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Research Team Sequences Common Cold Virus Collection

NEW YORK (GenomeWeb News) – In a paper appearing online today in Science, researchers from the University of Wisconsin at Madison, the J. Craig Venter Institute, and the University of Maryland School of Medicine reported that they have sequenced the complete genomes of all 99 catalogued human rhinoviruses, the viruses that cause the common cold, along with ten new field samples.

Together, the genome sequences and other biological data are garnering new insights into HRV biology and providing the basis for a new HRV phylogenetic tree that reveals relationships between HRV strains with unprecedented resolution. Researchers say such findings could eventually lead to new treatments and better diagnoses for the common cold.

"Many clades were not fully appreciated [in the past]," senior author Stephen Liggett, director of the University of Maryland School of Medicine's Cardiopulmonary Genomics Program, told GenomeWeb Daily News. "That may be why we've had a failure of drugs so far."

Human rhinoviruses are single-stranded RNA viruses that belong to the Picornaviridae family and cause upper and lower respiratory tract disease. In general, most of the HRV strains identified so far have been classified as one of two species — HRV-A or HRV-B — though another species called HRV-C was recently identified in patients with severe respiratory symptoms.

Although the common cold is often considered fairly innocuous, Liggett noted that it can be dangerous for individuals who are very young or elderly. And, he added, research suggests that colds can not only exacerbate asthma, but can also increase young children's risk of developing asthma later in life. Consequently, the direct and indirect cost of common colds in the US annually is estimated to be as high as $60 billion.

For this paper, Liggett and his team used sequencing to create a more complete set of HRV reference strains.

Scientists at the University of Maryland School of Medicine and The Institute for Genomic Research, now part of the J. Craig Venter Institute, generated enough data to get about six times coverage each for all 99 HRV strains in the existing repository — along with ten new field isolates. Because other groups had done some of the sequencing already, Liggett noted, the team didn't have to do this from scratch: they ultimately sequenced about 80 historical strains and ten field samples.

"We know a lot about the common cold virus, but we didn't know how their genomes encoded all that information," lead author Ann Palmenberg, a researcher at the University of Wisconsin at Madison's Institute for Molecular Virology, said in statement. "Now we do, and all kinds of new things are falling out."

For instance, contrary to previous research, the team found evidence that HRVs can recombine. Their analysis also uncovered new information about HRV RNA structures, translation, and other aspects of HRV biology.

When the researchers generated a phylogenetic tree using the new sequence data, published HRV-A and HRV-B sequence data, and HRV-C sequence data, they came up with a tree distinct from any seen before — not because previous studies were inaccurate, Liggett emphasized, but because they did not have as much data available. "It's just gotta look different," he said.

The results support the notion that HRV-A, HRV-B, and HRV-C are distinct serotypes with each containing a few to many small clades or sub-groups. The team also found evidence suggesting a sub-group within HRV-A may actually be its own species, HRV-D.

"It was clear to us that the spectrum of rhinoviruses out there was probably much greater than we realized," co-author Claire Fraser-Liggett, a professor at the University of Maryland School of Medicine and director of the Institute for Genome Sciences, said in a statement.

Still, Liggett predicts that there won't be an endless number of different groups. For instance, he noted, all of the new field isolates tested fit nicely into the phylogenetic tree — some even nestling into the tree next to strains collected much earlier.

With the genomes and new phylogenetic analysis in hand, Liggett explained, it may now be possible to come up with new drug candidates against specific HRV sub-groups. He suspects it may even be possible to come up with effective treatments by tweaking earlier HRV therapeutic attempts. Because the HRV genome is small — just 7,000 bases — "everything is important," Liggett added.

Though Liggett said he has not yet discussed the study's results with companies interested in pursuing HRV treatments, he anticipates interest in the results.

In an effort to flesh out the new reference sequence collection and gain new insights into clinical characteristics associated with various strains, Liggett said he and his colleagues plan to sequence 1,000 additional HRV field isolates collected from across the US. Sequencing for that project will likely be done at the University of Maryland, Liggett noted, using one or more types of high-throughput sequencing approaches.

"There is no reason any longer to focus on a very limited part of the rhinovirus molecule to learn what it's doing, what the predominant strain is in a population, or to try to infer what the evolution of the entire molecule might be," Fraser-Liggett said in a statement. "Instead, by studying the complete genome sequence, we can answer multiple questions in parallel."

Data from the sequencing study will be made publicly available through GenBank.

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