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**Commonground** · April 10, 2009, 04:50 AM

Re: Help in interpreting an Abstract

Can someone(s) please put this into laymen's terms....

ABSTRACT: BACKGROUND: Avian influenza virus H5N1 is a major concern as a potential global pandemic. It is thought that multiple key events must take place before efficient human-to-human transmission of the virus occurs. The first step in overcoming host restriction is viral entry which is mediated by HA, responsible for both viral attachment and viral/host membrane fusion. HA binds to glycans-containing receptors with terminal sialic acid (SA). It has been shown that avian influenza viruses preferentially bind to alpha2,3-linked SAs, while human influenza A viruses exhibit a preference for alpha2,6-linked SAs. Thus it is believed the precise linkage of SAs on the target cells dictate host tropism of the viruses. Results: We demonstrate that H5N1 HA/HIV pseudovirus can efficiently transduce several human cell lines including human lung cells. Interestingly, using a lectin binding assay we show that the presence of both alpha2,6-linked and alpha2,3-linked SAs on the target cells does not always correlate with efficient transduction. Further, HA substitutions of the residues implicated in switching SA-binding between avian and human species did not drastically affect HA-mediated transduction of the target cells or target cell binding. Conclusions: Our results suggest that a host factor(s), which is yet to be identified, is required for H5N1 entry in the host cells.

HighWire Medline Abstract

http://highwire.stanford.edu/cgi/medline/pmid;19341465

**JJackson** · April 13, 2009, 09:54 AM

Re: 2008/09 flu season question

<o:smarttagtype namespaceuri="urn:schemas-microsoft-com:office:smarttags" name="stockticker"></o:smarttagtype> A while back there was a lot of interest in the difference between the Receptor Binding Sites (RBS) on the flu’s Hemagglutinin (HA or H) surface protein and the way it was optimised to bind with the different sugar isomers found in the glycocaylx of the avian intestinal tract and the smooth epithelial cells of our nasopharynx. The speculation was that adaption from the avian optimised form in HP AI H5N1 to a more mammalian form of the RBS was the main stumbling block to the virus going pandemic. The best explanation of the binding process, I know of, was written in a series of four posts by the Reveres in January 2006, links below.<o:p></o:p>
<o:p> </o:p>

Effect Measure: Background science for the Turkish mutations, I.

http://effectmeasure.blogspot.com/2006/01/background-science-for-turkish.html

Effect Measure: Background science for the Turkish mutations, II.

http://effectmeasure.blogspot.com/2006/01/background-science-for-turkish_18.html

Effect Measure: Background science for the Turkish mutations, recap and III.

http://effectmeasure.blogspot.com/2006/01/background-science-for-turkish_19.html

Effect Measure: Background science for the Turkish mutations, IV (conclusion)

http://effectmeasure.blogspot.com/2006/01/background-science-for-turkish_20.html

<o:p> </o:p>
The short version is that seasonal flu binds to an a2,6 isomer and avian flu’s bind to a2,3. The RBS on the HA of each is optimised to bind to its usual target however these are very common sugars and we do have a2,3 in many places including the lower respiratory tract, the eyes and the gut so it is obviously not the whole story. When H5N1 has got a foothold in a human it does not seem to have any great problem in then infecting lots more cells, each of which will need to have been bound to via a sialic acid molecule on its surface.
<o:p> </o:p>
Things have moved on somewhat and it now appears that while an understanding of the function of some of the key biological sites – like the RBS – is important there may have been an underestimation of how important it is to take all the proteins coded for across the eight segments as a holistic set. Numerous experiments have now been performed that show simple substitutions can turn on, and off, functions such as virulence or drug resistance, but that applying the same substitution on a different serotype does not reproduce the effect. Similarly deliberate Reassortments tend not to ‘work’ quite as planned. The general lesson seems to be firstly each protein in successfully reproducing strains is optimised to work with the other proteins as a set and secondly it is dangerous to think of each protein only having one biological function, most seem to play some secondary enabling role – or roles – most of which are not understood.
<o:p> </o:p>
I don’t have access to the paper but from the abstract it would appear they have created a synthetic virus with an HA surface protein to look at binding. Having tried versions with both a2,3 and a2,6 optimised binding sites they discovered that they are not getting the level of correlation they expected when they measure transduction (this is the <st1:stockticker>RNA</st1:stockticker> transference) for host cells with various surface sugars. In vivo a major limiting factor in human infection is not the a2,6 for binding but a suitable host protease for cleavage, which is another essential step in getting into the host cell, which I assume they provided.
In conclusion they state “Our results suggest that a host factor(s), which is yet to be identified, is required for H5N1 entry in the host cells.” which is, I regret, likely to be a fairly common refrain from anyone studying any single function in isolation.
Considering just how simple this virus’ genome is it is amazing just how much is going on.

