Last night CIDRAP published a piece by News Editor Robert Roos which looks at genetic characterizations of H5N1 viruses sampled from Egyptian poultry recently. According to the FAO, this analysis showed signs of several troubling `mammalian adaptations’, although two isolates taken from humans recently reportedly showed no major genetic changes.
First some excerpts from Robert’s detailed report (but you’ll want to read the whole thing), then I’ll be back with a little more.
Jan 07, 2015
Amid a flurry of human H5N1 influenza cases in Egypt, scientists have found H5N1 viruses in Egyptian poultry that have two mutations that are usually associated with adaptation to mammals, a United Nations Food and Agriculture Organization (FAO) official reported today.
Juan Lubroth, DVM, PhD, the FAO's chief veterinary officer, told CIDRAP News that the mutations were identified through genetic sequencing of 52 recent isolates from poultry. But he also said a recent analysis of viruses from two human patients in Egypt showed no major genetic changes.
Egypt has had a surge of human H5N1 cases over about the past 7 weeks, after reporting very few during the preceding 2 years. According to media reports based on health ministry statements, the country had 29 cases with 11 deaths in 2014, most of them in November and December. All or nearly all of the patients had contact with poultry, and no signs of human-to-human transmission have been reported, but the cases have prompted some speculation about whether the virus has changed in some way.
In addition, Egypt has had a big increase in reported poultry outbreaks of H5N1 recently, according to the FAO. A graph supplied by Lubroth showed about 70 outbreaks in November (2014) and close to 180 outbreaks in December, compared with fewer than 10 in each of those months in 2013.
The evolutionary path that would take an avian influenza virus – like H5N1 – to the point where it was well-enough adapted to mammals to pose a pandemic threat isn’t well mapped. There are a lot of interactive `moving parts’ inside a virus, and how evolutionary changes (via accrued amino acid substitutions) affect the virus’s behavior are only partially understood.
On a `macro level’, we know that avian viruses bind preferentially to the type of receptor cells (α-2,3) found in the gastrointestinal tract of birds, and that mammalian-adapted viruses would have to evolve to bind preferentially to α-2,6 receptor cells – they type found in the upper respiratory tract of mammals.
We also believe that an adapted virus would have to thrive and replicate in the slightly cooler environment found in their upper respiratory tracts (birds run `hotter’ than mammals by several degrees).
While both are viewed as important, it is likely that there are other – perhaps subtle – changes that must occur before an avian virus can effectively jump to a mammalian host. Robert’s article cites the following changes:
Genetic sequencing of 52 isolates revealed that the hemagglutinin (H5) genes in the virus continue to evolve but that all the isolates belong to clade 2.2.1, the same as seen in previous years. However, the scientists also identified two "fixed mutations": a "combination of [delta]129 and I151T," and a "T156A causing a loss of glycosylation at receptor binding site."
"Both mutations enhance alpha 2-6 receptor binding (which is associated with mammalian adaptation)," the statement said. It added that the virus is nonetheless still regarded as an avian one.
However, the FAO also reported the emergence in 2014 of a new H5N1 cluster with three other mutations—D54N, R189K, and R474K. It said this cluster also remains within clade 2.2.1, but the significance of the mutations needs to be assessed.
Although we talk about the H5N1 virus as if it were a single entity, the virus has evolved into numerous clades, and sub-clades, around the globe – with a range of variants within each. As a result, the H5N1 virus circulating in Egypt is not the same H5N1 virus circulating in Cambodia.
H5N1 alone has produced more than 20 clades and sub-clades over the years (not all continue to circulate).
Diversity of circulating H5N1 Clades – Credit WHO
While these evolutionary variations mostly come about slowly due to antigenic drift, more abrupt changes can come through antigenic `shift’ – or reassortment. With the recent expansion of the constellation of HPAI H5 viruses expanding around the globe (including H5N1, H5N8, H5N6, H5N2, H5N3), the opportunities for reassortment only increase.
Although concerning, we’ve seen similar pronouncements regarding `mammalian adaptations’ detected in H7N9, H9N2, and even H5N1 virus in recent years (see Study: H5 Clade 188.8.131.52 Receptor Binding & Nature Comms: Host Adaptation Of Avian Influenza Viruses), and yet none of these viruses has managed to make the leap to mammals.
Some scientists suspect there may be some kind of `species barrier’ that will prevent any of these avian viruses from ever making the jump, pointing out that only H1, H2, and H3 influenza viruses have (at least, in the 120 year history we know about) caused significant human illness (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?).
Other scientists point out that 120 years of influenza observation is hardly enough to base any solid conclusions. That nature is full of surprises.
So we watch these viruses circulate in the wild, watching for changes both in their genetics and in their behavior, in the hopes that we might get some early warning of a pandemic. Time enough to make a vaccine, or with a lot of luck, time enough to contain an outbreak.
The biggest problem being - that when you don’t know exactly what any novel pandemic virus will look like - you never really know how close – or how far away - you are to seeing one emerge.