Multiple Reassortment Events in the Evolutionary History of H1N1 Influenza A Virus Since 1918

Abstract

The H1N1 subtype of influenza A virus has caused substantial morbidity and mortality in humans, first documented in the global pandemic of 1918 and continuing to the present day. Despite this disease burden, the evolutionary history of the A/H1N1 virus is not well understood, particularly whether there is a virological basis for several notable epidemics of unusual severity in the 1940s and 1950s. Using a data set of 71 representative complete genome sequences sampled between 1918 and 2006, we show that segmental reassortment has played an important role in the genomic evolution of A/H1N1 since 1918. Specifically, we demonstrate that an A/H1N1 isolate from the 1947 epidemic acquired novel PB2 and HA genes through intra-subtype reassortment, which may explain the abrupt antigenic evolution of this virus. Similarly, the 1951 influenza epidemic may also have been associated with reassortant A/H1N1 viruses. Intra-subtype reassortment therefore appears to be a more important process in the evolution and epidemiology of H1N1 influenza A virus than previously realized. The periodic occurrence of influenza epidemics in humans caused by viruses of the A/H1N1 subtype remains a key question in viral epidemiology and evolution and a major issue for public health. Since the first documentation of A/H1N1 in humans in 1918, this virus has been associated with a variety of epidemics and influenza vaccine failures. Using 71 representative whole-genome sequences of A/H1N1 influenza virus sampled between 1918 and 2005, we show that reassortment occurs frequently throughout the evolutionary history of this virus. Critically, two of these reassortment events appear to be associated with particularly severe epidemics, those of 1947 and 1951. Our analysis reveals that the virus associated with the 1947 epidemic was composed of genome segments with differing phylogenetic histories, suggesting that this virus was created through an intra-subtype reassortment event. Notably, of the two main antigenic proteins, the segment encoding the HA (hemagglutinin) is related to isolates circulating in a later time period, while the NA (neuraminidase) is related to earlier sampled isolates. This explains previous observations that the HA circulating at this time exhibited extensive antigenic drift while the NA appeared to be conserved. In addition, a virus likely associated with the 1951 epidemic also appears to have been generated by a reassortment event. Overall, our findings suggest that reassortment is an important factor in the long-term evolution of influenza A virus, including the periodic emergence of epidemic viruses. However, to more fully capture the evolutionary history of this important virus, additional sequencing of influenza viruses from earlier time periods is clearly needed.