All of the above should be taken with my usual proviso that I am a layman and am explaining the situation as I understand it - which may not be right. I am very happy to be corrected, its how I learn.

**sharon sanders** · April 13, 2009, 06:14 PM

Re: 2008/09 flu season question

Thanks! Basically doesn't this abstract say that there is a factor which we do not know that we are missing for the development of sustained and efficient human to human transmission?

**JJackson** · April 14, 2009, 05:58 AM

Re: 2008/09 flu season question

Originally posted by Florida1 View Post

Thanks! Basically doesn't this abstract say that there is a factor which we do not know that we are missing for the development of sustained and efficient human to human transmission?

**sharon sanders** · April 14, 2009, 10:07 AM

Re: 2008/09 flu season question

Thanks JJackson.

So since it is a fairly complicated process for a virus to evolve to the point where it can infect a person, isn't the most likely strain of a pandemic influenza a strain that is already circulating, that has attained some genetics of H5N1, vs. a 100% H5N1 virus that has evolved to be efficient and sustained in humans?

**JJackson** · April 14, 2009, 01:00 PM

Re: 2008/09 flu season question

Originally posted by Florida1 View Post

Thanks JJackson.

So since it is a fairly complicated process for a virus to evolve to the point where it can infect a person, isn't the most likely strain of a pandemic influenza a strain that is already circulating, that has attained some genetics of H5N1, vs. a 100% H5N1 virus that has evolved to be efficient and sustained in humans?

<o:smarttagtype namespaceuri="urn:schemas-microsoft-com:office:smarttags" name="State"></o:smarttagtype><o:smarttagtype namespaceuri="urn:schemas-microsoft-com:office:smarttags" name="place"></o:smarttagtype><o:smarttagtype namespaceuri="urn:schemas-microsoft-com:office:smarttags" name="stockticker"></o:smarttagtype> Foul Ref! She is asking hard questions.
The serious answer is I do not know. There is so little data to go on, we have never been able to watch a flu pandemic emerge before – if that is what is happening now.
<o:p> </o:p>
Extrapolating from my previous posts there are two competing issues. In the event that a human optimised seasonal flu acquires some H5N1 genetic material it could do so by Reassortment or Recombination. If Recombination then is it likely to be enough of a change to be viewed as novel by our immune system, if not then not a pandemic candidate. If Reassortment then which segments get shuffled? The immune response is primarily initiated by the prominent surface proteins H & N so at least one of these would need to change for the virus to be viewed as novel. While N1 is also found in seasonal H1N1 they are phylogenically fairly distant so I would not want to rely on it affording me any acquired immunity. If Reassorted then the virus has to overcome the fitness penalty associated in not having a ‘matched set’ of proteins discussed earlier. If this penalty is not great enough to reduce the Reproductive Number (Ro) to below 1 then I would expect the virus to quickly adapt until it negated any handicap. I would also expect the same rapid adaption if any of the currently circulating strains of HP AI H5N1 got its Ro above 1.
<o:p> </o:p>
This virus produces so many slightly imperfect copies of itself that regardless of how it achieves it if it can just keep reproducing for a few generations in a new host species I expect it to nudge Ro up with each generation until it is unstoppable.
<o:p> </o:p>
Historically we have the last three pandemics to look at – which is not enough to draw any meaningful conclusions – but as it is all we have we may as well look at what happened. 1918 seems to be an avian virus jumping directly to us. In 1957 the circulating H1N1 became H2N2 by picking up a new HA, <st1:stockticker>NA</st1:stockticker> & PB1 (keeping the other 5 strands) and in 1968 it morphed to H3N2 by swapping out HA & PB1. So apart from PB1 and the two surface proteins we have 5 <st1:stockticker>RNA</st1:stockticker> strands that have survived since 1918 and the overall Reassortment vs Zoonosis score is 2-1 in Reassortment’s favour but I shall not be betting on what happens next time based on these 3 results. In ’68 we did have the situation where only one surface protein was swapped out and yet the ‘familiar’ N2 was not enough to stop it going pandemic.
<o:p> </o:p>
I do not know if our current situation is historically normal or aberrant. We have H7N7 and H5N1 both of which seem good pandemic candidates in that they have shown the ability to infect humans directly from their avian hosts (B2H) and some ability to go H2H. What they don’t seem to be doing is either sustaining H2H or going H2B. If – as I suspect – each passage in a mammalian host ‘improves’ the virus’ adaption it all comes to nought as H2H is petering out and without transmission of adaptive SNPs back into the avian gene pool the changes are not sustained and each zoonotic emergence needs to solve the same problems from scratch. Is it normal to have at least two AIs this close to jumping the species barrier? If we knew this to have been a historical norm – and yet we have only one case of it going all the way in 100 years - then it may be safer to assume H5N1 could stay in its current spluttering stage for some time. What we can say with some certainty is we have no evidence we have ever been threatened by anything which is either HP or this virulent.
<o:p> </o:p>
The use of HP (Highly Pathogenic) to describe the extended cleavage site in some H5 & H7 flus is confusing as it means much the same as virulent. In practice HP H5N1 is unusually virulent in most species of birds and all HP flus (as far as I know) are highly virulent in poultry (which is why it got the HP label). However as this is a disease of birds its effects on us are unpredictable. HP AI H5N1 is highly virulent in poultry and us but there was an LP AI H7N3 out break in a poultry shed in <st1:state><st1:place>British Columbia</st1:place></st1:state> which caused mild illness in the poultry. The H7N3 spread to a second shed and mutated at the cleavage site to an HP form which killed the poultry but only caused mild infections in two farm workers.
<o:p> </o:p>
I am not sure I answered your question so much as danced around it.

