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Mutating Virus Keeps Scientists Chasing SARS
By Matt Pottinger in Hong Kong and Antonio Regalado in New York
The lethal virus believed to cause SARS is mutating. How concerned should the world be?
To date, the virus behind severe acute respiratory syndrome has infected more than 7,000 people world-wide and killed more than 500. But it may get worse: Scientists in Hong Kong and elsewhere suspect two versions may already exist, and constant changes in the virus's genetic makeup could help it find new ways to infect people.
The research so far shows some mutations have already occurred. Scientists are watching such changes carefully because they may "help us see what direction the virus is evolving in," says Dennis Lo, associate dean for research at the Chinese University of Hong Kong's medical school and the leader of an effort to see if mutations are responsible for an outbreak of a more severe form of SARS at a Hong Kong apartment complex.
Mutability is a family trait among RNA viruses such as the coronavirus that scientists have pinpointed as the cause of SARS. Unlike viruses whose genes are made of DNA, such as the hepatitis B virus, coronaviruses are chemically less stable and therefore more prone to make errors as they replicate, causing mutations.
That could have a big impact on world-wide efforts to keep the disease under control. For one, an effective SARS vaccine could prove much harder to produce. HIV is an RNA virus, and its constant mutation is one of the key reasons an AIDS vaccine has remained elusive. Another concern is that the disease may become more virulent as it changes. SARS has already killed about one in five people hospitalized with the disease in Hong Kong, according to a study released this week.
That said, it is far from clear that SARS mutations are necessarily dangerous. In fact, mutations can sometimes make viruses less deadly. Ebola outbreaks, though fearsome, tend to burn out after three to four rounds of transmission because of changes in the virus.
But don't expect SARS to turn from a "tiger to a pussycat," says Earl Brown, a viral geneticist at the University of Ottawa. Dr. Brown published a study Friday in the Lancet, a British medical journal, saying that the virus's genome looks relatively stable overall, which would suggest the SARS virus is already well-adapted to humans.
Scientists may get a better idea of the threat posed by mutations in the SARS virus later this month, when laboratory results from a key study are expected. A research team at the Chinese University of Hong Kong is compiling genetic data from virus samples taken from people who caught SARS at Amoy Gardens, a crowded residential complex in Hong Kong's Kowloon district. Cases from Amoy Gardens, where about 300 people caught the disease, have on average been more severe than other clusters of cases, with a markedly greater proportion of patients who need intensive care and have diarrhea.
But the reasons behind the nastier symptoms remain a mystery, and health authorities have speculated on a variety of possible answers, including that the route of transmission at Amoy was different.
City health investigators say there is strong evidence the virus entered the Amoy apartments through faults in the sewage system. Minute droplets of virus-laden human waste may have then found their way into people's mouths as well as their lungs, which might explain why the disease is affecting Amoy patients' bowels. It might also be that fecal droplets carry a bigger load of the virus than typical respiratory droplets, which could aggravate symptoms. A third possibility is that people at Amoy Gardens have actually been simultaneously infected by another pathogen in addition to the coronavirus, although health officials say no evidence has yet been found of a co-infection.
Researchers in Hong Kong are now testing the most disturbing hypothesis: that the greater misery of Amoy Gardens patients stems from a new strain -- or strains -- of coronavirus. Chinese University's Dr. Lo says his team is planning to compare the genetic makeup of the virus in Amoy Gardens patients to the one in more mildly affected patients.
Already, Dr. Lo's team has found evidence of fast change in a key area of the SARS coronavirus: the protein spikes that give it its crown-like halo. Microbiologists believe the spikes are what allow the virus to attach itself to healthy human cells and to invade them.
The team's study of samples from 11 Hong Kong patients turned up four distinct variations in the RNA code of the spike gene. The virus in a group of seven people who caught the disease at Prince of Wales Hospital had one sequence, but it was different from the one in two patients who were infected at another hospital. Another patient, believed to have caught the disease in Shenzhen, just north of Hong Kong's border with mainland China, showed still another variation. Scientists now are tracking the changes as they happen: They found the spike gene had changed yet again in a Prince of Wales Hospital patient who caught the disease two weeks after the initial group of seven patients.
While the differences were found in only one or two chemical letters of the 4,000 or so that make up the spike gene, those changes are enough to alter the amino acids that can dictate what kind of tissue the virus infects. Indeed, past research on a type of coronavirus that infects pigs showed that similar variations in the spike were enough to change the virus from something that causes a gastrointestinal disorder into something that causes respiratory illness.
Similarly, the Hong Kong scientists may find it is a mutation in the spike gene of the SARS virus that allowed it to affect gastrointestinal cells as well as the lung, researchers theorize.
Even if the mutations don't have any biological effects, tracking them may help scientists reconstruct how the infection has traveled. Friday, Singapore scientists reported in the Lancet that they had found changes in the spike gene in people who acquired SARS at Hong Kong's Metropole Hotel, but not in other cases.
Scientists say it is urgent to understand how the virus is changing because that knowledge may point them to its Achilles' heel. With influenza, researchers use their detailed understanding of the bug's most variable regions to design new vaccines each year, as well as to monitor emerging avian versions. "This is a brand-new human virus, and it's fundamentally very important to know how it tries to persist," says Mark Denison, a Vanderbilt University professor who joins other virologists in a weekly conference call to discuss the outbreak.
Changes in the spike protein are also likely to hold the answer to the riddle of where SARS came from. If scientists can locate a similar virus in animals, they may be able to determine exactly what mutation permitted it to infect humans for the first time.
Write to Matt Pottinger at matt.pottinger@wsj.com and Antonio Regalado at antonio.regalado@wsj.com
Updated May 9, 2003 3:36 a.m.
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