A vaccine prepared from a non-pathogenic H7N7 virus isolated from natural reservoir conferred protective immunity against the challenge with lethal dose of highly pathogenic avian influenza virus in chickens
Saori SakabeYoshihiro SakodaYoshinari HaraguchiNorikazu IsodaKosuke SodaHiroki TakakuwaKazue SaijoAkira SAWATAKatsumi KUMEJunko HagiwaraKotaro TuchiyaZhifeng LinRyuichi SakamotoTakashi ImamuraTakashi SasakiNorihide KokumaiYoshihiro KawaokaHiroshi Kida
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Reassortment
Natural reservoir
H5N1 genetic structure
Viral Shedding
Abstract A segmented genome enables influenza virus to undergo reassortment when two viruses infect the same cell. Resulting reassorted progeny have a spectrum of gene constellations and potentially different phenotypes. Although reassortment is involved in the creation of pandemic influenza strains and is routinely used to produce influenza vaccines, our understanding of the factors that drive the emergence of dominant gene constellations during this process is incomplete. Using an influenza vaccine seed production model, reassortant genotypes were tracked through the reassortment process under antibody selective pressure. We discovered that certain gene constellations conferring low replicative fitness were selected at the expense of more fit progeny. Nevertheless, relatively unfit reassortants likely provide high hemagglutinin antigen yields through co-production of non-infectious particles and/or by more hemagglutinin molecules per virion. Our data illustrate the dynamics and complexity of reassortment and highlight how gene segment interactions formed during packaging, in addition to antibody pressure, restrict the final viruses that dominate.
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ABSTRACT The evolution of influenza B viruses is poorly understood. Reassortment of influenza B viruses in nature as a means of genetic variation has not been considered to be a major contributor to their evolution. However, the current practice of assigning evolutionary relationships by antigenic analysis of the hemagglutinin of influenza B viruses would fail to detect reassortants. In this study, influenza B viruses isolated within the past 10 years from sites in the United States and China were studied by nucleotide sequencing of the hemagglutinin and neuraminidase genes and construction of phylogenetic trees to assess evolutionary relationships. A group of viruses represented by B/Houston/1/92 possess a hemagglutinin derived from a B/Yamagata/16/88-like strain and a neuraminidase derived from a B/Victoria/2/87-like strain. A second reassortment event between the hemagglutinin of a B/Yamagata/16/88-like virus closely related to the B/Beijing/184/93 strain and the neuraminidase of a B/Victoria/2/87-like strain is represented by a single virus, B/Memphis/3/93. The neuraminidase of the reassortant viruses is most closely related to that of B/Victoria/2/87-like viruses currently circulating in Nanchang, China. A pattern of insertions and deletions in the hemagglutinin and the neuraminidase of different strains of influenza B viruses is observed. Reassortment plays a role in the evolution of influenza B viruses and may necessitate a change in the methods used to assess and identify new influenza viruses.
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H5N1 genetic structure
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Viral evolution
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H5N1 genetic structure
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Influenza A viruses cause natural infections of humans, some other mammals and birds. Few of the 16 haemagglutinin and nine neuraminidase subtype combinations have been isolated from mammals, but all subtypes have been isolated from birds. In the 20th century, there were four pandemics of influenza as a result of the emergence of antigenically different strains in humans: 1918 (H1N1), 1957 (H2N2), 1968 (H3N2) and 1977 (H1N1). Influenza A viruses contain eight distinct RNA genes and reassortment of these can occur in mixed infections with different viruses. The 1957 and 1968 pandemic viruses differed from the preceding viruses in humans by the substitution of genes that came from avian viruses, suggesting they arose by genetic reassortment of viruses of human and avian origin. Up to 1995, there had been only three reports of avian influenza viruses infecting humans, in 1959, 1977 and 1981 (all H7N7), but, since 1996, there have been regular reports of natural infections of humans with avian influenza viruses: in England in 1996 (H7N7), Hong Kong 1997 (H5N1), 1999 (H9N2), and 2003 (H5N1), in The Netherlands 2003 (H7N7), Canada 2004 (H7N3), Vietnam 2004 (H5N1) and Thailand 2004 (H5N1). The H5N1 virus is alarming because 51 (64 %) of the 80 people confirmed as infected since 1997 have died.
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ABSTRACT Influenza A viruses cause pandemics at sporadic intervals. Pandemic viruses can potentially be introduced into the human population through in toto transfer of an avian influenza virus or through reassortment between avian and human strains. Pigs are believed to play a central role in the creation of pandemic viruses through reassortment because of their susceptibility to infection with both avian and human influenza viruses. However, we recently found that a human-lineage H3N2 influenza virus was highly restricted in its ability to infect pigs after intranasal inoculation. We hypothesized that this restricted infectivity phenotype was controlled by the hemagglutinin (HA) and neuraminidase (NA). To test this, we infected pigs with reverse genetics-created HA plus NA reassortant viruses. Specifically, introduction of the HA and NA genes of a contemporary H3N2 swine virus into the genetic background of the wholly human virus resulted in a significant increase in virus shedding and pathogenicity. These data indicate that the HA/NA can play important roles in controlling human influenza virus infectivity in pigs. The results further support the premise that a barrier exists to human influenza virus infection in pigs, which may limit the role of pigs in pandemic virus creation through reassortment of human and avian influenza viruses.
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Pigs are susceptible to both human and avian influenza viruses and have been proposed to be intermediate hosts, or mixing vessels, for the generation of pandemic influenza viruses through reassortment or adaptation to the mammalian host. In this study, we summarize and report for the first time the coexistence of wholly human-like H3N2 viruses, double-reassortant H3N2 viruses, and triple-reassortant H3N2 viruses in pigs in China by analyzing the eight genes of swine influenza A (H3N2) viruses found in China from 1970 to 2006. In 1970, the first wholly human-like H3N2 (Hong Kong/68-like) viruses were isolated from pigs in Taiwan, and then in the next years Victoria/75-like, Sydney/97-like, New York/99-like, and Moscow/99-like swine H3N2 viruses were regularly isolated in China. In the 1980s, two triple-reassortant viruses were isolated from pigs. Recently, the double-reassortant viruses containing genes from the human (HA and NA) and avian (PB2, PB1, PA, NP, M, and NS) lineages and the triple-reassortant viruses containing genes from the human (HA and NA), classical swine (NP), and avian (PB2, PB1, PA, M, and NS) lineages emerged in pigs in China. The coexistence of wholly human-like and reassortant viruses provides further evidence that pigs serve as intermediate hosts, or mixing vessels, and emphasizes the importance of reinforcing swine influenza virus surveillance in China.
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