By David N. Leff

A sixth victim of Hong Kong bird flu died Thursday.

The 25-year-old woman had contracted the avian virus infection before Hong Kong health authorites, in late December, oversaw the slaughter of more than 1.5 million chickens and other fowl populating the island territory.

Besides the six deaths, the avian influenza virus has infected another 16 or 17 human Hong Kong inhabitants, but no new cases have arisen since the extermination of the domestic bird population last month.

Chinese chickens and ducks are the traditional origin of avian-type flu, which typically infects humans only after genetic passaging and mutating in an intermediate mammalian host, such as swine. The fact that the present mini-outbreak in Hong Kong apparently passed directly from birds to people is worrying influenza-watchers worldwide. They fear a possible global influenza pandemic, such as the one that killed 21 million people in 1918. (See BioWorld Today, March 21, 1997, p. 1.)

Since then, most people have known "the flu" as a relatively mild seasonal contagion, scarcely worse than a bad cold, although children and the elderly are urged to get annual flu shots in advance of the late fall and early winter peak of the viral appearance.

Influenza's sniffles, sore throat, cough, painful breathing, stomach upset and general feeling of washout usually spread from person to person via exhaled breath, sneezing and other transfer of respiratory fluids. Some say that going to bed with half a bottle of whiskey will shake the flu symptoms in a week, but otherwise it may hang on for seven days.

Virologist Kanta Subbarao is chief of the Molecular Genetics Section in the Influenza Branch of the Centers for Disease Control and Prevention (CDC), in Atlanta. "Normally," she told BioWorld Today, "the avian influenza viruses that infect birds have their replication limited to the gut and/or respiratory epithelium.

"This infectivity," she explained, "requires the cleavage of hemagglutinin, a protein on the surface of the viral envelope. Host-cell enzymes, similar to trypsin proteases, carry out this cleavage. They are present only on the gut and epithelium of the viral target organism."

Highly pathogenic strains of the flu virus cause severe systemic sickness, and frequently death, because of a variation in their genome. In such killer viruses, Subbarao pointed out, "a genomic motif, or sequence pattern, has been observed adjacent to that cleavage site. It expresses multiple amino acids, which increase the range of proteases that can cleave the hemagglutinin. These non-trypsin-like enzymes are present on cells throughout the body, so the result is a systemic, rather than local, viral infection of vital organs."

Researchers Characterize First Victim's Virus

Subbarao in first author of an article in today's Science, dated Jan. 16, 1998. Its title: "Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness."

That child was a three-year-old Hong Kong boy, who came down with a sore throat, dry cough and high fever on May 9, 1997. Antibiotics and aspirin had no effect, and six days later he was hospitalized with what was diagnosed as acute respiratory distress syndrome.

The first death from Hong Kong bird flu, he died on May 21 with severe systemic complications, including respiratory and kidney failure, blood coagulation problems and postmortem cerebral signs of Reye's syndrome, which often follows acute viral infection.

Since then, Subbarao and her co-authors at the CDC have been "looking closely at each of the human isolates to determine whether viral reassortment has taken place," she said, "and we are going to maintain a heightened surveillance to see if any other cases emerge."

Specifically, she continued, the reassortment search involves "actually looking at each of the gene segments on every patient isolate that we receive, to determine if they are human influenza genes or avian."

As the Science paper reports, the team sequenced every gene that codes for proteins on the viral surface, and some partial ones below the surface.

Subbarrao and her colleagues "are still concerned about the possibility of genetic reassortment [reshuffling] between this avian H5 virus and human influenza viruses that are currently circulating in Hong Kong."

"We think," she added, significantly, "that contrary to the traditional view, perhaps an intermediate host would not be required for such a reassortment to occur — that it could possibly take place in a human rather than, for instance, a pig."

A Vaccine Or Else . . .

Given the time lag of many months that slows the development of flu vaccines to meet the annual viral reassortment, the CDC team hopes to play a different card altogether.

"What we are most optimistic about, and almost hopeful about," Subbarao said, "is to find a surrogate avirulent virus that would not cause disease in poultry or in humans, but that is antigenically related enough to the Hong Kong human isolates to provide protection against this danger. So there is a search on for a candidate surrogate strain. If something materializes, that would be used as a vaccine strain.

"That 'something,'" she went on, "is what the avian influenza virologists are spearheading. They're using their global network to look for candidates. It would probably be from a bird species," Subbarao surmised, "because we're looking for an H5 virus, which typically is seen in birds."

Should the H5N1 Hong Kong flu virus begin to spread human-to-human, for lack of a chicken vector, pending discovery and production of a vaccine, mankind would not be entirely defenseless, as it was in the 1918 pandemic.

Two potent antiviral compounds are specifically effective against the Hong Kong flu virus. "We established very early on," Subbarao recalled, "even with that first case, the first isolate, that the virus is susceptible to rimantidine and amantidine, which are available antivirals. We have not conducted sensitivity studies with some of the neuraminidase inhibitors that are in development, but I assume some of the other groups that are working with the virus have done so."

A subhuman worry also exists, as a commentary accompanying the Science paper observed: "If a human were to carry the flu back from Hong Kong, it could be devastating to U.S. poultry." *