In April 2009, a new strain of human H1N1 influenza A viruswas identified in Mexico. According to the World Health Organization(www.who.int/csr/don/2009_05_25), as of May 25, 2009, the virushad spread to 43 countries, with 12,515 reported cases and 91associated deaths, and it has been assessed as having pandemicpotential.1
Genomic analysis of the 2009 influenza A (H1N1) virus in humansindicates that it is closely related to common reassortant swineinfluenza A viruses isolated in North America, Europe, and Asia(Figure 1).2,3,4 The segments coding for the polymerase complex,hemagglutinin, nuclear protein, and nonstructural proteins showhigh similarity with the swine H1N2 influenza A viruses isolatedin North America in the late 1990s (Table 1). H1N2 and othersubtypes are descendants of the triple-reassortant swine H3N2viruses isolated in North America. They have spread in swinehosts around the globe and have been found to infect humans.5The segments coding for the neuraminidase and the matrix proteinsof the new human H1N1 virus are, however, distantly relatedto swine viruses isolated in Europe in the early 1990s (Table 2).In particular, the closest isolated relatives of the neuraminidasesegment have 94.4% similarity at the nucleotide level with Europeanswine influenza A virus strains from 1992.
Figure 1. History of Reassortment Events in the Evolution of the 2009 Influenza A (H1N1) Virus.
The eight segments shown within each virus code for the following proteins of the influenza A virus (top to bottom): polymerase PB2, polymerase PB1, polymerase PA, hemagglutinin, nuclear protein, neuraminidase, matrix proteins, and nonstructural proteins. The segments of the human 2009 influenza A (H1N1) virus have coexisted in swine influenza A virus strains for more than 10 years. The ancestors of neuraminidase have not been observed for almost 20 years. The mixing vessel for the current reassortment is likely to be a swine host but remains unknown.
Table 1. Nucleotide Identities of Swine Influenza A Viruses Most Similar to the Ancestor of Segments 1, 2, 3, 4, 5, and 8 of the 2009 Swine-Origin Human Influenza A (H1N1) Virus.
Table 2. Nucleotide Identities of Swine Influenza A Viruses Most Similar to the Ancestor of Segments 6 and 7 of the 2009 Swine-Origin Human Influenza A (H1N1) Virus.
In the past few years, there has been a worldwide effort toisolate and sequence the genomes of influenza A viruses, whichhas led to the depositing of more than 46,000 sequences in theInfluenza Virus Resource of the National Center for BiotechnologyInformation (NCBI) (www.ncbi.nlm.nih.gov/genomes/FLU/FLU.html).As of May 25, 2009, the NCBI database included sequences frommore than 220 strains from the 2009 swine-origin human influenzaA (H1N1) virus isolated at various sites around the world. Consequently,the origin and recent history of new strains can be inferredfrom study of the most similar deposited sequences. The percentageof matching nucleotides (the nucleotide identity) after nucleotidealignment, as determined with the use of the NCBI Basic LocalAlignment Search Tool (BLAST) or other tools, is a common measureof similarity used by researchers in the field.
Figure 2 shows the nucleotide identities and the numbers ofyears between the initial isolation of a given sequence of influenzaA virus deposited in the NCBI database and the initial isolationof its closest relative. A total of 98% of all sequences ofhuman influenza A viruses have relatives with at least 99% nucleotideidentity, and 95% have a relative that was initially isolatedwithin 2 years before their own first appearance. These numberssuggest that researchers have sampled human influenza A virusesefficiently — and point to a high degree of homogeneityamong human influenza A viruses. Swine influenza A viruses havenot been sampled as efficiently as human influenza A viruses;nevertheless, 86% of all segments from such strains have relativeswith at least 99% nucleotide identity, and 71% have a relativethat was initially isolated within 2 years before their ownfirst appearance. Only 2% of all swine influenza A virus sequenceshave 94% nucleotide identity with their closest relative, andin 2% of cases, the closest relative appeared at least 20 yearsearlier.
Figure 2. Nucleotide Identities and Numbers of Years between Initial Isolations of Influenza A Viruses and Their Closest Relatives Deposited in the NCBI Database.
Panel A shows the cumulative proportion of sequences with a given degree of nucleotide identity with their closest relative. Panel B shows the cumulative proportion of sequences appearing a given number of years after the closest relative was identified.
Figure 3 shows the numbers of sequences from human and swinehosts isolated on various continents and deposited in the NCBIdatabase. The numbers have increased dramatically over the pastfew years, and geography plays an important role. Most isolatesof human influenza A viruses are from North America, Oceania,Asia, and Europe, and though there are many swine influenzaA viruses from North America, Asia, and Europe, there are nonefrom Africa, Oceania, or South America. North American and Europeanswine influenza A (H1N1) viruses show strong geographic homogeneity,whereas some Asian isolates contain an admixture of both NorthAmerican and European lineages (Figure 4). Although human influenzaA viruses travel around the world with their hosts, swine viruseson different continents have largely distinct lineages.
Figure 3. Numbers of Sequences of Influenza A Viruses from Human and Swine Hosts Isolated on Various Continents and Deposited in the NCBI Database.
Sampling has increased in recent years. No sequences of swine influenza A virus strains from Africa, Oceania, or South America have been deposited in the database.
Figure 4. Nucleotide Identities of Human and Swine Influenza A (H1N1) Viruses from within and outside North America, Europe, and Asia.
Human influenza A virus strains show strong worldwide homogeneity. North American and European swine influenza A virus strains are homogeneous within each continent. Asian swine influenza A virus strains contain an admixture of North American and European strains.
Given both the dependence of the distribution of swine influenzaA viruses on geographic location and the lack of sampling incertain parts of the world, it is perhaps not surprising thatthe ancestors of the new human influenza A (H1N1) virus havegone unnoticed for almost two decades. Only more efficient surveillancecould prevent such an event from happening in the future.
No potential conflict of interest relevant to this article hasbeen reported.
Source Information
From the Department of Biomedical Informatics, Center for Computational Biology and Bioinformatics, Columbia University College of Physicians and Surgeons, New York.
This article (10.1056/NEJMp0904572) was published on May 27, 2009, at NEJM.org.
References
Fraser C, Donnelly CA, Cauchemez S, et al. Pandemic potential of a strain of influenza A (H1N1): early findings. Science 2009 May 14 (Epub ahead of print).
Trifonov V, Khiabanian H, Greenbaum B, Rabadan R. The origin of the recent swine influenza A(H1N1) virus infecting humans. Euro Surveill 2009;14:pii=19193-pii=19193.
Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med 2009;360:2605-2615. [Free Full Text]
Garten RJ, Davis CD, Russell CA, et al. Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science 2009 May 22 (Epub ahead of print).
Shinde V, Bridges CB, Uyeki TM, et al. Triple-reassortant swine influenza A (H1) in humans in the United States, 2005-2009. N Engl J Med 2009;360:2616-2625. [Free Full Text]
Previous
