时间：
2006-07-01
影响因子：
7.6
通讯作者：
Govorkova, Elena A.
中科院分区：
文献类型：
--
作者：
Ilyushina, Natalia A.;Bovin, Nicolai V.;Govorkova, Elena A.
金刚烷胺治疗后耐药流感变异的快速发展是M2阻滞剂的主要缺点之一。另一方面，对神经氨酸酶（NA）抑制剂具有低敏感性的变体的出现是有限的。在本研究中，我们研究了两类抗流感药物的联合治疗是否会影响体外耐药变异体的出现。我们观察到人A/Nanchang/1/99（H1N1）、A/Panama/2007/99（H3 N2）、和A/Hong Kong/156/97（H5 N1）病毒在MDCK细胞中显著减少当用金刚烷胺和低剂量的奥司他韦羧酸盐联合处理细胞时（P < 0.005），（= 0.001 μ M）具有血凝素（HA）蛋白的突变。这些变体显示与唾液酸受体结合的效率降低，并且在空斑减少测定中对NA抑制剂的敏感性降低。重要的是，当药物组合使用时，未检测到HA、NA和M2蛋白的突变。我们的研究结果表明，M2阻断剂和NA抑制剂的联合化疗减少了体外耐药流感病毒变体的出现。这种策略可能是控制流感病毒感染的一种选择，应探索与其他新药的联合用药。(c)2006 Elsevier B. V.保留所有权利。
Rapid development of resistant influenza variants after amantadine treatment is one of the main drawbacks of M2 blockers. On the other hand, the emergence of variants with low susceptibility to the neuraminidase (NA) inhibitors is limited. In the present study we examined whether combination therapy with two classes of anti-influenza drugs can affect the emergence of resistant variants in vitro. We observed that virus yields of human A/Nanchang/1/99 (H1N1), A/Panama/2007/99 (H3N2), and A/Hong Kong/156/97 (H5N1) viruses in MDCK cells were significantly reduced (P < 0.005) when the cells were treated with the combination of amantadine and low doses of oseltamivir carboxylate (= 0.001 mu M) possessed mutations in the hemagglutinin (HA) protein. These variants showed reduced efficiency of binding to sialic acid receptors and decreased sensitivity to NA inhibitor in plaque reduction assay. Importantly, no mutations in the HA, NA, and M2 proteins were detected when the drugs were used in combination. Our results suggest that combination chemotherapy with M2 blocker and NA inhibitor reduced the emergence of drug-resistant influenza variants in vitro. This strategy could be an option for the control of influenza virus infection, and combinations with other novel drugs should be explored. (c) 2006 Elsevier B.V. All rights reserved.