**sharon sanders** · April 14, 2009, 02:51 PM

Re: 2008/09 flu season question

Thanks! You are clarifying the processes.

**Commonground** · April 14, 2009, 03:28 PM

Re: Analysis of hemagglutinin-mediated entry tropism of H5N1 avian influenza

Thank you so much JJackson,

**mixin** · April 14, 2009, 03:52 PM

Re: Analysis of hemagglutinin-mediated entry tropism of H5N1 avian influenza

The full study is available:

http://www.virologyj.com/content/pdf/1743-422x-6-39.pdf

Vaious points of interest throughout the study:
The sixteen cell lines can be roughly classified into three different groups, susceptible, moderately susceptible, and resistant to the HA-mediated transduction. The susceptible cells include 293T, A549, and Huh8, all of which were derived from human tissues. These cells, when challenged with HA(QH)/HIV virions, gave luciferase levels of roughly 100-1000-fold higher than
the background controls (106-107 RLUs vs 103-104 RLUs with HIV vector alone). HeLa (human), HepG2 (human), SAOS2 (human), Vero E6 (African green monkey), and two avian cell lines
(QT6, quail, and DF-1, chicken) are moderately susceptible to the HA-mediated transductions, giving approximately 5-10 fold higher RLUs than the HIV alone controls. The other seven cell
lines from different species (CHO, Lec1, COS-7, MDBK, Jurkat, 3T3, and RAW264.7) were resistant to the HA-mediated transductions under the experimental conditions.

These results demonstrated that human lung cells, but not rat lung cells, are susceptible to HA mediated transduction.

A comparison between transduction levels and either 2,3SA or 2,6SA reveals that there is no correlation between either receptor level or the level of entry. The human lung cell line, A549, and the HeLa cell line have similar profiles for both 2,3SA and 2,6SA, however A549 cells are susceptible to H5N1 HA-mediated transduction while HeLa cells are not, suggesting that the overall level of either 2,3SA or 2,6SA does not correlate with H5N1-HA mediated transduction. Thus, we do not see a correlation between the levels of either 2,3, or 2,6 SA receptor and the HA-mediated transduction, suggesting a possible role of a co-factor in H5N1 entry either in conjunction with or perhaps independently of sialic acid.

Together these studies strongly suggest that residues 190, 226 and 228 are crucial for sialic acid binding and in fact, determine the preference for either 2,3SA or 2,6SA.

In this report, we have examined the cell tropism of a highly pathogenic avian influenza virus H5N1, which was originally isolated from the infected migratory birds in Qinghai Lake of Western China, at the entry step. The surprising finding is that the most susceptible cell lines for the HA(QH)-mediated transduction are those derived from humans, 293T (kidney) and Huh 8 (liver), and all of the human lung cell lines tested, A549 and NCI-H661 consistent with the recent reports that H5N1 virus can attach to the lower respiratory tract and lung of humans. In stark contrast, two avian cell lines, QT6 (quail fibroblasts) and DF-1 (spontaneously immortalized
chicken embryo fibroblasts), were transduced by HA(QH)/HIV virions at much lower frequencies. These results indicate that this highly pathogenic H5N1 virus can enter numerous human cells including those derived from human lungs more efficiently than that in the
two avian cell lines, suggesting that the HA protein of H5N1 can effectively interact with the cognate cellular receptor(s) on human cells to initiate viral infection. Furthermore it appears that
other viral and/or human determinants, rather than HA, restrict efficient transmission of H5N1 to humans in a sustained manner.

