Friday, September 22, 2017

Virology: Five Distinct Reassortants of HPAI H5N6 In Japan - Winter 2016–2017


While it seems longer, it was just over ten months ago that HPAI H5N6 broke out from its original range of China/Laos/Vietnam and turned up - first in South Korea - followed days later in Japan (see Japan: H5N6 Virus Detected At Izumi, Kagoshima).
South Korea was hardest hit, but within three weeks Japan had reported 53 separate detections (of one or more) HPAI positive wild birds across 11 Prefectures, along with several poultry outbreaks.  Numbers that would steadily grow over the winter.
Like its more famous cousin H5N8, the evidence suggested that HPAI H5N6 was expanding its geographic horizons via enhanced carriage by wild and migratory birds (see map above).  While H5N1 spread around the globe in a similar fashion, both clade H5N8 and H5N6 have moved farther and faster than any HPAI virus previously seen.  
As these viruses have conquered new territories, they've encountered a variety of other Avian Influenza (AI) viruses along the way, and being both promiscuous and out on a spree, have generated a large number of reassortants. 
Influenza A viruses are broadly categorized by two proteins they carry on their surface; their HA (hemagglutinin) and NA (neuraminidase), producing subtypes like H5N1, H7N9, or H5N6.  There are currently 18 known HA subtypes and 11 known NA subtypes.

So, when we talk about a subtype, we're aren't necessarily just talking about a single viral threat, but often an expanding array of related viruses sharing the same (or similar) HA and NA genes.

Within each HA subtype there can be genetic groupings called clades, and often within each clade - subclades. Within each of these, many minor variants may exist. Add in the ability to mix-and-match internal genes, and you can come up with literally dozens of genotypes for each subtype.
Each can have different properties (virulence, transmissibility, host range, etc.), and each is on its own evolutionary path. 
Last December, in Cell Host Microbe: Genesis, Evolution and Prevalence of HPAI H5N6 In China, we saw a report that found that H5N6 had become the dominant HPAI H5 virus in Chinese ducks (replacing H5N1), with 34 distinct H5N6 genotypes, including 4 that have infected people.

When H5N6 invaded South Korea last winter, reports suggested continual evolution of the virus (see Korea H5N6: New Genetic Analysis & Investigating Its Rapid Spread), with researchers reporting no fewer than 5 new genotypes during the first month.

We've a new report this week in the journal Virology that finds similar rapid evolution took place with the H5N6 virus during its foray into Japan last winter.  The full report is available via PDF, and is well worth reading in its entirety.

Five distinct reassortants of H5N6 highly pathogenic avian influenza A viruses affected Japan during the winter of 2016–2017
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•    H5N6 HPAIVs affected poultry and wild birds in Japan during the winter of 2016–2017.
•    HA genes of the Japanese H5N6 strains belonged to the clade
•    Existence of 3 distinct AIV-derived PA genes in the Japanese H5N6 HPAIVs was evident.
•    NS genes of the Japanese H5N6 HPAIVs originated from 2 distinct Chinese H5N6 HPAIVs.
•    Five distinct genotypes among the Japanese H5N6 HPAIVs were found.


To elucidate the evolutionary pathway, we sequenced the entire genomes of 89 H5N6 highly pathogenic avian influenza viruses (HPAIVs) isolated in Japan during winter 2016–2017 and 117 AIV/HPAIVs isolated in Japan and Russia. 

Phylogenetic analysis showed that at least 5 distinct genotypes of H5N6 HPAIVs affected poultry and wild birds during that period. 

Japanese H5N6 isolates shared a common genetic ancestor in 6 of 8 genomic segments, and the PA and NS genes demonstrated 4 and 2 genetic origins, respectively. Six gene segments originated from a putative ancestral clade H5N6 virus that was a possible genetic reassortant among Chinese clade H5N6 HPAIVs. In addition, 2 NS clusters and a PA cluster in Japanese H5N6 HPAIVs originated from Chinese HPAIVs, whereas 3 distinct AIV-derived PA clusters were evident.

These results suggest that migratory birds were important in the spread and genetic diversification of clade H5 HPAIVs.

 (Continue . . .  )

The H5N6 virus has caused at least 17 human infections in China, with a high fatality rate, but thus far we've seen no reports of human infection out of South Korea, Japan (or later Taiwan and the Philippines).  The following passage from the study's discussion addresses this:
From May 2014 through December 2016, 17 human cases of clade H5N6 HPAIV infection were reported in China (Jiang et al., 2017). Our analysis indicated that amino acid substitutions responsible for adaptation to mammalian hosts (Bussey et al., 2010; Hatta et al., 2001; Min et al., 2013; Steel et al., 2009; Yamada et al., 2010) were missing from the Japanese H5N6 isolates.
The T160A mutation in the HA protein is linked to the acquisition of binding specificity for α2,6- linked sialic acid receptors, which are predominant in the human upper respiratory tract (Gu et al., 2017; Wang et al., 2010); however, some clade H5Nx HPAIVs that carry the T160A mutation show limited binding specificity for α2,6-linked receptors (Guo et al., 2017; Kaplan et al., 2016). Additional studies are needed to definitively understand the effect of T160A on the receptor specificity of clade H5N6 HPAIVs.
In addition, to our knowledge, no human cases resulting from a G1.1.9 H5N6 HPAIV that is a potential progenitor of Japanese H5N6 HPAIVs have been reported. Thus, the zoonotic potential of Japanese H5N6 HPAIVs is considered to be low.

As we've discussed before, even small changes in a virus can either enhance, or reduce, its virulence, transmissibility, or host range  (see Differences In Virulence Between Closely Related H5N1 Strains).  
While it has been a stroke of good fortune that recent strains of H5N6 have - at least temporarily -  evolved away from mammalian adaptation, there are no guarantees how long that trend will continue.
The take away from all of this is that H5N6, like its H5N8 cousin, are rapidly spreading, multifaceted, and continually evolving avian flu threats. What we can say about their behavior and threat to public health today may not hold true tomorrow.

For more on the rapid evolution of clade  H5 viruses, you may wish to revisit:

J. Virulence : Altered Virulence Of (HPAI) H5N8 Reassortant Viruses In Mammalian Models
J Vet Sci: Evolution, Global Spread, And Pathogenicity Of HPAI H5Nx Clade
Study: Virulence Of HPAI H5N8 Enhanced By 2 Amino Acid Substitutions

J. Virology: Molecular Evolution and Emergence of Avian H5N6

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