#18,545
There is much interest in exactly what changes the HPAI H5Nx virus would need in order to become a more `humanized' virus; like seasonal H3N2 and H1N1 which have a strong affinity for the alpha 2,6 receptor cells most commonly found in the human respiratory system.
While several concurrent mammalian adaptations are likely required to create a pandemic strain, the ability of avian flu viruses to bind to human α2-6 receptor cells is considered the single biggest obstacle the virus must overcome in order to successfully spread in humans.Last month, in Science: A Single Mutation in Bovine Influenza H5N1 Hemagglutinin Switches Specificity to Human Receptors, we saw a study that focused on the Q226L mutation, which we've looked at often over the years (see here, here, and here):
Past cases in which avian viruses adapted to infect and transmit between people required multiple mutations, usually at least three. But for the H5N1 2.3.4.4b strain (A/Texas/37/2024) isolated from the first human infection with a bovine H5N1 virus in the United States, researchers found that just a single amino acid mutation in the hemagglutinin could switch specificity to binding human-type receptors.
The shift alone, however, may not be enough to enable human-to-human transmission. Other genetic changes—such as mutations in polymerase basic 2 (E627K) that enhance viral replication and stability in human cells—would likely be necessary for the virus to spread efficiently among people.
Today we have another example, in a preprint that finds that this Q226L mutation may be far more successful in altering the behavior of some subclades than others.
Specifically, they found that Q226L by itself was enough to switch an avian (H5N6) clade 2.3.4.4e virus to bind preferentially to mammalian a2,6 receptor cells, yet the same mutation failed to do so with a (2016) H5N8 2.3.4.4b virus.
First the abstract, and some excerpts from the report. Follow the link to read it in its entirety. I'll have a postscript after the break.
The Q226L mutation can convert a highly pathogenic H5 2.3.4.4e virus to bind human-type receptors
Maria Rios Carrasco, Ting-Hui Lin, Xueyong Zhu, Alba Gabarroca Garcia, Elif Uslu, Ruonan Liang, Cindy Spruit, Mathilde Richard, Geert-Jan Boons, Ian A. Wilson, Robert Paul de Vries
doi: https://doi.org/10.1101/2025.01.10.632119
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Abstract
H5Nx viruses continue to wreak havoc in avian and mammalian species worldwide. The virus distinguishes itself by the ability to replicate to high titers and transmit efficiently in a wide variety of hosts in diverse climatic environments. Fortunately, transmission to and between humans is scarce. Yet, if such an event were to occur, it could spark a pandemic as humans are immunologically naive to H5 viruses.
A significant determinant of transmission to and between humans is the ability of the influenza A virus hemagglutinin (HA) protein to shift from an avian-type to a human-type receptor specificity.
Here, we demonstrate that a 2016 2.3.4.4e virus HA can convert to human-type receptor binding via a single Q226L mutation, in contrast to a cleavage-modified 2016 2.3.4.4b virus HA.
Using glycan arrays, x-ray structural analyses, tissue- and direct glycan binding, we show that L133adelta and 227Q are vital for this phenotype. Thus, whereas the 2.3.4.4e virus HA only needs a single amino acid mutation, the modified 2.3.4.4b HA was not easily converted to human-type receptor specificity.
(SNIP)
Discussion
With the continuous and massive circulation of 2.3.4.4b viruses in both avian and mammalian species, it may be just a matter of time before different adapted gene segments collide. It is, therefore, vital to know which mutations in NA and HA are essential to adapt to the respiratory tract of humans.
One such phenotype, human-type receptor binding, is described here, and we demonstrate that previously circulating 2.3.4.4e viruses only needed a single Q226L mutation to do so. The France16 2.3.4.4b H5N8 HA used in this study has six mutational differencers and a modified cleavage site compared to the A/Texas/37/2024 2.3.4.4b HA (12).(Continue . . . )
Perhaps France16 HA’s ability to bind human tracheal epithelial cells is already an indicator for its zoonotic abilities (40). Also, whether or not the current H5N1 2.3.4.4b HAs would require additional amino acid changes to bind more strongly to less complex glycan structures that are more abundant in the human respiratory tract (38, 69), although increased avidity to complex 295 biantennary glycans may suffice.
The good news is the H5N6 clade 2.3.4.4e virus used in this study circulated primarily in Asian poultry between 2014-2017, and hasn't been reported in the wild in years.
Less reassuringly, we now have another example of an HPAI H5 clade 2.3.4.4x virus switching receptor cell binding from a single (Q226L) mutation.
And of course, Q226L isn't the only HA mutation known to switch receptor binding in H5 viruses (see Emerg. Microb. & Inf.: HA N193D Substitution Alters Receptor Binding Affinity & Enhances Virulence in Mammalian Hosts). Another - A134V - was recently detected in the fatal Louisiana case.
While the barriers that restrict human adaptation are steep, complex, and only partially understood, they are obviously not insurmountable.
All of the `humanized' flu viruses through the ages are believed to have originated in birds, before adapting to mammals. While it isn't known whether HPAI H5 can make that leap, it is far from guaranteed that it can't.