Although no such molecule(s) has been identified up to date, a recent report indeed suggests that a host N-linked glycoprotein is required for human influenza virus entry. Therefore, a similar (or different) protein on the human cells such as A549 can act as
the co-factor in mediating efficient H5N1 entry, while the same protein on the avian cells is not as efficient as the co-factor either due to a low level of surface expression or low binding affinity to
HA

**JJackson** · April 15, 2009, 10:40 AM

Re: Analysis of hemagglutinin-mediated entry tropism of H5N1 avian influenza

<meta http-equiv="Content-Type" content="text/html; charset=utf-8"><meta name="ProgId" content="Word.Document"><meta name="Generator" content="Microsoft Word 10"><meta name="Originator" content="Microsoft Word 10"><link rel="File-List" href="file:///D:%5CDOCUME%7E1%5CADMINI%7E1%5CLOCALS%7E1%5CTemp%5 Cmsohtml1%5C01%5Cclip_filelist.xml"><o:smarttagtyp e namespaceuri="urn:schemas-microsoft-com:office:smarttags" name="State"></o:smarttagtype><o:smarttagtype namespaceuri="urn:schemas-microsoft-com:office:smarttags" name="City"></o:smarttagtype><o:smarttagtype namespaceuri="urn:schemas-microsoft-com:office:smarttags" name="place"></o:smarttagtype><o:smarttagtype namespaceuri="urn:schemas-microsoft-com:office:smarttags" name="stockticker"></o:smarttagtype><style>  </style> Mixin thanks for the link.

Having now read the paper I was intrigued by this bit

Although HA1 binds to SA with a low affinity, it is believed that interaction of multiple HA molecules on the viral surface with the SA-containing glycoproteins or glycolipids on the cell surface increases the avidity of influenza virus to the target cells[15], and this interaction facilitates viral infection through endocytosis in a pH-dependent manner

[15] gives

15. Sauter NK, Hanson JE, Glick GD, Brown JH, Crowther RL, Park SJ, Skehel JJ, <st1:place><st1:city>Wiley</st1:city> <st1:state>DC</st1:state></st1:place>:
Binding of influenza virus hemagglutinin to analogs of its cell-surface receptor, sialic acid: analysis by proton nuclear magnetic resonance spectroscopy and X-ray crystallography. Biochemistry 1992, 31:9609-9621.

I had not heard of this before and wondered if anyone else knew anything about HA working better en mass. This might have several repercussions. Without having any direct evidence I always thought viral load important in initiating infection. I also have been unable to understand why H5N1 seems to go wild once it gets a foothold in a human but have difficulty infecting its first cell. From the virus' point of view a life cycle starts with binding to that sialic acid residue and ends with successful release of the next batch of virons. Why should it rampage through the cells in A's lungs with abandon and yet not be able to jump to B? The droplet transmission system, thought to be the main vehicle for spread, is not dependent on viral surface characteristics as a true airborne pathogen would be. As long as the patient coughs or sneezes new virons should be able to get to a new host and if they happily infect cells in host A why can they not do so just as easily in host B?

Reasons I can think of include
Critical Mass: Either the extra-cellular innate immune system is very effective until a certain level is reached after which it is swamped and fails catastrophically (this can not be the NS protein/Interferon or any other intra cellular reaction as it needs to be per organism not per cell), or ? as the quote above suggests ? there may be a need to mass multiple virons on one cell so the HAs can act cooperatively in some way.
Immune own goal: If the immune system reacts inappropriately and, once initial infection occurs, it releases something which makes life much easier for further infections to occur.
<o:p> </o:p>
While I am asking the questions. Why didn?t very high levels of exogenous neuraminidase reduce HA binding? When new virons are released they have a tendency to clump by immediately rebinding to the cell that just released them. The <st1:stockticker>NA</st1:stockticker> proteins catalyse the hydrolysis of the binding sites rendering them ineffective and allowing the virus to go off and find new host cells to infect. Neuraminidase inhibiters block this and slow release by increasing clumping. Why does the neuraminidase not stop initial infection if it is merrily breaking suitable binding sites and why if you swamp the supernatant with neuraminidase does it not destroy all, or at least enough of, the a2,3 or a2,6 sites to interfere with binding? <o:p></o:p>

