# 5579
The mantra over the past five years or so on H5N1 bird flu has been that:
The H5N1 virus remains poorly adapted to human physiology, and despite ample opportunities in places like Egypt and Indonesia, only causes rare, sporadic infections in humans.
H5N1 is generally a gastrointestinal malady in birds, and the virus is usually spread via infected feces. The virus binds preferentially to the kind of receptor cells commonly found in avian digestive and respiratory tracts; alpha 2,3 receptor cells.
Human influenzas, on the other hand, are adapted to bind to the kind of receptor cells that line the surfaces of the human respiratory system; alpha 2,6 receptor cells.
While not an absolute, flu viruses that bind to one type of receptor cell, tend not to bind well to the other.
This ability to bind to a specific type of cell has often been described as the host cell being a padlock, and the virus needing a specific key (determined by the genetics of the virus’s Receptor Binding Domain: RBD) to unlock it.
(A Very Simplified Illustration of RBDs)
Now humans do have some avian-like alpha 2,3 receptor cells, particularly deep in the lungs.
This has been suggested as the reason that - when on rare occasions humans contract H5N1 - it is usually a deep lung infection.
It has also been postulated that H5N1’s deeper lung infections may reduce human-to-human transmission, as sneezing is a less common symptom.
The concern is that over time, the H5N1 (or some other avian flu) virus might mutate in such a way as to be able to bind to human α2,6 receptor cells of the upper airway.
And while that may not be the only obstacle keeping the virus from becoming a pandemic strain, it does appear to be a major one.
Although only introduced to the region in 2006, Egypt has rapidly become a hotspot for avian flu (see this list of human cases maintained on FluTrackers).
Unlike some Asian countries, where the virus has proved fatal in 80% of reported cases, the CFR (Case fatality ratio) in Egypt has ranged from 10% (2009) to 34% (2010).
This variability in virulence has sparked concerns that important changes were taking place in the virus.
Which brings us to an open access research article (excerpts slightly reformatted for readability) appearing today in PLoS Pathogens called:
Acquisition of Human-Type Receptor Binding Specificity by New H5N1 Influenza Virus Sublineages during Their Emergence in Birds in Egypt
Yohei Watanabe, Madiha S. Ibrahim, Hany F. Ellakany, Norihito Kawashita, Rika Mizuike, Hiroaki Hiramatsu, Nogluk Sriwilaijaroen Tatsuya Takagi, Yasuo Suzuki, Kazuyoshi Ikuta
PLoS Pathog 7(5): e1002068.
doi:10.1371/journal.ppat.1002068
AUTHOR SUMMARY
Even though highly pathogenic avian H5N1 influenza viruses lack an efficient mechanism for human-human transmission, these viruses are endemic in birds in China, Indonesia, Viet Nam and Egypt. Hotspots for bird-human transmission are indicated in areas where human cases are more than 80% of total H5N1 influenza cases.
Circulation among hosts may allow H5N1 virus to acquire amino acid changes enabling efficient bird-human transmission and eventually human-human transmission. The receptor specificity of viral hemagglutinin (HA) is considered a main factor affecting efficient transmissibility. Several amino acid substitutions in H5 virus HAs that increase their human-type receptor specificity have been described in virus isolates from patients, but their prevalence has been limited.
In contrast, we show here that new H5 sublineages in Egypt have acquired a change in receptor specificity during their diversification in birds. We found that viruses in those sublineages exhibited increased attachment and infectivity in the human lower respiratory tract, but not in the larynx.
Our findings may not allow a conclusion on the high pandemic potential of H5N1 virus in Egypt, but helps explain why Egypt has recently had the highest number of human H5 cases worldwide.
Since the entire research article is open access (and quite lengthy), I’ll not go into great detail on how they conducted this research here.
Instead, we’ll focus on what all of this might mean.
While we tend to talk about the H5N1 virus as if it were a single, monolithic entity, in truth it is more akin to the mythical Hydra that is continually growing new heads.
The virus, as it spread from birds to other species and around the world, has evolved into a number of distinct genetic groupings called clades. As of 2009, the World Health Organization had classified the H5N1 virus into 10 first order clades (0-9).
As you can see from the chart below, while additional clades have been established over the past 10 years, the greatest diversity has been among the Clade 2 viruses.
Within each of these clades, the virus is continually evolving into subclades and sublineages. A few are biologically fit and manage to persist and spread, while others are not, and eventually die off.
Essentially H5N1 is a moving target; constantly changing, looking for an evolutionary advantage.
What the authors of today’s study found was that among recent human infections in Egypt, examination of viral isolates showed that several new H5 sublineages have emerged with an increased affinity for (human) α2,6 SA receptor cells while still retaining their binding ability to (avian) α2,3 SA receptor cells.
Using reverse genetics, they identified the the amino acid mutations that produced this new receptor binding affinity (essentially, a single mutation at HA residue 192 or a double mutation at HA residues 129 and 151).
They believe that the emergence of these new sublineages of H5N1 explains the increase in human cases in Egypt over the past three years.
Before anyone decides its time to head down to the bunker, it should be noted that this move towards greater `humanization’ of the H5N1 virus is far from complete.
The authors found `increased attachment and infectivity in the human lower respiratory tract, but not in the larynx.’
Many scientists believe the virus must learn to bind to, and replicate in, the upper airway of humans in order to transmit efficiently from human to human.
Something that hasn’t happened yet.
And there may very well be other – as yet unidentified -genetic changes that must occur before the virus can acquire human pandemic capability.
Something that could take years or even decades to evolve. Or admittedly, might never happen.
But today’s study is a not-so-gentle reminder that the H5N1 virus has not gone away, that it continues to try out new evolutionary tricks, and that it could still some day pose a pandemic threat to humanity.
Which is why the world remains at Pre-pandemic Phase III for the H5N1 virus.
