on flu pandemics - briefing document
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on immunology

 

 


a briefing document

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Index
introduction
on serious responses to flu and tamiflu effects
protein amino acids
antigenic shift - explaining labels like H1N1
how coding for mutations work - the position numbers can also change through mutation
non-covalent forces holding together antigen/antibody complex
for endless hours of fun - folding virus proteins
end notes

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In part, I am assembling this page to allow intelligent readers to find their way more easily through the jargon-loaded sources on the area of immunology. Secondarily, this page provides summary notes from all my wading through book and journal sources.

A fundamental idea is to think in terms of keys and locks. These can be both ‘one’-dimensional and three-dimensional. On this page, I shall deal only with the three-dimensional type. While the examples used on this page relate primarily to influenza, the mechanisms in this area are widely applicable, say to vaccinations, medicines and immunology theory.

health warning
I am no expert in this field, so you are always advised to check details for yourself. Any suggestions from readers for improving these pages, or clarifying unclear details, will, as ever, be welcome.

 

on serious responses to flu and tamiflu effects

Summary from three recent studies.
My impression is that the whole system is becoming more responsive, and that flu is going high in priorities as other more annoying diseases are coming under greater control. Anti-virals is becoming an advancing area of study as were antibiotics many decades ago.

“Many patients in all three regions were also given the flu medication oseltamivir phosphate (Tamiflu), with apparent benefit. In the Mexican analysis, critically ill patients who survived were seven times more likely to have received the drug than those who died.

“All three groups of critically ill patients included very few people over the age of 60 and few young children. The numbers support a widespread hypothesis that older people carry some residual immunity against H1N1 flu, Fowler says. The new data don't explain why very young children were underrepresented in these critically ill groups.

“On the other hand, the data fail to explain why people in the prime of life would be most susceptible to the lethal effects of H1N1, a trend eerily reminiscent of the 1918 flu pandemic, which was also caused by an H1N1 strain.” [Quoted from sciencenews.org]

There are two main strains of flu virus, named A and B. A includes the H1N1 strain. Meanwhile, flu mutates like billyo in normal circumstances.

The present main concerns are with the recent H1N1 strain (‘swine flu’) and Tamiflu.

“Which antiviral drugs should health care providers prescribe for chemophrophylaxis of 2009 H1N1?

“For antiviral chemoprophylaxis of 2009 H1N1 influenza virus infection, either oseltamivir or zanamivir are recommended. Currently, circulating 2009 H1N1 viruses are susceptible to oseltamivir and zanamivir, but resistant to amantadine;” [Quoted from cdc.gov]

  1. Last year there was a Tamiflu-resistant H1N1 strain. I repeat, flu mutates like billyo!!
  2. There is no time to test in the window between infection and treatment. Thus, best recommendations are made, rather than 100% prescriptions to medics.

Once it is decided which strain of flu virus is being discussed, then suitable treatments can be suggested, but as the window is longer than testing times and there are several variants around at any one time, it is a matter of guesswork which vaccinations or anti-virals are relevant.

Tamiflu is a neuraminidase inhibitor. There are two of these so far FDA approved, with trade names Tamiflu and Relenza. There are two other treatments used for flu called adamantanes, they are Amantadine and Rimantadine. These latter two are not deemed useful for B viruses (H1N1 is an A virus), and the H3N2 virus currently circulating is resistant to them.

As you will have noticed, there was an H1N1 virus around last year that was resistant to Tamiflu, while the present H1N1 (‘swine flu’) resistance has not been found - yet. The ‘N’ molecule (neuroamidase) is made up of about 467/8 amino acids. Now these complex (neuroamidase) molecules fold predictably according the amino acid sequence. Keeping in mind that the flu virus relies on rapid mutation, certain random changes in the amino acid sequence can result in the Tamiflu molecule not fitting tightly enough, or as accurately, and thus may fail to block/disrupt the neuroamidase action of the virus. This is approximately how resistance to a substance like Tamiflu develops.

Of course, a change in the neuroamidase may also make the virus ineffective - typical evolution in action. Meanwhile, the biochemists are understanding the little beggar ever better and are working on improving the inhibitor molecules and on developing new attacks on the virus.

These drugs are fall-backs if vaccination does not work, or if the current flu version gets a start. (It takes about six months to obtain a useful vaccine.) Each year, the medical warriors are trying to keep ahead or get ahead of flu, but flu is a very crafty and agile monster.

protein amino acids

Proteins are built of long chains of amino acids.

General amino acids structure:

General amino acids structure

There are twenty different types of R side chains, each with a different structure, making twenty amino acids. The R side chain is attached to the central carbon [C].

