The selection pressure on the neuraminidase gene of influenza viruses isolated in Ukraine from 2009 to 2015

A broad range of naturally occurring antigenic variants of the influenza virus is caused by its rapid evolutionary variability. The survival of viable influenza virus variants occurs through natural selection. The treatment of influenza infection with modern antiviral drugs – neuraminidase (NA) inhibitors – leads to the occurrence of mutations in the NA gene, which thereby result in the emergence of virus resistance to these drugs. The goal of this study was to determine the selection pressure on the NA protein of influenza viruses isolated in Ukraine from 2009 to 2015. The main method for assessing the selection pressure on proteins is to quantify the ratio of substitution rates at nonsynonymous (dN) and synonymous (dS) sites. With the help of this method, we showed that only a few codons in the NA gene were under positive selection resulting in mutations at the following sites: for influenza A viruses of the A(H1N1)pdm09 subtype – site 40, for viruses of the A(H3N2) subtype – sites 93 and 402, for Influenza B viruses of the B/Yamagata lineage – sites 74, 99, and 268, and for the viruses of the B/Victoria lineage – sites 358, 288, and 455. These sites are not associated with the NA active site, transmembrane domain, or the antigenic sites of this protein. We concluded that NA inhibitors are not a significant factor in the process of selection of the influenza viruses in Ukraine because the sites associated with the resistance of influenza viruses to NA inhibitors were not affected by positive selection. This finding could be explained by the limited use of NA inhibitors for the treatment of influenza infections in Ukraine. A broad range of naturally occurring antigenic variants of the influenza virus is caused by its rapid evolutionary variability. The survival of viable influenza virus variants occurs through natural selection. The treatment of influenza infection with modern antiviral drugs – neuraminidase (NA) inhibitors – leads to the occurrence of mutations in the NA gene, which thereby result in the emergence of virus resistance to these drugs. The goal of this study was to determine the selection pressure on the NA protein of influenza viruses isolated in Ukraine from 2009 to 2015. The main method for assessing the selection pressure on proteins is to quantify the ratio of substitution rates at nonsynonymous (dN) and synonymous (dS) sites. With the help of this method, we showed that only a few codons in the NA gene were under positive selection resulting in mutations at the following sites: for influenza A viruses of the A(H1N1)pdm09 subtype – site 40, for viruses of the A(H3N2) subtype – sites 93 and 402, for Influenza B viruses of the B/Yamagata lineage – sites 74, 99, and 268, and for the viruses of the B/Victoria lineage – sites 358, 288, and 455. These sites are not associated with the NA active site, transmembrane domain, or the antigenic sites of this protein. We concluded that NA inhibitors are not a significant factor in the process of selection of the influenza viruses in Ukraine because the sites associated with the resistance of influenza viruses to NA inhibitors were not affected by positive selection. This finding could be explained by the limited use of NA inhibitors for the treatment of influenza infections in Ukraine.

Давление отбора на ген нейраминидазы вирусов гриппа, выделенных в Украине с 2009 по 2015 гг

A broad range of naturally occurring antigenic variants of the influenza virus is caused by its rapid evolutionary variability. The survival of viable influenza virus variants occurs through natural selection. Treatment of influenza infection with modern antiviral drugs – neuraminidase (NA) inhibitors – leads to occurrence of mutations in the NA gene, which result in emergence of virus resistance to these drugs. The goal of this study was to determine the selection pressure on the NA protein of influenza viruses isolated in Ukraine from 2009 to 2015. The main method for assessing the evolutionary pressure on proteins is to quantify the ratio of substitution rates at nonsynonymous (dN) and synonymic (dS) sites. With the help of this method we showed that only a few codons in the NA gene were under the positive selection resulting in mutations at the following sites: for influenza A viruses of A(H1N1)pdm09 subtype – site 40, for viruses of A(H3N2) subtype – sites 93 and 402, for B/Yamagata lineage viruses – sites 74, 99, and 268, and for the B/Victoria lineage viruses – sites 358, 288, and 455. These sites are not associated with NA active site, transmembrane domain, or the antigenic sites of this protein. We concluded that NA inhibitors are not a significant factor in the process of selection of the influenza viruses in Ukraine because sites associated with the resistance of influenza viruses to NA inhibitors were not affected by positive selection. This finding could be explained by the limited use of NA inhibitors for the treatment of influenza infections in Ukraine.Большое разнообразие существующих в природе антигенных вариантов вируса гриппа вызвано его быстрой эволюционной изменчивостью. Отбор жизнеспособных вариантов вируса гриппа происходит за счет естественного отбора. Лечение гриппозной инфекции с помощью современных противовирусных препаратов – ингибиторов нейраминидазы (NA) – приводит к возникновению мутаций в гене NA, которые ведут к появлению резистентности вирусов к данным препаратам. Цель работы состояла в определении давления отбора на белок NA вирусов гриппа, выделенных в Украине в период с 2009 по 2015 год. Основным методом оценки эволюционного давления на белки является определение количественного соотношения частот замен в несинонимических (dN) и синонимических сайтах (dS). С помощью этого метода мы показали, что лишь некоторые кодоны в гене NA были под влиянием положительного отбора: для вирусов гриппа типа А подтипа A(H1N1)pdm09 – сайт 40, для вирусов подтипа A(H3N2) – сайты 93 и 402, для вирусов гриппа типа B разновидности B/Yamagata – сайты 74, 99 и 268, и для вирусов разновидности В/Victoria – сайты 358, 288 и 455. Указанные сайты не связаны ни с активным центром NA, ни с трансмембранным доменом, ни с антигенными сайтами. Ингибиторы NA не являются селективным фактором отбора вирусов гриппа в Украине, поскольку, сайты, ассоциированные с резистентностью вирусов гриппа к ингибиторам NA, не попали под влияние положительного отбора, что, вероятно, объясняется низким уровнем применения данных противовирусных препаратов в Украине