**FrenchieGirl** · May 3, 2009, 04:38 PM

Re: 2008/09 flu season question

Originally posted by JJackson View Post

The short version is that seasonal flu binds to an a2,6 isomer and avian flu?s bind to a2,3. The RBS on the HA of each is optimised to bind to its usual target however these are very common sugars and we do have a2,3 in many places including the lower respiratory tract, the eyes and the gut so it is obviously not the whole story. When H5N1 has got a foothold in a human it does not seem to have any great problem in then infecting lots more cells, each of which will need to have been bound to via a sialic acid molecule on its surface.

Originally posted by medstudent55

...This virus does not have any of the HA (hemagglutinin) gene mutations at the 226-228 amino acid positions that would allow the virus to bind to the alpha 2-6 sialic acid receptor sites located in the human upper respiratory tract. It does not have the poly-basic clevage sites. All human influenza viruses have the alpha 2-6 sialic acid receptors. This virus has only the alpha 2-3 sialic acid receptors and thus can only bind to the alveoli deep down in the lungs.

Originally posted by JJackson

For HP flus condition 3] is very much more relaxed as proteases are very common and the polybasic cleavage site of HP strains is easily cleaved so if conditions 1] & 2] can be met 3] is not likely to be a problem. Now if we return to the strange tale of WSN/33 we have an LP virus which behaves more like an HP virus because of an oddity in its Neuraminidase allows it to wrangle the common protease plasminogen ? which can not normally cleave LP HAs - and modify its behaviour so it does achieve cleavage.

JJackson, I have read yours and others' explanations with interest but find the subject difficult.

I think what I understand is that it's not enough to postulate an avian H5N1 virus, should have preference for sa2,6 to make it go pandemic. There may be an additional requirement for some further item for cleavage. Yes?

With respect to the novel H1N1 just emerged, from what I understand on another thread (partial quote above), the virus is for the moment equipped to bind to sa2,3 rather than sa2,6.

You mention that we have sa2,3 receptors not only deep in our lungs, but also in our eyes and guts.

Despite the scarcity of symptoms on the epidemic currently running through Mexico and the US, there are those following symptoms described from news reports: the eyes are getting quite sick from this new flu and many sick people are quoted as having diaorrhea.

Could one hypothetically imagine that perhaps our sa2,3 receptors in the eyes and guts are particularly vulnerable to this H1N1, and perhaps researchers might want to investigate whether the requirement for an additional cleavage characteristic has been met in this H1N1?

Or did I get the whole lot completely wrong?

Many thanks

**AlaskaDenise** · May 3, 2009, 05:02 PM

Re: Analysis of hemagglutinin-mediated entry tropism of H5N1 avian influenza

Frenchie;

We need to review MAmabird's comments in the "sequences are at genbank" thread - she has read those sequences & understands them fully.

Mamabird said (in sequences at genbank thread) that this new virus does not have the poly-basic cleavage site, so there are no additional enzymes needed to cleave the virus. She also said the receptor binding was perfectly comfortable with human cells.

I believe there may be some confusion between cleavage conditions and receptor/binding conditions. While they're both part of the infectivity process, they are 2 different things. The cleavage is when the virus unwinds and stretches out to find a human cell, and the binding is what happens with the keys at the end of the long string that was stretched out. Those keys must be set correctly to fit in the keyholes of the human cells (the a2,3 style or a2,6 style).

Here is an old post with a diagram of the virus unwinding (cleavage) and the keys/fingers at the ends fitting into the host cell.

Here's the best picture of the 4 from that post:

The unwinding cannot happen without the correct enzyme and the fingers cannot dock without a good fit (given that humans contain different styles in different places).

.

