Explaining Avian Flu Virus and Possible Pandemic

[Avalux]

Here’s an unsolicited lesson in viruses and how they survive – particularly the influenza A virus causing the current outbreaks of avian flu. I’ll do my best to write an explanation without being too technical. Let me add a disclaimer here – no one can predict when a pandemic will occur but I do believe it is inevitable; either in a few years or as many as 50. As advanced as we humans are, we can’t stop mother nature - it's that pesky "E" word (evolution).

A virus is a parasite – it is comprised of genetic material enclosed in a protective coat. The genetic material may be DNA or RNA depending on the type of virus. The protective coat is called a capsid. Not only does it protect the genetic material inside, but the capsid also helps the virus infect host cells. Some viruses even have an additional outer envelope of proteins, sugars and lipids stolen from the host cell in which it has been made. The complete virus "particle" – genetic material, capsid and envelope (if it has one) - is called a virion.

We aren’t sure of the origins of viruses, but most virologists agree that each virus got started by copying a few useful genes from their host cells. Viruses are ignorant of any patent or copyright laws. They are brilliant at making copies out of whatever they find useful in the host’s genetic code and move on from there. The ‘useful’ gene that’s stolen is intimately involved in the host cell’s reproduction, food gathering, cell communication or other essential function. Viruses mutate the stolen genes and when a particularly useful mutation comes along, the virus uses it for it’s own survival, usually to the detriment of its host. Over many generations and years, viruses have the ability to switch over the other species, find new genes to copy and then continue evolving in their own selfish way.

The avian flu virus is an orthomyxovirus – it’s genetic material is RNA. When a virus with RNA replicates, the copies tend to have more errors than when a virus with DNA replicates. These extra errors provide mutations upon which natural selection may act. That means RNA viruses have a high mutation rate and can evolve quickly - faster than a DNA virus or any DNA cell. Over time these mutations accumulate and eventually the virus evolves into a new strain. This progressive accumulation of individual mutations is called antigenic drift. The shape of the viral protein (antigen) slowly drifts into a different shape with each generation of virus. Eventually they drift so much that the original antibody can no longer bind to it. That means a host can become infected with this newly evolved virus. All viruses show antigenic drift, but RNA viruses mutate faster so they drift faster. Antigenic drift is responsible for many of the localized outbreaks of different strains of influenza, especially influenza A and B. In practical terms, antigenic drift is the reason we need to develop a new flu vaccine every year for human influenza and why it’s never 100% effective.

Here’s where it get pretty amazing – influenza A. This virus has the ability to undergo a kind of gene swapping or genetic reassortment that other viruses do not have. If a host cell is simultaneously infected by two different strains of influenza A, the copies of the virion may contain mixtures of each parents' genes. This makes it very easy for influenza A to quickly evolve into new combinations of genes. This is called antigenic shift; a newly created virus strain with mixed genetic material that’s different from it’s parents. This phenomenon is different from antigenic drift which occurs slowly and without change in the gene associations. The new combinations are such a unique strain of virus that the immune system has to start all over to make new antibodies to combat it.

Influenza A can infect mammals other than humans including birds (avian flu). It's very unusual for a virus to have such a wide host range, but influenza A somehow manages this trick. It probably has to do with the fact that the virus gains entry to a host cell by using receptors common to many species. That means a strain of influenza A may infect one species for decades and then suddenly jump to a new species. This sudden jump, due to antigenic shift, can produce a very serious epidemic. For example, several years ago many seals washed up on the east coast of the US dying from a strain of influenza A that, until then, had only been found in birds. Horse and swine influenza A have turned up in humans. Influenza A is the nightmare of science fiction - a virus that normally causes only a slight illness, undergoes genetic recombination with other species and comes back as a very deadly virus.

We know that influenza A has been conducting random, unlicensed recombinant genetics "experiments" for centuries and will continue to do so regardless of what any of us try to do about it. We watch and wait. Avian influenza A virus has a very high mortality rate (about 75%) and that’s why the present scenario is so scary. If avian influenza A were to recombine with human influenza A within a host cell, it may give the virus the ability to pass from one human to another quite rapidly. This would cause a worldwide pandemic. We may be getting dangerously close to this reality as there were two documented cases of human to human transmission last year in Asia. Another significant change we’ve seen in bird to human transmission is the large amount of viral particles in respiratory secretions of birds where in the past the virus was only found in bird feces.

