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Marvellous mutants: how nimble flu viruses outsmart drugs

Mutations of the flu virus render drugs ineffective for treating infected patients. Leonid Mamchenkov

The United Nations Food and Agricultute Organisation is warning authorities to be on high alert after a mutant strain of bird flu was found to be spreading across Asia. While bird flu hasn’t traditionally spread easily to humans, it’s know to be very virulent, killing half of the 600 people infected since it was first detected in 2003.

Fortunately in Australia we don’t have the highly pathogenic bird flu known as A(H5N1), although many of us of course experience colds and sniffles as a result of other influenza A viruses during the winter months.

Influenza accounts for over 300,000 general practitioner consultations and over 18,000 hospitalisations in a typical year in Australia.

Man vs flu

While most people are aware that the influenza vaccine prevents infection, many don’t know about the antiviral drugs available for either treatment or short-term prevention of influenza infection in both children and adults.

These antivirals can be particularly useful during a pandemic (a worldwide epidemic caused by the introduction of a new influenza A virus into the human population).

More specifically, they can play a key role during the period while a new vaccine is being made.

The most common class of influenza antiviral drugs is known as neuraminidase inhibitors (NAIs), and includes Tamiflu (oseltamivir) and Relenza (zanamivir).

NAIs are designed to inhibit the neuraminidase, a spike on the surface of the influenza virus that plays a key role in infection. These inhibitors fit precisely into a cavity on top of the neuraminidase, mimicking how a key fits into a lock.

Once locked in, the inhibitors block its function and reduce the capacity of the virus to multiply and spread from cell to cell. But genetic mutations in the virus lead to changes in the cavity of the neuraminidase, altering the shape of the “lock” so the inhibitors no longer fit as well.

Some mutations in the neuriminidase can cause such large changes in the shape of the cavity that drugs may bind very poorly. This can result in the virus becoming drug resistant and the NAIs becoming ineffective for treating a patient infected with this virus.

Other mutations can cause smaller changes in the shape of the “lock” so the “key” only partially fits and the drug’s effectiveness is reduced but not completely eliminated.

Resistance becomes fertile

Before 2007, resistance to neuraminidase inhibitors was rare.

Even more importantly, of the influenza viruses that were resistant, the majority had impaired fitness as a result of the altered shape of their neuraminidase cavity. (“Fitness” is used to describe the ability of the virus to multiply, replicate and spread.)

In other words, the mutation that was causing resistance was at the same time affecting the ability of the neuraminidase to function normally and restricting viral fitness.

This was the ideal scenario because the resistant viruses that emerged from time to time in individual patients were unlikely to spread widely throughout the community.

But this human-friendly state of affairs was about to be challenged.

The head of four neuraminidase molecules with their cavities in red. Jason Roberts. Jason Roberts

The plot thickens

In early 2008, laboratories in Europe began reporting an increasing frequency of resistance to Tamiflu in the influenza subtype A(H1N1), due to a neuraminidase mutation called H275Y.

In Norway, the frequency of resistance in tested influenza viruses had increased from the normal level of less than 1%, to more than 70%. That means 70 out of 100 A(H1N1) viruses circulating in Norway at the time were resistant to Tamiflu.

Relenza, due to its different chemical structure to Tamiflu, remained effective.

Laboratories throughout Europe rapidly tested influenza viruses within their countries and demonstrated retrospectively that the resistant virus had emerged in late 2007 and spread throughout Europe within just a few months.

It didn’t take long for this virus to spread to the southern hemisphere – first to South Africa and then South-East Asia, Australia and New Zealand.

By the end of the 2008 southern hemisphere winter – a mere nine months after the resistant virus first emerged in Europe – it had spread so widely that almost all of the circulating A(H1N1) viruses detected worldwide were resistant to Tamiflu.

Significantly, this virus didn’t conform to the accepted viral behaviour theory - not only was it resistant but its mutation didn’t appear to affect its ability to multiply and spread in humans.

This Tamiflu-resistant virus continued to circulate globally during late 2008 and early 2009, but its fate was about to change.

Saved by the pandemic?

In April 2009, the world experienced the first influenza pandemic of the 21st century with the emergence of a new influenza A strain that apparently crossed from pigs into the human population – the swine flu.

The new pandemic strain, called “A(H1N1)2009” was of the same influenza subtype as the “seasonal A(H1N1)” Tamiflu-resistant virus, but it was a very different beast.

In past pandemics (1957 and 1968), the newly-emerged pandemic strain out-competed the previously circulating influenza A strain, driving the “older” virus into history.

And fortunately, the same was about to occur in the 2009 pandemic. In less than a year, the new pandemic A(H1N1)2009 virus had “out-muscled” the Tamiflu-resistant seasonal A(H1N1) virus from human circulation.

It’s impact was such that the earlier resistant strain is now virtually extinct. And since then, resistance has been detected in only a few circulating influenza strains.

But the experience of the rapid spread of the “fit” Tamiflu resistant A(H1N1) strain in 2008 raises concerns about this scenario being repeated in the now widely circulating pandemic A(H1N1)2009 strain.

Recent analysis of viruses from the Asia-Pacific region during the early months of 2011 found that more than a third of pandemic A(H1N1)2009 strains from Northern Australia and more than a tenth in Singapore contained a new neuraminidase mutation, called S247N.

Importantly, the S247N mutation has a relatively mild effect on the binding of Tamiflu, compared to the large effect of the previous H275Y mutation.

Nevertheless, the mutation had modified the shape of the “lock” and while it’s expected that the inhibitors will remain effective, any additional mutations may mean that at least one of the “keys” may no longer work.

Of greater concern is the very recent detection of pandemic A(H1N1)2009 strains with the highly resistant H275Y mutation in community cases in the region of Newcastle, New South Wales.

At this stage, the resistant virus has been detected in 14% of the pandemic A(H1N1)2009 strains from the Newcastle area.

So now scientists in Australia and around the world are actively monitoring both the movement drug-resistant human influenza viruses and new mutant bird flu strains. It seems there’s never a quiet day in the world of influenza.

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