Day 1: Liveblogging the Molecular Evolution/Infectious Diseases Keystone Conference

Day 1

Today’s talks were focused on the evolutionary dynamics of RNA viruses, including influenza, dengue, measles, and SARS coronavirus.

Morning session:

Jeffrey Taubenberger led off the day by talking about influenza, the “continuously emerging infectious disease.” He emphasized the importance of the explosion of sequenced influenza genomes that have become available in the past several years. Starting with a 2005 PLoS Biology paper that looked at H3N2 influenza viruses, he discussed the process by which a minor influenza clade can transition into a dominant clade. A recent PLoS Pathogens paper used concatenated genomes to generate a phylogenetic tree. This analysis showed that there is little antigenic drift during the influenza season – drift seems to occur primarily between seasonal peaks of flu. This leads to a “source-sink” model of the generation of influenza diversity: sites in the tropics may serve as a supply of genetic diversity that leads to differences in seasonal strains elsewhere. Also, there is tremendous influenza sequence diversity within wild birds, and within host genetic transfer is thought to generate a large pool of reassortant viruses. A host switch to humans leads to a dropoff in diversity, thought to be due to lack of access to this tremendous sequence pool. The selective pressures on influenza viruses within avian hosts are only beginning to be explored.

Holmes, E.C., Ghedin, E., Miller, N., Taylor, J., Bao, Y., St. George, K., Grenfell, B.T., Salzberg, S.L., Fraser, C.M., Lipman, D.J., Taubenberger, J.K. (2005). Whole-Genome Analysis of Human Influenza A Virus Reveals Multiple Persistent Lineages and Reassortment among Recent H3N2 Viruses. PLoS Biology, 3(9), e300. DOI: 10.1371/journal.pbio.0030300

Nelson, M.I., Simonsen, L., Viboud, C., Miller, M.A., Holmes, E.C. (2007). Phylogenetic Analysis Reveals the Global Migration of Seasonal Influenza A Viruses. PLoS Pathogens, 3(9), e131. DOI: 10.1371/journal.ppat.0030131


Edward Holmes talked about the molecular evolution and phylodynamics of dengue virus. The 4 serotypes of dengue (DENV-1 through -4) seem to have split ~2000 years ago, with most diversity appearing in the past several hundred years. Studies of the microevolution of dengue in Bangkok showed complex interactions among serotypes, with DENV-1 through -3 largely in phase and DENV-4 predominating when other serotypes were less prevalent. There are also distinct genotypes within each serotype, with DENV-2 undergoing significant genotype changes in Vietnam between 1999-2007. Importantly, as we move toward phase 3 trials of investigational dengue vaccines, the combination of detailed spatial data and dengue genome sequences will be indispensable for understanding the consequences of vaccination.

Oliver Pybus from Oxford presented new data about the complex within-host evolution of hepatitis C virus that occurs during chronic infection. Using longitudinal data from a number of chronically infected patients, they derived multiple viral sequences over several years. They found marked diversity over time, considerably more than was seen in a similar longitudinal study of HIV. This was thought to be consistent with discontinuous variation – i.e. low-level variation of HCV punctuated by periods of vastly increased diversity. This may be the result of a sequestered hepatic pool of HCV genetic diversity, which seeds the plasma at different times.

Paul Rota from CDC gave an overview of the global laboratory-based surveillance for measles and mumps. This talk was particularly important in light of the ongoing outbreak of measles in Switzerland that has led to a number of imported cases in the U.S. (the index case was, not surprisingly, an unvaccinated child). Genotyping of measles viruses worldwide has greatly enhanced our understanding of its epidemiology. There is a reasonable amount of geographic restriction of measles genotypes. Importantly, though, genotyping can help trace the origin of imported cases. Despite the presence of multiple genotypes, measles is still a monotypic virus, and the vaccine (which is a genotype A virus) provides protection across all measles genotypes. Likewise with mumps, where vaccination with the Jeryl Lynn strain continues to provide protection across all circulating mumps strains.

These were followed by two short talks. The first was by Phillipe Lerney, who uses Bayesian models to infer probable modes of geographic spread of a variety of viral diseases. Naomi Forrester spoke about rabbit haemorrhagic disease virus. Her group did a phylogenetic analysis of circulating RHD sequences in healthy rabbits in the UK. There were 2 major circulating subtypes, an epidemic strain and a “widely divergent” strain, and they hypothesize that there may be some degree of cross-protection between these two clades.


In the evening session, Kathryn Holmes gave a great talk on coronaviruses (CoV) and host adaptation. The groups of CoV (1, 2a, 3, and 3b) each contain tremendous diversity with respect to host range and receptor specificities. The spike glycoprotein (through its S1 region) dictates receptor binding, but CoV accessory genes are important in host tropism as well. However, many of the accessory genes have unknown origins and functions. There is little homology in these accessory genes among groups, and while they are generally not necessary for in vitro replication, they can have important effects on fitness in vivo. She finished by using mouse hepatitis virus and bovine CoV as models to ask whether viruses can drive the evolution of host receptors.

Alan Barrett from UTMB traced the global spread of west nile virus (WNV) and the incredible diversity of hosts (>300 species of birds, >60 species of mosquitoes) that it can utilize. Sequence analysis showed the presence of 3 distinct clades of WNV (the old world, Eastern U.S., and North American clades), and phenotype analysis of these is ongoing.

Michael Katze gave a description of his systems biology-based investigations of host response to influenza infection. Both reconstructed 1918 and H5 flu are highly virulent in murine and primate models of infection. Microarray-based profiling of host responses showed an important role of control of the early inflammatory response in the lung for survival. Animals infected with 1918 flu had a rapid and uncontrolled response that led to death.

The final talk of the day was from Chun-Chau Hon, who did a phylogenetic analysis of coronaviruses and a Bayesian molecular clock analysis. By examining a novel clade of bat SARS-like CoV, he made predictions regarding the potential ancestor of human SARS CoV. Some of this work was recently in J Virol.

Hon, C., Lam, T., Shi, Z., Drummond, A.J., Yip, C., Zeng, F., Lam, P., Leung, F.C. (2007). Evidence of the Recombinant Origin of a Bat Severe Acute Respiratory Syndrome (SARS)-Like Coronavirus and Its Implications on the Direct Ancestor of SARS Coronavirus. Journal of Virology, 82(4), 1819-1826. DOI: 10.1128/JVI.01926-07