And when it comes to vaccines, there are obstacles to the rapid development of a vaccine for a pandemic outbreak. Flu vaccines are normally grown in chicken eggs, but this will not be useful because avian influenza A is deadly to the chicken embryo. The only other option will be to use ‘reverse genetics’, which involves merging selected genetic material from the natural virus with a laboratory virus, with the resulting virus stimulating an immune response, but no disease when injected into humans. This of course, is easier said than done.

I happen to respect viruses a great deal - they are amazing creatures. I ask myself frequently how a one-celled organism dependent on others for survival can be so smart – they always seem to be one step ahead of us.

My advice if an avian flu pandemic happens - stock up on supplies and stay home.

[FloridaPat]

1. Thank you for a very informative and interesting study of viruses.

It has helped my understanding a lot. Stocking up sounds like a good idea. One question - what is the difference between an epidemic and a pandemic?

[Avalux]

2. You're welcome

and to answer your question - an epidemic is regional; a very large number of people are affected in a certain area or region. A pandemic is global; a very large number of people are affected everywhere.

[Media_Lies_Daily]

3. That was an outstanding summary...thank you very much! :-)

[Avalux]

4. Thanks! Glad you like it! n/t

[kineneb]

5. Thanks for the info

I read it aloud to Hubby, who also liked it. After reading Laurie Garrett's books and the Hot Zone, I have profound respect for all those viruses and bacteria out there. They are soooo successful.

[sharonking21]

6. Recommended

I like the way you explain it thoroughly and with the correct degree of seriousness without resorting to scare tactics. The latter is counterproductive because it first causes unreasoned fear and then, when the fear is not realized, causes people to discount messages that might actually help them. Good job.

[Avalux]

7. thanks -

and also for recommending. :hi:

[sharonking21]

8. A resource List of Books

I have posted a resource list of books on epidemics and outbreaks (and other medical topics) written for the general public and am inviting people to give their opinion of them and, especially, to add other books that I didn't think of. I would welcome your additions or comments.

http://www.democraticunderground.com/discuss/duboard.php?az=show_mesg&forum=209&topic_id=1562&mesg_id=1562

[Wickerman]

9. That was pretty damn interesting - recommended!

thanks for posting.

Keep the kids at home!

[Avalux]

10. Well apparently,

the boy king signed a quarantine executive order last week. Just in case....

http://query.nytimes.com/gst/abstract.html?res=F40A14FA3A5B0C718CDDAD0894DD404482

Thanks for the recommendation!

:hi:

[JitterbugPerfume]

11. Thank you

that is fascinating !

[ArchTeryx]

12. Excellent summary...

I'm a molecular virologist by trade, and in my opinion that was a great summary. In fact, I'd only add a couple of points.

1) The reason that influenza and other orthomyxoviruses can gene-swap so effectively is because it has a "multi-partite" genome -- rather then one long strand of RNA, it's split into several smaller segments. When the virus reproduces, each of those segments must be correctly packaged in a virion, and the way that they sort themselves out is a marvel in itself. But when different strains infect, say 'A' and 'B' each contributes its own segments. Many viruses may have all 'A' or all 'B' segments, but many will have combinations of 'A' and 'B' -- and when virus A suddenly gets a coat protein from B, you have a brand new virus in one generation!

2) Viruses normally co-evolve with their hosts, and deadly viruses are rarely successful. The most successful viruses are ones which leave the host alive to spread the virus. Influenza gets away with a high mortality rate because it can spread so easily and quickly, but most airborne viruses are NOT fatal. It is interesting to note though that most (but not all!) lethal viruses are fast-evolving RNA viruses.

-- ArchTeryx

[Sufi Marmot]

13. Virology question...

Thank you for your informative commentary.

Question: It's my understanding that influenza viruses can also exchange genetic material by "recombination" between homologous RNA molecules when cells are coinfected. (That is, cells coinfected with two distinct subtypes, one AAA and the other aaa for one of the 8 "chromosomes", can recombine (in the classical way that DNA does) to make a new AAa subtype for that "chromosome") Is this correct?

And it appears that new variants can also arise by ectopic combination between non-homologous regions. link

So including the "reassortment" of whole segments you described above (roughly analagous to reassortment of meiotic chromosomes during gametogenesis), and also mutations due to replication errors, there are at least 4 ways that genetic diversity is generated in influenza viruses.

