Now that India has been spared the initial wrath of the avian flu virus, you may breathe a sigh of relief. Chicken is back on the dinner plate and stories on bird flu have been relegated to the inside pages of newspapers. But seasoned microbiologists have little to rejoice about, for they know that the threat of avian flu is here to stay. The virus, H5N1, has already shown that it can be deadly to people who come into direct contact with infected birds or eat uncooked poultry. The worst fear is that the virus will soon begin to swap genes with its human counterpart and turn itself into a more lethal form, transmissible from human to human, triggering a once-in-a-century catastrophe.

What makes influenza such a fearsome virus? Why is it called the ultimate master of disguise? How does it wreak havoc on the fittest human immune system? Essentially, the influenza virus is highly elusive and has evolved over millions of years. Like any other virus it is caught between the world of the living and non-living. But the greatest danger it poses arises from the fact that it’s airborne and is capable of entering the body via the throat or lungs. Unlike other infections such as polio (spreads in the water) or HIV (spreads through body fluids), flu viruses spread by aerosols, which are dispersed as particles through air.

“Influenza, like some other viruses (such as HIV), carries its genetic information as ribonucleic acid or RNA,” Prof. J.S. Malik Peiris, a microbiologist from the University of Hong Kong, told KnowHow in an exclusive interview. Peiris was the scientist who discovered severe acute respiratory syndrome (SARS) in 1997 and the highly lethal H5N1 six years later. Unlike viruses that are made of deoxyribonucleic acid (DNA), such as smallpox, the primordial RNA viruses mutate fast, generating many new variants each time they invade a cell. Each infected cell bears hundreds of thousands of offspring, each subtly different and competing against one another for survival. “The high mutation rate allows the virus to keep changing and stay one step ahead of the immune system of birds, pigs, cats or humans,” added Peiris.

Spiky pin cushion

An influenza virus measures just about 100 nanometres (one thousand-millionth of a metre) and resembles a spiky pin cushion under the microscope. The spikes that stick out of the pin cushion are pieces of two key proteins, neuraminidase (N) and haemagglutinin (H), the most destructive weapons in the virus’ arsenal. The H protein helps the virus invade the cells in the throat (in birds it’s the digestive tract), while the N protein allows viral progeny to chop their way out of infected cells. In fact, the H protein has an amazing ability to unlock the cells of the host animal. It latches onto the receptors on the surface of the host’s cells, which are duped to believe that the enemy is a hormone or a protein. On the other hand, the N protein slices through newly-made bits of viruses so that it’s freed from the host cell and is ready to spread to the rest of the body. Anti-viral drugs like oseltamivir (Tamiflu) and zanamivir (Relenza) target this protein. “However, drugs become ineffective when a virus like H5N1 changes its genetic makeup,” says Dr T.N. Naik, deputy director of the National Institute of Cholera and Enteric Diseases in Calcutta. “Tamiflu-resistant strains of the virus have already been reported in Vietnam,” he adds.

There are nine types of N and 16 types of H, making it possible to create 144 possible flu strains. However, only three have so far made it to humans. “Just like the current strain, which has the pattern H5N1, the earlier pandemics had thrown up H1N1 (1918), H2N2 (1957) and H3N2 (1968),” notes Dr Penmetcha K.R. Kumar, a senior researcher at the National Institute of Advanced Industrial Science and Technology (AIST) at Tsukuba in Japan. Even a single mutation that causes a slight change in H or N, called antigenic drift, can be significant, allowing the virus to acquire a completely new outer coat.

The antigenic drift makes the virus a master of disguise. “This is why every now and then a flu virus appears with surface proteins so different that our immunity to past infections does not offer any protection,” says Peiris. “The changeable nature is also the reason we can’t produce a perfect vaccine (that lasts long) as we don’t know exactly what form the virus will take,” he adds. “In addition, we have shown that the H5N1 virus across Asia is not a homogeneous entity. There are many variants of the virus. So we may have to innovate more than one candidate H5N1 vaccine.”

What makes the virus replicate so fast and produce such swarms of variants? It’s the primitive and error-prone genetic machinery that helps the virus reproduce vigorously and evolve so fast. Unlike a sophisticated DNA virus, it makes small mistakes when it makes copies of its own genes. In fact, these errors produce enormous variations, particularly on the spikes of the protein. Such variant strains fight among themselves and Darwinian selection favours the strongest and the most resistant strain, which eventually becomes transmissible. “Influenza has its genetic information in eight segments rather than in a continuous strand,” says Naik. “This allows different influenza virus from different species to rearrange, recombine and swap genes among themselves.”

Reshuffling genes

The ability to swap genes helps the virus to survive and adapt to different species. “Many related influenza viruses circulate in animal and bird populations, especially from chickens, ducks, turkeys, pigs, horses and humans,” says Prof. Subhash Chandra Parija, the head, department of microbiology, Jawaharlal Institute of Post-Graduate Medical Education and Research, Pondicherry. “All the previous influenza virus causing epidemics were combinations of the avian and human influenza virus. The recombination that occur in pigs can be most dangerous because pigs have receptors for both avian and human flu virus,” adds Parija. Virologists believe that unhygienic pigsties in south-east Asia could provide a launch pad for a human flu pandemic.

According to Peiris, the reshuffling of genes of viruses across species can create the most dangerous hybrid flu from H5N1. “When this happens, you may have a new virus with a brand new disguise (comprising H and N) and the human population will have no immunity at all to fight it off,” Peiris says. A pandemic may begin only when such hybrid influenza begins to spread from human to human. “Although this virus has still not acquired the ability to transmit from human to human, it certainly has the potential to do so. That is how the three pandemics of the last century arose. We will certainly have such pandemics this century too,” he says.