WHO Collaborating Centre for Reference and Research on Influenza, At the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, 3000, Australia; Department of Microbiology and Immunology, The University of Melbourne, At the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, 3000, Australia.
WHO Collaborating Centre for Reference and Research on Influenza, At the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, 3000, Australia.
Antiviral Res. 2019 Aug;168:68-75. doi: 10.1016/j.antiviral.2019.05.009. Epub 2019 May 25.
Avian A(H7N9) infections in humans have been reported in China since 2013 and are of public health concern due to their severity and pandemic potential. Oseltamivir and peramivir are neuraminidase inhibitors (NAIs) routinely used for the treatment of A(H7N9) infections, but variants with reduced sensitivity to these drugs can emerge in patients during treatment. Zanamivir and laninamivir are NAIs that are used less frequently. Herein, we performed in vitro serial passaging experiments with recombinant viruses, containing the neuraminidase (NA) from influenza A/Anhui/1/13 (H7N9) virus, in the presence of each NAI, to determine whether variants with reduced sensitivity would emerge. NA substitutions were characterized for their effect on the NA enzymatic activity and surface expression of the A/Anhui/1/13 (Anhui/1) NA, as well as NAs originating from contemporary A(H7N9) viruses of the Yangtze River Delta and Pearl River Delta lineages. In vitro passage in the presence of oseltamivir, peramivir and laninamivir selected for substitutions associated with reduced sensitivity (E119D, R292K and R152K), whereas passage in the presence of zanamivir did not select for any viruses with reduced sensitivity. All the NA substitutions significantly reduced activity, but not the expression of the Anhui/1 NA. In contemporary N9 NAs, all substitutions tested significantly reduced NA enzyme function in the Yangtze River lineage background, but not in the Pearl River Delta lineage background. Overall, these findings suggest that zanamivir may be less likely than the other NAIs to select for resistance in A(H7N9) viruses and that the impact of substitutions that reduce NAI susceptibility or enzyme function may be less in A(H7N9) viruses from the Pearl River lineage.
自 2013 年以来，中国已报告了人感染甲型 H7N9 禽流感病例，由于其严重性和大流行潜力，引起了公众的健康关注。奥司他韦和帕拉米韦是常用于治疗甲型 H7N9 感染的神经氨酸酶抑制剂（NAI），但在治疗过程中，患者可能会出现对这些药物敏感性降低的变异体。扎那米韦和拉尼米韦是较少使用的 NAI。在此，我们在存在每种 NAI 的情况下，通过对含有来自流感 A/安徽/1/13（H7N9）病毒的神经氨酸酶（NA）的重组病毒进行体外连续传代实验，以确定是否会出现敏感性降低的变异体。对 NA 取代物的特征进行了研究，以确定它们对 A/安徽/1/13（安徽/1）NA 的 NA 酶活性和表面表达的影响，以及源自长江三角洲和珠江三角洲谱系的当代甲型 H7N9 病毒的 NAs。在奥司他韦、帕拉米韦和拉尼米韦存在的情况下进行体外传代选择与敏感性降低相关的取代（E119D、R292K 和 R152K），而在扎那米韦存在的情况下未选择出任何敏感性降低的病毒。所有 NA 取代均显著降低了活性，但并未降低安徽/1 NA 的表达。在当代 N9 NAs 中，所有测试的取代均显著降低了长江谱系背景下的 NA 酶功能，但在珠江三角洲谱系背景下则没有。总体而言，这些发现表明扎那米韦可能比其他 NAI 更不容易选择对甲型 H7N9 病毒产生耐药性，并且降低 NAI 敏感性或酶功能的取代对来自珠江谱系的甲型 H7N9 病毒的影响可能较小。
