Flu viruses can evolve in unsuspected ways, study says

Jul 26, 2005 (CIDRAP News) – A large-scale study of genetic data on influenza shows that viruses of the same strain or serotype have more genetic differences than previously suspected and can exchange genetic material in ways that make them more infectious.

Researchers report that three different groups, or clades, of influenza A/H3N2 viruses have circulated at the same time for the past several years. In 2002, two of the groups acquired a gene from the third. This "reassortment," the authors say, probably gave rise to the Fujian strain of flu, which predominated during the 2003-04 flu season and was not included in the vaccine for that year.

"These data, derived from the first large-scale study of H3N2 viruses, convincingly demonstrate that multiple lineages can co-circulate, persist, and reassort in epidemiologically significant ways, and underscore the importance of genomic analyses for future influenza surveillance," says the report, published by the Public Library of Science Biology (PloS Biology).

The study was authored by Edward C. Holmes of Pennsylvania State University and colleagues from the Institute for Genomic Research, the New York State Department of Health, the National Center for Biotechnology Information, and the Armed Forces Institute of Pathology.

The authors did an initial analysis of genetic sequence data collected under the National Institutes of Health's Influenza Genome Sequencing Project. The analysis dealt with the genomes of 156 human H3N2 viruses collected in New York state from 1999 to 2004. Also included in the study were partial sequence data from other flu virus studies.

The researchers grouped the isolates according to sequence similarities. They also traced gene trees (phylogenetic trees) for each of the virus's eight genes, depicting the inferred relationships among them. They found that most of the genomes fell into one group, called clade A, but a few fell into two other groups, clades B and C.

The gene trees for the viral genes all differed in ways that fit their respective clades, except for the gene for hemagglutinin (HA), the surface protein that enables the virus to attach to host cells. The HA gene tree grouped all the clade A viruses that emerged after 2002 together with the clade B and C viruses from the same period.

"These results indicate that different viral strains had circulated in the same populations until 2002 and then the clade A and C viruses acquired a common HA gene from clade B through reassortment," says an article summary published in the same journal. The phylogenetic analysis also indicated that two other reassortment events involving two other genes occurred.

The authors further determined that the Fujian strain of H3N2 shared certain key amino-acid changes with the clade A reassortant strains and the clade B viruses from 2003-04. They concluded that the reassortment in which clades A and C acquired the HA gene from clade B was "central" to the rise of the Fujian strain and the resulting reduction of vaccine effectiveness in 2003-04.

The conventional understanding of flu virus evolution in nonpandemic (interpandemic) periods describes it as a series of minor mutational changes in the dominant strain, mostly involving HA, the article says. In the process known as antigenic drift, the changes help the virus persist—and necessitate the creation of a new vaccine each year. But the new findings suggest that the conventional model is incomplete.

"We found that at least four reassortment events occurred among human viruses during 1999-2004 and that two of these involved a major change in HA," the authors write. Citing another recent study that also provided evidence of the clade A-B reassortment, they add, "To our knowledge, these analyses are the first demonstrations of the emergence of a major antigenically variant virus derived by reassortment between two distinct clades of co-circulating H3N2 viruses rather than by antigenic drift."

They conclude that the finding has "major significance" for the task of selecting which flu strains to use in each year's vaccine.

Holmes EC, Ghedin E, Miller N, et al. Whole-genome analysis of human influenza A virus reveals multiple persistent lineages and reassortment among recent H3N2 viruses. PloS Biol 2005 Jul 26 (early online publication) [Full text]

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