Am I missing any other mechanisms?

-SM

[ArchTeryx]

14. Not 100% sure.

Homologous recombination requires double-stranded molecules to work properly, and genomic viral RNA is single stranded, though it DOES have double-stranded replication intermediates. However, NON-homologous recombination can be a major factor in gene rearrangement of RNA viruses, just as you noted. I'd suspect NHR would be more important, simply because the RNA spends far more time as a single strand then a double strand.

But I think you pretty much nailed it otherwise. RNA viruses are incredibly plastic things. The one good thing is that the *VAST* majority of resorted combinations will simply produce DI (Defective Intefering) particles -- noninfectious, 'dead' viroids. It's the tiny minority that are changed in some way, AND viable, AND replicate well enough independently to form a new strain, that cause all the problems.

And natural selection is a wonderful thing. The immune system is every bit as plastic, but changes at a slower rate, so eventually even the deadliest virus will find itself up against an immune nut it cannot crack, or even evolve down to a harmless form when it starts running out of hosts. I would rather *NOT* be on the wrong end of that bit of evolution, though!

[countryjake]

15. Thank you for such concise info!

The idea of a pandemic seems so remote to many, but dismissing it as right-wing hysteria or silly conspiracy theory, rather than paying attention & educating ourselves about the possibility (very likely, I fear) will only make our survival much harder, if things do get out of hand. This recent mishandling of that 1957 killer virus should be seen as a warning to all...is our country competent to deal with a serious threat to the world population?

[sharonking21]

16. Kick! People need to see a reasoned discussion

of this topic.

[Hugin]

17. Excellent... Excellent write up!

Glad you pointed it out sparosnare.

[Avalux]

18. Thank you very much!

The more exposure the better! :hi:

[Hugin]

19. I have a question for you...

Which is a slight aside from this thread... But, related.

I've been studying the so-called "Cambrian Explosion". Prior to that
period almost to the formation of the Earth the only critters
around were bacteria (and probably viruses).

This amazingly long time span with not much happening as far
as evolution is concerned demonstrates the inherent robustness
of bacteria. But, what do you think caused the ultimate beginning
of complex multicellular life? How and why did it happen?

Any thoughts?

[Avalux]

20. Sorry it's taken so long to respond -

I had to think about this a bit -; mostly I think of how inorganic matter became organic - how single-celled organisms arose out of a mixture of inorganic elements and became 'alive'.

So here's my take - it all started as small as possible; with a single molecule which eventually evolved into a single cell in fluid (water) - bacteria. The fluid environment enabled these cells to have some control over the environment around them and eventually, the single-celled organisms formed large colonies that became more interdependent on each other and at some point merged and became multi-cellular. It goes on from there; the multi-cellular organisms formed organization patterns that eventually turned into multi-cellular creatures. All of this, of course, took quite a bit of time. And remember this - bacteria are the most abundant life form on this planet, and the most evolved.

I tend to agree with American biologist Lyn Margulis, who believes in endosymbiosis - that bacteria (single-celled organisms) are responsible for the creation of complex forms of life, including us. We're just an amalgam of differerent kinds of bacteria. All seems rather simple when you think of it that way, doesn't it? :hi:

I didn't answer the "why" part of your question because I honestly don't know. It just did.

[NNN0LHI]

21. I found your post interesting but I have a couple of questions

You suggest that "We may be getting dangerously close to this reality as there were two documented cases of human to human transmission last year in Asia."

I have not been able to find any evidence to back up that claim. Actually I can find only evidence that the opposite is more likely true.

http://www.who.int/csr/disease/avian_influenza/avian_faqs/en/

Is there evidence of efficient human-to-human transmission now?

No. However, in Thailand, on 27 September 2004 the Ministry of Health announced possible human-to-human transmission in a family cluster. Thai officials have concluded that the mother could have acquired the infection either from some environmental source or while caring for her daughter, and that this represents a probable case of human-to-human transmission. While the investigation of this family cluster provides evidence that human-to-human transmission may have occurred, evidence to date indicates that transmission of the virus among humans has been limited to family members and that no wider transmission in the community has occurred. Continued vigilance is needed to determine whether the epidemiological situation in humans remains stable. (published 5.10.04)

Also you suggest that "Avian influenza A virus has a very high mortality rate (about 75%) and that’s why the present scenario is so scary."

