Characterization of the 1918 influenza virus polymerase genes

Abstract

Understanding the origin and virulence of the virus that caused 1918–19 influenza pandemic is vital, not least because of the risk that a similar virus could arise in the human population. No isolates of the virus were made in 1918, so direct study was not possible, but a project to sequence its genome was begun in 1995, using RNA fragments from autopsy tissues of victims of the pandemic. Now, with the coding sequences of the viral polymerase complex established, that sequence is complete. These data and other recent results suggest that the 1918 virus was an avian strain that adapted to humans, a sobering thought at a time when human cases of the H5N1 avian virus have been reported in Indonesia. Also out this week (on Nature online) is the first report from a large US project that is using novel sequencing techniques to capture the entire genome of modern influenza virus isolates. The first batch of data, to be made publicly available as a baseline for future studies, includes the genomes of 209 influenza isolates. Already the data point to mutations and segment exchanges that might lead to new viruses. The influenza A viral heterotrimeric polymerase complex (PA, PB1, PB2) is known to be involved in many aspects of viral replication and to interact with host factors1, thereby having a role in host specificity2,3. The polymerase protein sequences from the 1918 human influenza virus differ from avian consensus sequences at only a small number of amino acids, consistent with the hypothesis that they were derived from an avian source shortly before the pandemic. However, when compared to avian sequences, the nucleotide sequences of the 1918 polymerase genes have more synonymous differences than expected, suggesting evolutionary distance from known avian strains. Here we present sequence and phylogenetic analyses of the complete genome of the 1918 influenza virus4,5,6,7,8, and propose that the 1918 virus was not a reassortant virus (like those of the 1957 and 1968 pandemics9,10), but more likely an entirely avian-like virus that adapted to humans. These data support prior phylogenetic studies suggesting that the 1918 virus was derived from an avian source11. A total of ten amino acid changes in the polymerase proteins consistently differentiate the 1918 and subsequent human influenza virus sequences from avian virus sequences. Notably, a number of the same changes have been found in recently circulating, highly pathogenic H5N1 viruses that have caused illness and death in humans and are feared to be the precursors of a new influenza pandemic. The sequence changes identified here may be important in the adaptation of influenza viruses to humans.