Flu viruses are RNA animal viruses. An individual flu virus resembles a rod studded with spikes composed of two kinds of protein (Figure 29.11). There are three general "types" of flu virus, distinguished by their capsid (inner membrane) protein, which is different for each type: Type A flu virus causes most of the serious flu epidemics in humans, and also occurs in mammals and birds. Type B and Type C viruses are restricted to humans and rarely cause serious health problems.

HOW STRAINS OF FLU ARE DIFFERENT
Different strains of flu virus differ in their protein spikes. One of these proteins, hemagglutinin (H) aids the virus in gaining access to the host cell's interior. The other, neuraminidase (N) helps the daughter virus break free of the host cell once virus replication has been completed. The structures of both the H and N molecules are known in detail. The H molecule, for example, is made of three parts, and stands on the surface of the virus somewhat like a tripod, with clublike projections on top. Each "leg" of the H molecule contains "hot spots" that display an unusual tendency to change as a result of mutation of the virus RNA during imprecise replication. Point mutations cause changes in these spike proteins in 1 of 100,000 viruses during the course of each generation. These very variable segments of the H molecule functions as targets against which the body's antibodies are directed. Because of accumulating changes in the H and N molecules, different flu vaccines are required to protect against different subtypes. Type A flu viruses are currently classified into 13 distinct H subtypes and 9 distinct N subtypes, each of which requires a different vaccine to protect against infection. Thus the type A virus that caused the Hong Kong flu epidemic of 1968 has type 3 H molecules and type 2 N molecules, and is called A(H3N2).

HOW NEW STRAINS OF FLU ARISE
The problem in combating flu viruses arises not through mutation, but through recombination. Viral genes are readily reassorted by genetic recombination, sometimes putting together novel combinations of H and N spikes unrecognizable by human antibodies specific for the old configuration. Viral recombination of this kind seems to have been responsible for the three major flu pandemics (that is, world wide epidemics) that have occurred in this century, by producing drastic shifts in H N combinations. The "killer flu" of 1918, A(H1N1), killed 21 million people. The Asian flu of 1957, A(H2N2), killed over 100,000 Americans. The Hong Kong flu of 1968, A(H3N2), infected 50 million people in the United States alone, of which 70,000 died.

WHY FLU EPIDEMICS ARISE SO OFTEN IN ASIA
It is no accident that new strains of flu usually originate in the far east. The most common hosts for influenza virus are ducks, chickens, and pigs, which in Asia often live in close proximity to each other and to humans. Pigs are subject to infection by both bird and human strains of the virus, and individual animals are often simultaneously infected with multiple strains. This creates conditions favoring genetic recombination between strains, producing new combinations of H and N subtypes. The Hong Kong flu, for example, arose from recombination between A(H3N8) [from ducks] and A(H2N2) [from humans]. The new strain of influenza, in this case A(H3N2), then passed back to humans, creating an epidemic because the human population has never experienced that H N combination before.

THE "BIRD FLU"
A potentially deadly new strain of flu virus, A(H5N1), has emerged in the last few months, again in Hong Kong. Its arrival was greeted with unusual caution by scientists for two reasons. First, A(H5N1) represents a novel combination of H and N spikes, the sort of new combination that has in the past been associated with major flu epidemics. Second, unlike all previous instances of new flu strains, A(H5N1) passed to humans directly from birds, in this case chickens. A(H5N1) was first identified in chickens in 1961, and in the spring of 1997 devastated flocks of chickens in Hong Kong. The first human case of "bird flu" occurred in May, 1997, in a 3-year-old boy who died of the infection. The number of human infections by A(H5N1) remains small, with 17 confirmed cases by the end of the year. Five have died, and three more are in intensive care units, surviving with the aid of mechanical respirators.

Fortunately the bird flu virus does not appear to spread easily from person to person. Public health officials remain concerned that the genes of A(H5N1) could yet mix with those of a human strain to create a new strain that could spread widely in the human population. To prevent this, health officials have ordered the killing of all 1.3 million chickens in Hong Kong. Thousands of blood samples have been sent to the Center for Disease Control and other laboratories to determine the extent of the A(H5N1) infection among people, chickens and other animals in the Hong Kong area. Tests must be done carefully in high-level biosafety laboratories, as any one of the samples may contain infectious A(H5N1) virus.

CAN WE DEVELOP A VACCINE?
No decision has been taken to produce a vaccine directed against the bird flu virus. Such a vaccine will not be easy to produce, as the virus kills the chicken eggs usually used to mass-produce flu vaccines. One approach being contemplated is to produce the vaccine from a similar (but not egg-killing) strain isolated from ducks in Singapore in 1997. Public health scientists have injected the duck virus into laboratory ferrets, often used as test animals in flu research because they develop classic respiratory symptoms. Is the duck virus enough like bird flu that the ferrets develop antibodies that protect against A(H5N1)? It will take months to kno