**JJackson** · May 4, 2009, 03:50 PM

Re: Analysis of hemagglutinin-mediated entry tropism of H5N1 avian influenza

<o:smarttagtype namespaceuri="urn:schemas-microsoft-com:office:smarttags" name="stockticker"></o:smarttagtype> FrenchieGirl
Firstly this thread, although recent, is pre H1N1(2009) and is related to H5N1 and to avoid any confusion they are quite different regarding cleavage – but the same re-binding (although with different preferences).
<o:p> </o:p>
As Denise points out these are two separate processes. Binding happens first – then some other stuff happens – then the HA is cleaved into HA1 & HA2. This is done by a host protease and, for low path strains (everything apart from a few H7 & H5 variants – inc HPAI H5N1 AKA ‘bird flu’) like H1N1(2009), the proteases capable of doing this are very limited. HPs are not so fussy. So to get into the cell it needs a suitable binging site – with the right sialic acid residue – but it has to be somewhere where there is a supply of a suitable protease. The problem with HP flus is this can be almost anywhere in the body as proteases are everywhere and some ubiquitous ones are capable of HP cleavage. LP flus only have very limited points of entry with the need for a specialist protease acting as the limiting factor.
<o:p> </o:p>
Of the three quotes you selected in the first I point out that H5N1 is avian optimised, as far as binding is concerned, but, being HP, cleavage enzymes are not a problem. Once it is in a human host it tends to cause severe illness so obviously has no problem causing widespread cellular invasion. The only mystery is why then does it not spread more easily from person to person.
<o:p> </o:p>
In Medstudent55’s quote he is pointing out that H5N1, being a bird flu, is optimised to bind to alpha 2,3 receptors and these are common in the <st1:stockticker>LRT</st1:stockticker> rather than the normal point of human flu infection in the <st1:stockticker>URT</st1:stockticker>. However as HP viruses don’t have to worry about finding a suitable protease near by any as2,3 will do (that is a bit of an exaggeration but less other variable are mandatory). As2,3 are not absent in other locations they are just uncommon. A further complication is that the alpha 2,3 /alpha 2,6 is not all or nothing there are degrees of preference. If you have journal access the first link in post #5 is to a modeling paper that looks at how changes in the primary amino acid sequence is likely to affect the tertiary protein structure and the environment around the binding site. It then goes on to calculate binding affinities for the sialic acid isomers. What it shows is a range of affinities from no binding, strong binding for one or other isomer or some kind of intermediate value. (If you don't have access then this paper on H7N3 in British Columbia has some graphics and covers a non-homologus recombination event were the H7 went for LP to HP and they look at the structure - open access)

<o:p> </o:p>
Your third quote box (mine) is best ignored as it will confuse the issue. Another point I was trying to make at the time of the original posting was a warning that while each viral protein may perform a primary function and it is common to see thing like HA controls entry, <st1:stockticker>NA</st1:stockticker> controls release, NS block interferon activity, M2 is the ion pump etc many also perform a secondary role which is not always understood but may be important. I use a rather obscure example involving a lab created strain in which the <st1:stockticker>NA</st1:stockticker> sequesters plasminogen and lets it act as a cleavage protease. This is not an important mechanism in vivo but is an example of an unexpected secondary role of the type that may be happening in nature without our knowledge.
<o:p> </o:p>

I think what I understand is that it's not enough to postulate an avian H5N1 virus, should have preference for sa2,6 to make it go pandemic. There may be an additional requirement for some further item for cleavage. Yes?

Yes. H5N1 is not sa2,6 optimised and yet once infection gets a foothold it can spread throughout the lung and spread into other areas of the body so poor sa2,6 is not the whole story or you could not catch H5N1.
<o:p> </o:p>

With respect to the novel H1N1 just emerged, from what I understand on another thread (partial quote above), the virus is for the moment equipped to bind to sa2,3 rather than sa2,6.

This I don’t know. As far as I can see it is not having a problem and while the RBS binding site may not be full optimised it seems to have found somewhere in the body where it can bind and where it can find a suitable cleavage protease. If it hadn’t we would not be on the verge of level 6. At some point some path lab will provide histology slides and we will learn which cells are loaded with virus.
<o:p> </o:p>
As to the eyes and gut I do not know enough about the disease course in humans we need a doctor and Medstudent55 may be better able to help with this. If the balance of symptoms is skewed away form the nasopharynx it may be due to less binding in this area – due to a poor as2,6 fit. In today’s press briefing WHO estimated 40% for diarrhoea, which is high, and I have heard of a cough being prominent.
<o:p> </o:p>
I think the main point I would make is that binding preference is not all or nothing and while we talk about as2,6 in the <st1:stockticker>URT</st1:stockticker> and as2,3 in the <st1:stockticker>LRT</st1:stockticker> this is does not mean they do not occur in other ares just that they are concentrated at these sites.

Announcement

Analysis of hemagglutinin-mediated entry tropism of H5N1 avian influenza

Analysis of hemagglutinin-mediated entry tropism of H5N1 avian influenza

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