Characterization of multidrug-resistant influenza A/H3N2 viruses shed during 1 year by an Immunocompromised child
Characterization of multidrug-resistant influenza A/H3N2 viruses shed during 1 year by an Immunocompromised child
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DOI：
10.1086/508777
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发表时间：
2006-12-15
影响因子：
11.8
通讯作者：
Boivin, Guy
中科院分区：
文献类型：
--
作者：
Baz, Mariana;Abed, Yacine;Boivin, Guy
背景资料。流感耐药性的产生是免疫低下儿童的一个重要问题，可能导致治疗失败和病毒向他人传播。在一年的时间里，从一名免疫功能低下的儿童身上恢复了17株甲型H3N1流感病毒株，该儿童最初接受奥司他韦治疗，然后接受金刚烷胺和扎那米韦治疗病毒性肺炎。用神经氨酸酶(NA)抑制法检测奥司他韦、扎那米韦和帕拉米韦的药敏表型，并对病毒关键基因(M2、NA和血凝素[HA])进行序列分析。使用重组NA蛋白分析在奥司他韦耐药分离株中发现的NA突变的影响。在奥司他韦治疗38天后，首次检测到具有NA突变E59G、E119V和I222V的甲型流感变异株。在安娜抑制试验中，该变异株对奥司他韦的抗性是原始菌株的274倍，但对扎那米韦敏感。I222V替换增强了重组NA蛋白中主要由E119V突变引起的奥司他韦耐药水平。值得注意的是，停用奥司他韦后，E119V突变持续了8个月。金刚烷胺治疗导致M2突变S31N迅速出现，这是已知的赋予金刚烷胺耐药性的突变。患者在接受扎那米韦雾化治疗时间歇性地脱离病毒，尽管没有耐药表型，这可能是药物传递不佳和宿主免疫受损的结果。这项研究强调了即使在停止治疗后，在免疫功能低下的受试者中也可能出现和持续出现多药耐药流感分离株，从而加强了开发新的抗流感化合物的必要性。
Background. Development of influenza drug resistance is an important problem in immunocompromised children that could result in treatment failure and viral transmission to others.Methods. A total of 17 influenza A/H3N2 isolates were recovered over a period of 1 year from an immunocompromised child who was initially treated with oseltamivir and then with amantadine and zanamivir for viral pneumonitis. Drug susceptibility phenotypes to oseltamivir, zanamivir, and peramivir were evaluated by neuraminidase (NA) inhibition assays, and sequence analysis of key viral genes (i.e., M2, NA, and hemagglutinin [HA]) was performed. The impact of NA mutations identified in oseltamivir-resistant isolates was analyzed using recombinant NA proteins.Results. An influenza A variant with NA mutations E59G, E119V, and I222V was first detected after 38 days of oseltamivir treatment. In an NA inhibition assay, this variant was 274 times more resistant to oseltamivir than the original isolate but was susceptible to zanamivir. The I222V substitution enhanced the level of oseltamivir resistance that was primarily conferred by the E119V mutation in recombinant NA proteins. Remarkably, the E119V mutation persisted for 8 months after cessation of oseltamivir. Amantadine therapy led to rapid emergence of the M2 mutation S31N, which is known to confer amantadine resistance. The patient shed the virus intermittently while receiving nebulized zanamivir therapy despite the absence of a resistance phenotype, which could be the result of nonoptimal drug delivery and impaired host immunity.Conclusions. This study highlights the potential for emergence and persistence of multidrug-resistant influenza isolates in immunocompromised subjects even after cessation of treatment, reinforcing the need for development of new anti-influenza compounds.