VIRUSES  VERSUS  HUMANS:  CAN  WE  WIN  THE  WAR?

MANILA
, JANUARY 23, 2007
  (STAR) STAR SCIENCE By Eduardo A. Padlan, PhD - Last week, Mishail Tupas told us how viruses, those tiniest of parasites, manage to make us suffer again and again, and sometimes even kill us. Those pesky little critters do it by continually mutating, so that, although we have an immune system that defends us against their attack, we continue to be victims of viruses year after year. This is because our immune system only reacts to an attack Ė it only defends Ė it does not take the fight to the enemy.

In a fight, if we choose only to defend, the best that we can hope for is a draw.

But, we have big brains. We should be able to figure out how to win. Right?

Let us consider what we do to fight the flu virus.

The flu virus has two molecules on its surface which it uses to infect cells: hemagglutinin and neuraminidase. The hemagglutinin recognizes and binds to a carbohydrate moiety on the surface of a victim cell; the hemagglutinin is then activated (by enzymatic cleavage) and is transformed into a structure that allows it to be inserted into the cell membrane; the hemagglutinin, with the rest of the virus in tow, then enters the cell. Once inside the cell, the virus takes over the cellís biosynthetic machinery and dictates the production of many copies of itself. The newly formed virus particles emerge from the cell, but their hemagglutinins bind to the nearest carbohydrate moiety that they recognize Ė which is that of the cell they just emerged from. The neuraminidase comes into play at this point, cutting off the attached piece of the carbohydrate, thereby freeing the new virus to infect some other cell.

Knowing this much, scientists have devised ways to fight the virus. Antiviral drugs that act as neuraminidase inhibitors and M2 (another flu protein) inhibitors have been designed. These drugs can shorten the course of infection and make it less severe, but they cannot prevent infection. Other ways of interfering with viral replication have been developed. Molecules that prevent the initial binding of the hemagglutinin to the cell have been employed, for example, antibodies that we produce ourselves through vaccination, or ones that had been synthesized in the lab or obtained from other animals.

But, then, the virus mutates. We may find that our inhibitors no longer work, or that our antibodies are no longer effective. We are back to square one. The usual strategy for fighting the mutating flu virus is to produce a different vaccine every year. But, since we cannot really know what the virus will mutate to, we can only guess which viral strain(s) to use as vaccine.

Can we, for once, be a step ahead of the virus? Can we devise a means of fighting the virus even if it mutates?

A good way to know how to defeat an enemy in battle is to know beforehand how he fights.

Letís see what we can do about designing better vaccines against the flu virus. First, let us figure out how the virus manages to evade our immune system. The answer seems simple enough: when the virus mutates, it localizes its mutations in its "immunodominant epitopes."

Antibodies can be produced against any exposed part of the hemagglutinin and neuraminidase. But, like all molecules, some parts of the hemagglutinin and neuraminidase elicit a greater antibody response than other parts; in other words, some parts are more attractive to antibodies than others. Those are the so-called "immunodominant epitopes." Now, antibodies are very specific. When the virus mutates and changes even just one amino acid in an immunodominant epitope, the antibodies that used to bind to that epitope may no longer recognize the altered molecule. Our immune system will produce new specific antibodies, but it takes four to seven days for this to happen; in the meantime, we suffer from the flu.

If we could locate the immunodominant epitopes in the hemagglutinin and neuraminidase and generate new molecules in which those epitopes are no longer immunodominant (we can do this by protein engineering, whereby we replace the residues in the immunodominant epitopes with amino acids whose presence results in lower attractiveness to antibodies), we could use those engineered molecules as vaccines and our immune system will produce antibodies that would be directed against other parts of the hemagglutinin and neuraminidase, the parts that the virus doesnít normally mutate. As long as the virus continues to localize its mutations in its immunodominant epitopes (of course, it cannot know that our vaccines no longer contain those immunodominant epitopes), we have a weapon against it. Nature is on our side in this regard. The virus tends to confine its mutations in its immunodominant epitopes because there are "hot spots" (highly mutable codons) in those epitopes. Further, the virus is under no selection pressure to change this tendency because the flu virus victimizes not just humans, but other animals as well, including chickens, ducks, turkeys, and wild birds, and cats, dogs, pigs, and horses, and even whales and seals. (Those poor animals donít know how to engineer proteins. Only we humans do.)

Can we win the war against viruses? Yes! (I think.)

* * *

Eduardo A. Padlan has a PhD in Biophysics and was a research scientist at the (US) National Institutes of Health until his retirement in 2000. He is currently an adjunct professor in the Marine Science Institute, College of Science, University of the Philippines Diliman. He is a corresponding member of the National Academy of Science and Technology, Philippines. He can be reached at edpadlan@aol.com or edpadlan@yahoo.com.


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