Influenza virus carrying neuraminidase with reduced sensitivity to oseltamivir carboxylate has altered properties in vitro and is compromised for infectivity and replicative ability in vivo
Influenza virus carrying neuraminidase with reduced sensitivity to oseltamivir carboxylate has altered properties in vitro and is compromised for infectivity and replicative ability in vivo
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DOI：
10.1016/s0166-3542(01)00215-7
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发表时间：
2002-05-01
影响因子：
7.6
通讯作者：
Roberts, N
中科院分区：
文献类型：
--
作者：
Carr, J;Ives, J;Roberts, N
磷酸奥司他韦（达菲）Ro 64-0796)是首个经批准用于治疗和预防人类流感病毒感染的口服神经氨酸酶（NA）抑制剂。磷酸奥司他韦是活性代谢物羧化奥司他韦的前药（Ro 64-0802）。在整个奥司他韦开发规划中进行的广泛监测发现，携带耐药病毒的患者发病率非常低。主要的突变是在病毒NA的292位上精氨酸取代赖氨酸。临床分离的携带该突变的流感病毒A/Sydney/5/97 （H3N2）在流感病毒感染动物模型中的适应度明显降低，R292K突变病毒在流感病毒感染小鼠模型中的传染性和复制能力分别降低了至少2个对数，在雪貂模型中分别降低了2和4个对数。R292K流感病毒A/Sydney/5/97在雪貂中的致病性降低，通过炎症和发热反应来测量，至少与复制能力的降低平行。数据表明，R292K NA突变损害了病毒适应性，因此携带该突变的病毒不太可能对人类产生显著的临床后果。(C) 2002 Elsevier Science B.V.版权所有
Oseltamivir phosphate (Tamiflu. Ro 64-0796) is the first orally administered neuraminidase (NA) inhibitor approved for use in treatment and prevention or influenza virus infection in man. Oseltamivir phosphate is the pro-drug of the active metabolite oseltamivir carboxylate (Ro 64-0802). Extensive monitoring throughout the oseltamivir development programme has identified a very low incidence of patients who have carried drug-resistant virus. The predominant mutation seen is the substitution of arginine for lysine at position 292 of the viral NA. The fitness of clinically isolated influenza virus A/Sydney/5/97 (H3N2) carrying this mutation was markedly reduced in animal models of influenza virus infection, The infectivity and replicative abilities of R292K mutant virus were reduced by at least 2 logs in a mouse model of influenza infection and by 2 and 4 logs, respectively, in the ferret model. Pathogenicity of R292K influenza virus A/Sydney/5/97 was reduced in ferrets as measured by inflammatory and febrile responses at least in parallel to the decrease in replicative ability. The data indicate that the R292K NA mutation compromises viral fitness such that virus carrying this mutation is unlikely to be of significant clinical consequence in man. (C) 2002 Elsevier Science B.V. All rights reserved.