Friday, January 13, 2006

More on the sequences from Turkey

The official WHO case count from Turkey has now risen to 18, matching the largest outbreak (Hong Kong 1997) to date for H5N1. A major question is whether there is something different about the Turkish virus.

The news dribbling out about the sequencing of the Turkish isolates is not encouraging but also not surprising. As I noted several days ago, the proposition that the hemagglutinin protein of the isolates is "very close" to the avian sequences is not very informative because extremely small changes can cause important changes in host range, as studies by Stevens et al. on the 1918 HA show. That paper described studies with glycan arrays (see previous post) that looked at the binding of various viral HAs to various linkages of sialic acid, the cellular receptor. Sialic acid is linked in two forms, one characteristic of bird intestinal cells, one characteristic of human lower respiratory tract cells, although we now know that humans have avian-type linkages in sialic acid in their upper respiratory tract. Most avian viruses bind well to the avian receptor, human viruses to the human linked receptor, but the HA protein from a case from New York's second wave in the 1918 pandemic showed some affinity for both humans and birds.

I haven't seen the sequences for the Turkish cases, but news reports suggest this kind of adaptation to humans is what is being seen in some of the Turkish isolates.
Genetic tests of samples taken from Turkish victims of the bird flu virus show it has made a small change, but probably not enough to make it more dangerous yet, researchers said on Thursday.
The mutation is one of those that would be expected in a highly changeable virus, the experts said -- and is one of those that would be predicted to eventually allow it to cause a pandemic.


Samples from two of the first Turkish victims were sent to a WHO-affiliated laboratory in Britain for analysis. Scientists are carefully watching the virus to see if it makes the changes needed to allow it to easily pass from human to human -- which could spark a pandemic that could kill millions.
There were two different strains of virus in the bodies of the teenage victims, said Dr. Ruben Donis, team leader of the molecular genetics team of the U.S. Centers for Disease Control and Prevention's Influenza branch.

"One was a regular virus like we have seen in poultry in Turkey before -- no surprises there," Donis said in a telephone interview.

But half the viruses had a mutation in the a protein called hemagglutinin, which influenza viruses use to attach to the cells they infect. This protein is the "H" in a flu virus's designation.

This mutation has been found in the past to allow the virus to infect a greater range of cells via a structure known as sialic acid, Donis said.
"If you have this mutation, you have virus that can bind to more different sialic acid variations," he said.
This is only theoretical, Donis stressed. But when researchers have tested flu viruses in the lab, they found this particular mutation gave the virus a better ability to attach to human-like cells.

"If this was a wildfire mutation that would have caused the virus to spread like wildfire in a population, we would have seen it more often," he said.(By-line Maggie Fox, Reuters)
This last comment is not very useful. We know it isn't a "wildfire" mutation simply because we haven't seen the wildfire, not because we understand the relationship between the genetic changes and the biology. We know some things, but mostly we are in the dark about what changes will turn this virus into a full-fledged pandemic strain. We may be one tiny change away or (in the best case) this is a change headed down an evolutionary cul de sac (not likely, but possible).

Which is why statements like this, from the same Reuters article, drive me crazy:
A spokeswoman at the World Health Organization said there was no evidence the mutation had much significance in making the virus either more transmissible to people, or more or less dangerous to them.

"It doesn't look as if it has significance regarding transmissibility or pathogenicity because it is not borne out by epidemiological evidence we have so far," WHO spokeswoman Maria Cheng said in Geneva.
First, it directly contradicts what the CDC scientist just said. More importantly, this proposition is not supported by the current state of our ignorance about the relationship between the genetic sequences and the biology.

The sequencing also shows that there are many genetic variants out there, sometimes infecting the same individual. Again, this is to be expected. This virus replicates into billions of copies in an infected person and it is lack of fidelity in this replication which is one source of the genetic variation upon which selective pressures act.

This mutation has been seen before in isolates from Hong Kong in 2003 and Vietnam in 2005 (Branswell, CTV). The Turkish sequences also bear similarity to the Chinese Qinghai viruses responsible for a mass kill of migratory birds there. For some technical details, see post by Henry Niman of Recombinomics which he has kindly reprinted in the comments of a recent post here. Many experts believe Turkey's location along north-south bird flyways has made it especially prone to infection of its poultry stock. Opponents of this notion point to the lack of documented outbreaks at intermediate points along the flyways. However we neither know the pattern of viral shedding along flyways nor can we be sure that outbreaks have not occurred undetected in many of the remote areas concerned.

There is some good news in the sequencing. Apparently the virus is sensitive to both classes of antivirals (amantadine/rimantadine and oseltamivir (Tamiflu)/zanamivir (Relenza). (Branswell, CTV). But all in all, the Turkish picture is one of continued progression geographically and genetically. It is not time to panic, because it is never time to panic. But making appropriate preparations in your area might be prudent.