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Page #20

LATE JUNE 2009

MA: What is the most efficient and economical way of fighting viral disease?

Q: Vaccination?

MA: Yes of course. Vaccines are the most efficient means for preventing human and animal disease.

Smallpox and measles are excellent examples of successful vaccines, however some enveloped viruses still are without vaccines think HIV as the most prominent example.

MA: So here is my question for you. How can the measles virus vaccine still function after over 40 years, whereas the influenza virus vaccine needs to be replaced almost every year, and it has proven impossible to produce an HIV vaccine?

Q: I don't believe I can answer that.

MA: It is all about mutations child - all about mutations. The replicating enzymes of RNA viruses, such as measles, influenza, and HIV, make approximately one mistake per every 10,000 nucleotides.

But the answer to the differences in affectivity lie in the peculiar structure of the measles H glycoprotein, against which neutralizing antibodies are produced.

The influenza virus hemagglutinin glycoprotein, which binds to the viral receptor sialic acid, is richly covered with sugar chains. The receptor binding site at the top of the molecule is a shallow hollow.

Most of the amino acids around this hollow and others on the surface of HA can mutate without significantly affecting receptor binding. However, HA has a rather rigid structure, and many mutations are not allowed because they would destabilize the molecule or lead to a nonfunctional molecule.

MA: You see why that could not be allowed?

Q: Sure, you get some mutations in non-essential areas, but none in the binding site or in a "mission critical" area.

MA: Yes. The accumulation of mutations, selected and directed by the immune pressure in the host population, is such that the vaccine strains have to be frequently replaced - in order to be effective. H1N1 is such a strain. The vaccine needs to be adjusted to be effective.

However, the HIV surface glycoprotein, against which neutralizing antibodies should be made, is GP120.

This molecule is much more flexible than influenza virus HA. GP120 has a number of highly variable surface loops that do not seem to have a specific three-dimensional structure.

These structural changes are very large and are possible because the molecule is plastic. The combination of the sugar chains on the surface of GP120 together with its plastic structure and the variable loops that have no sequence constraint results in a molecule that is too flexible and variable for the production of neutralizing antibodies.

Because of the flexibility in its design the glycoprotein for HIV (GP120) prevents the production of neutralizing antibodies - making an effective vacine targeted at the binding site an almost impossible task.

This is an important factor to consider when explaining how HIV could be so hard to defeat.

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