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Perspectives in Biology and Medicine 43.2 (2000) 173-192

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The Origin and Control of Pandemic Influenza

W. Graeme Laver, * Norbert Bischofberger, ** and Robert G. Webster ***


In 1918 an epidemic of influenza killed 20 million people worldwide. Spanish flu, as it was called, was a horrific disease. The flu would start with headaches, muscular pain, and fever. These would be rapidly followed by vomiting, dizziness, labored breathing, and profuse sweating. Sometimes purple blisters would appear on the skin, and often blood would spurt out of the nose from hemorrhages in the lungs. Some of the victims of this dreadful, sudden, and unexpected illness went into violent fits of coughing. Death often followed, sometimes only hours after the first symptoms appeared.

Influenza viruses infect a number of different animals, and some of these viruses can cause very serious disease indeed, particularly in domesticated chickens and turkeys. Avian influenza viruses sometimes rapidly kill these birds, with 100 percent mortality, and the symptoms resemble, at least to some extent, those of the Spanish flu in 1918. You can imagine, therefore, the concern felt when, in late 1997, a virulent bird flu virus, which had never before been seen in man, started infecting and killing people in Hong Kong [1]. This virus, designated H5N1, killed six of the 18 people it infected. The virus seems to have been transmitted to people from infected chickens in the live bird markets, but so far there has been no evidence that the virus had learned how to spread from person to person. But there is also no reason to suppose that this might not happen, some time in the future. Killing off all the chickens in Hong Kong seems to have stopped the epidemic, at least for the time being. What could be done to control such a virulent influenza virus, which, if it took off, would spread through [End Page 173] today's crowded communities with explosive violence? Vaccines probably could not be prepared in time, and the two anti-flu drugs available at the moment, amantadine and rimantadine, not only have undesirable side effects, but mutant viruses, resistant to these drugs, develop very rapidly.

Recently, a new approach to preventing and treating influenza in humans has been tested in clinical trials. These trials involved compounds that inhibit an enzyme on the virus (called neuraminidase) which the virus needs in order to complete its replication cycle in the body. These compounds are not vaccines, which prime the body's immune system; instead, they act directly on the virus itself to stop it replicating, in much the same way antibiotics act to prevent the replication of susceptible bacteria. This article tells the story behind the development of these new flu drugs.

The Virus

Viruses, unlike bacteria, can only grow inside living cells, using much of the cellular machinery to make thousands of new virus particles. This intimate relationship between virus and cell has made the development of anti-viral drugs very difficult, since many of the substances which "kill" the virus will also kill the host cell.

Unlike most viruses, which are regular in shape, flu virus particles may exist as long, spaghetti-like filaments, round balls, or any shape in between. They consist of a lipid membrane, inside which is the genome of the virus, associated with five different viral proteins. Flu therefore belongs to the "enveloped" group of viruses [2]. The influenza virus genome consists of eight separate pieces of ribonucleic acid (RNA) of negative sense each of which specifies the amino acid sequence of one (and sometimes two) of the virus's proteins. This segmented nature of the RNA allows different flu viruses to easily "mate" with each other, forming hybrid progeny viruses with bits of RNA from each parent virus.

Stuck onto the lipid envelope of the virus, like pins in a pincushion, are two glycoprotein molecules which play a vital role in the life-cycle of the virus. One of these surface "spikes" is a triangular, rod-shaped molecule called hemagglutinin, and one of...


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