Just to be clear on this point you made, is that 75% +or- mortality rate based on all reported cases of avian flu, or does that figure attempt to take into account that there may be many more unreported cases of avian flu that are not being counted due to the symptoms not being serious enough for those persons to require medical care and therefor are not being counted at all?

As an example in America even though 36,000 people die from the human form of the flu each year there's still "hundreds of thousands" of unreported cases. An estimated 20% of the American population will have had the flu or at least some flu-like symptoms at some time during this flu season. But only a small percentage of those will require medical care. And an even smaller percentage will actually die from it. Less than 1% will die. Couldn't something very similar be happening with avian flu where only about 50 people have actually died from it?

Don

[Avalux]

22. Cases were probable -

and by eliminating other variables, the avian flu family cluster reported in Thailand last year points to human to human transmission. Definitive evidence is difficult in a third world setting, but all experts I know believe the daughter passed the virus to her mother and then on to the aunt.

"During August to October 2004, sporadic human cases of H5N1 were reported in Vietnam and Thailand. Of particular note is one isolated instance of probable limited human-to-human transmission occurring in Thailand in September 2004."
http://www.cdc.gov/flu/avian/outbreaks/asia.htm

Of course, this is a limited cluster and there are no documented cases of human to human transmission since, but we know it’s possible, and there may be undocumented cases we don't know about.

A mortality rate is a calculation, much like an incidence rate - by dividing the number of deaths occurring in the population during a particular amount of time (usually a year), by the number of persons at risk of dying during the period (per 100,000). This would be a crude mortality rate.

A specific mortality rate (as in my summary), is the number of those persons at risk of dying due to a certain factor, such as an infection and it’s often reported per 1000 people.

The 75% +/- mortality rate for avian flu is based on what we know – # of deaths divided by reported number of cases (it doesn’t apply to the population at large). I will acknowledge that the mortality rate could in reality be much lower due to two factors. As you’ve pointed out – the number of unreported cases, and also that the mortality rate is based on data from Asia, where environmental variables must be considered. Until there’s more data though, “75% +/-” is accepted by the scientific community.

[NNN0LHI]

23. You are ignoring an important variable in this equation

You are saying the experts you know believe there were probably two cases of human-to-human transmission last year in Asia for which there is no physical evidence to back that assertion up.

The variable you omitted is these cases are from over a year ago. If avian flu had made the jump to humans a year ago as they suggest why did it stop? Wouldn't common sense dictate that as each day passes without any more such cases the probability that it actually did happen decreases exponentially? Do you see my point here?

Don

[Avalux]

24. You're not understanding influenza A -

Please read my initial post again. Avian influenza A can be transmitted from bird to human through feces and mucouse membrane excretions - THAT is documented.
A rare case of human to human transmission through very close personal contact might occur, like the cluster in Thailand. Here's why we're concerned - if that case had strayed outside of the cluster and started to spread through the general population, it would have meant that avian influenza A had combined with human influenza A (in a host) and formed a new virus - then we'd have a possible pandemic.
By itself, avian influenza A cannot cause a pandemic, only isolated cases of infection. It must combine with human influenza A to gain the ability to spread easily from human to human.

[sharonking21]

25. It might be useful to look at a stylized

graphic of an influenza virus. The protruding parts (molecules) represent the hemaglutinin and neuraminidase antigens.



The immune system and the microbes it tries to fight off work on a recognition and attachment system that is based on shapes. A virus has to have a way to attach to the outer membrane of a cell before it can invade the cell.

In the case of influenza, it does so by means of the hemaglutinin (H) and neuraminidase (N) antigens sticking up on the outside of the virus. These antigens lock onto shapes (molecules) called receptors on the surface of our cells. (Most of this docking seems to be via the H-antigen and the role of the N-antigen was, at least 10 years ago, not so well known.)

The immune system's recognition and attachment system is thus based on a lock-and-key type of arrangement. Obviously, the shape of the virus antigen cannot change so radically that it can no longer perform its function and lock on to a human receptor molecule. But, it can change its shape so severely that the other components of the immune system like antibodies can no longer readily recognize it

Influenza A has a tendency to change the shapes of its antigens fairly quickly compared to change that occurs in the rest of the virus and compared to other viruses. Every year these outer "shapes" evolve considerably: this is antigenic drift. It is fairly fast change, but still could be considered in the vernacular to be 'evolutionary change.'