The twenty different R side chains are divided into nine nonpolar, six polar, two acidic electrically charged, three basic electrically charged.

nonpolar polar electrically charged
glycine (gly) G serine (ser) S acidic aspartic acid (asp) D
alanine (gly) R threonine (thr) T glutamic acid E
valine (val) V cysteine (cys) C basic lysine (lys) K
leucine (leu) L tyrosine (tyr) Y arginine (arg) R
isoleucine (ile) I asparagine (asn) N histidine (his) H
methionine (met) M glutamine (gln) Q Taken from basic chemistry: proteins [includes the chemical structures], with standard one-letter codes added.
tryptophan (trp) W    
phenylalanine (phe) F    
proline (pro) P    

Amino acids link together in long chains using peptide bonds, a special covalent protein bond. These chains can be very long and, at body temperatures, they fold predictably into shapes of varying complexity.

 

antigenic shift - explaining labels like H1N1

Antigenic shift happens when a virus manages to swap a complete RNA strand. This happens when two substantially different variants of the virus enter into the same host. For instance, antigenic shift occurs when an avian RNA strand replaces its equivalent strand in a human flu virus while both are inside a pig. When this shift happens, it becomes particularly difficult to predict what delightful surprises the new virus may have in store.

The eight RNA flu virus strands are labelled:

H hemagglutinin
N neuraminidase
NP three nucleoproteins
M four matrix proteins plus two ion channel proteins
NS two non-structural proteins
PA sub-unit of RNA polymerase
PB1 sub-unit of RNA polymerase
PB2 sub-unit of RNA polymerase

Thus you may hear references to H1N1 flu, H5N1 flu etc., referring to the two first strands listed above. These are the genes expressed on the surface of the virus, and are, thus, most relevant to immune system response.

From an excellent and clear discussion of flu virus resistance through mutation, relative to Tamiflu (Oseltamivir). This is a useful page to see how the research is put into context.

“According to antigenic properties, influenza virus has two functional surface glycoproteins: hemagglutinin (HA) and neuraminidase (NA). So far 16 subtypes have been identified for HA (H1 to H16) and 9 for the NA (N1 to N9)”

From the World Health Organization - a revision of the system of nomenclature for influenza viruses, WHO Memorandum Bulletin 58 (1980) 585–591:

“The A in HA refers to an A-type virus. There are three types of human influenza viruses, labelled A, B and C. Influenza A is the most dangerous.”

 

how coding for mutations work - the position numbers can also change through mutation

“What are these mutation designations? The wildtype condition is the first letter in H274Y and gives the one letter code of the amino acid that was there before the change. 274 is the position along the length of the NA protein. The second letter is the amino acid after the mutation. Here the amino acid histidine (whose one letter code is H) has been changed or mutated to the amino acid tyrosine (one letter code Y) at position 274. We don't know all the mutations that might confer Tamiflu or Relenza resistance, but based on experience the Japanese have had with the H3N2 virus and some experiments with human volunteers infected with H1N1 viruses, the mutations R292K, N294S and H274Y seem to be important to drug binding in the pocket. Much of the previous predictions were based on three dimensional structures of N2 type neuraminidase, the 3D structure of N1 not having been worked out....” [Quoted from scienceblogs.com]

 

non-covalent forces holding together antigen/antibody complex

non-covalent force origin  
electrostatic forces attraction between opposite charges electrostatic forces
hydrogen bonds hydrogen shared between electronegative atoms (N, O) hydrogen bonds
van der waals forces fluctuations in electron clouds around molecules oppositely polarise neighbouring atoms Van der Waals forces
hydrophobic forces hydrophobic groups interact unfavourably with water and tend to pack together to exclude water molecules. The attraction also involves Van der Waals forces hydrophobic forces

It is important to keep in mind that the sum total of mechanisms looked at on this page (and there are others) mean that this area of science is becoming immensily complicated - and therefore interesting! - and that mechanisms are not just on-off. For example, the ligands have a very wide range of stickability, and the keys and locks vary in fitability as you will realise if you do real hard work on the above.

 

for endless hours of fun - folding virus proteins
[requires Java to be installed]

This one is bits of the 1918 flu, in several types of view. You can drag the model to change the position of the 3-D views at the website. The site has tens of thousands more protein models.

jmol view, a type of ribbon view. Image:  RSCB Protein DataBank
jmol view, a type of ribbon view. Image: RSCB Protein DataBank

webmol surface view. Image: RSCB Protein DataBank
webmol surface view. Image: RSCB Protein DataBank

KiNG view, a type of wire view. Image: RSCB Protein DataBank
KiNG view, a type of wire view. Image: RSCB Protein DataBank

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end notes

  1. Ligand:
    An ion, a molecule, or a molecular group that binds to another chemical entity to form a larger complex.

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