However, you can think of antigenic shift as 'revolutionary change.' This is what causes pandemics. Most think that antigenic shift is caused by swapping genes with bird flu viruses. In this case the other components of the immune system can no longer recognize it at all plus the gene swapping may cause it to have symptoms and lethality that are different and more severe than either of the two original viruses.

Here I am shifting to citing John M. Barry's book, The Great Influenza, Chapter 2, "The Swarm." He is talking about the 1997 Hong Kong outbreak of avian flu in humans. He notes that normally an avian flu could not bind to a human cell, but in this case there was enough change in the bird flu to where it could do so. It infected 18 people and 6 of them died, but he notes that it did not adapt to humans otherwise and all those who got sick got the virus directly from birds. He says (emphases are mine):

"But the virus can adapt to man. . . .For one final and unusual attribute of the influenza virus makes it particularly adept at moving from species to species.

. . .it also has a segmented genome . . Therefore if two different influenza viruses infect the same cell, "reassortment" of their genes becomes very possible.

Reassortment mixes some of the segments of the genes of one virus with some from the other. It is like shuffling two different decks of cards together, then making up a new deck with cards from each one . .

If the Hong Kong chicken influenza had infected someone who was simultaneously infected with a human influenza virus, the two viruses might have easily reassorted their genes. They might have formed a new virus that could pass easily from person to person."

The key here is two viruses infecting the same cell and then mixing it up to produce H- and N-antigens that we have no immunity to.

Barry also has a nifty explanation of "recombination" and I would like your opinion of how accurate his analogy is as well as of the one above he uses for reassortment. He says:

"Recombination means taking part of one gene and combining it with part of another gene. It is like cutting all the cards of two decks in pieces, taping the pieces together randomly, then assembling the first fifty-two for a new deck."

[Avalux]

26. Nice graphic

and description - thanks. However, I was trying to answer NNNOHLI's questions as simply as possible without getting into the whole virus structure thing. To clarify the role of the envelope glycoproteins - hemagglutinin helps the virus attach to the host cell, neuraminidase helps the newly created virus leave the host cell to infect new cells. Keys in a lock.

Your John Barry excerpt is great - he's spot on I'd say. The analogy of a deck of cards is an easy to understand way to describe both recombination and reassortment. He reinforces the point I made in my prior post - avian flu virus cannot start a pandemic on it's own, but if it infects a person with human influenza virus, the two viruses can form a new virus that can be easily transmitted from human to human.

I won't even start talking about pigs at this point, but you probably know they can be involved in the vector chain too (as well as horses). :hi:

[sharonking21]

27. I think that a stylized graphic

of the pig might help.

[sharonking21]

28. I'd like to

make it clear to new observers of this thread that my lovely pig graphic was not mocking Sparosnare's wry comment on pigs.

Instead I was mocking myself (see the similar subject lines) and my tendency to get quite carried away and want to explain gory details relating to immunology and epidemiology.

I am a retired epidemiologist in HIV and I find I still carry around a certain evangelical epidemiologic fervor, wanting to be certain everyone understands the underlying principles of things relating to epidemiology. :bounce:

Now, if you want to know more about the pig-influenza connection, drop me a note and I will write you a quick twenty pages on it and send it back.}(

[sharonking21]

29. Update

This is the first I've heard of molecular changes, be it ever so scanty information as to just WHAT has changed and the extent to which genetic change has occurred.


Avian flu virus changing
By HELEN BRANSWELL
Sunday, May 1, 2005 Updated at 6:06 PM EST
Canadian

Toronto — Ominous changes in the behaviour and the makeup of the H5N1 avian influenza virus in northern Vietnam has the flu world worried the virus may be getting better at infecting humans.

In recent months the virus has sparked increasing numbers of small clusters of cases, suggesting more frequent occurrences of limited person-to-person spread. As well, it appears not to be killing as many of its human hosts — a biological change that cannot be assumed to be an entirely positive sign.

. . .

The apparent changes to the pattern of human infections and an observed change in the molecular makeup of the few virus samples that have emerged from Vietnam this year account for his rising concern.

“The little (molecular) information that we have — and it's from a handful of isolates that have come out of Vietnam — is also concerning,” Dr. Dowell said in an interview from Bangkok. . . .

http://www.theglobeandmail.com/servlet/story/RTGAM.20050501.wvirus0501/BNStory/specialScienceandHealth/