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Monday, June 7, 2010


A ProMED-mail post

ProMED-mail is a program of the
International Society for Infectious Diseases

Date: Fri 4 Jun 2010
Source: Reuters Health News [edited]

Researchers reported on Thursday [3 Jun 2010] that 2 extra mutations
set the stage for the seasonal influenza virus to evolve into a form
that now resists 3 of the 4 drugs designed to fight it. Their study,
published in the journal Science, provides a way for scientists to
keep an eye out for dangerous mutations in new flu viruses, including
the ongoing pandemic of H1N1 swine flu [influenza pandemic (H1N1)
virus infection].

Only 4 drugs are on the market to treat flu and 2, the adamantines,
are useless against virtually all circulating strains because the
viruses have evolved resistance. Tamiflu, known generically as
oseltamivir, is the current drug of choice. It comes as a pill. An
inhaled drug that works in a similar manner is called Relenza, or
zanamivir generically. Both can help reduce flu symptoms if taken
quickly and can keep the most vulnerable patients out of the hospital,
or keep them alive if they are severely ill. But 2 years ago the
common circulating strain of seasonal H1N1 developed resistance to

Doctors were surprised, because the mutation that help the virus evade
the effects of Tamiflu also usually made it a weak virus that did not
infect or spread well. "People have known about this H274Y mutation
[in the neuraminidase protein] for over a decade, but the mutation
seemed to interfere with the virus's ability to replicate and be
transmitted," Jesse Bloom of the California Institute of Technology
[Caltech], who led the study, said in a statement. "Something happened
to make the Tamiflu-resistant virus also capable of replicating and
spreading like wild-type flu viruses."

Bloom and Dr David Baltimore, an expert on AIDS and on the genetic
functions of cells and viruses at Caltech, led a study to find out how
this happened. They found that 2 other mutations in the virus allowed
it not only to evade the effects of Tamiflu but also to survive and
spread. In addition, the mutations took place before the 3rd and final
mutation allowing the virus to evade the drugs. This means that
scientists can monitor flu viruses for the initial 2 mutations to give
early warning that they are about to become drug resistant.

This is important in planning for both seasonal influenza and
pandemics. Seasonal flu kills between 250 000 and 500 000 people every
year globally. H1N1 'swine' flu [influenza pandemic (H1N1) virus
infection] may have been just slightly more deadly -- statistics will
take years to gather -- but it affects younger adults and children in
contrast to seasonal flu, which kills more elderly people. Currently
'swine flu' is easily treated by Tamiflu but that could change at any
time. So doctors need drugs on hand to save lives and if one drug will
be useless, they need to know that because flu must be treated within
days of onset for treatment to be useful.

Earlier on Thursday [3 Jun 2010] the World Health Organization said
the H1N1 pandemic was not yet over although its most intense activity
has passed in many parts of the world.

Communicated by:

[The following is the abstract of the paper in Science referred to in
the preceding Reuters report

Bloom JD, Gong LI, Baltimore D (California Institute of Technology,
Pasadena, CA): Permissive Secondary Mutations Enable the Evolution of
Influenza Oseltamivir Resistance. Science. 2010 Jun 4; 328(5983):
"The His274 --- >Tyr274 (H274Y) mutation confers oseltamivir
resistance on N1 influenza neuraminidase but had long been thought to
compromise viral fitness. However, beginning in 2007/2008, viruses
containing H274Y rapidly became predominant among human seasonal H1N1
isolates. We show that H274Y decreases the amount of neuraminidase
that reaches the cell surface and that this defect can be counteracted
by secondary mutations that also restore viral fitness. Two such
mutations occurred in seasonal H1N1 shortly before the widespread
appearance of H274Y. The evolution of oseltamivir resistance was
therefore enabled by "permissive" mutations that allowed the virus to
tolerate subsequent occurrences of H274Y. An understanding of this
process may provide a basis for predicting the evolution of
oseltamivir resistance in other influenza strains."

The following commentary accompanies the paper above (Holmes EC.
Science. 2010 Jun 4; 328(5983): 1243-4;

"The evolution of antiviral drug resistance sounds like a simple
Darwinian story. The high mutation rate that characterizes RNA viruses
ensures that drug-resistant mutations are generated continuously, and
the global use of antivirals provides the selection pressure for these
mutations to sweep through viral populations. In some cases, however,
reality is more complex. The mutations that confer antiviral
resistance may have a detrimental effect on viral fitness in the
absence of the drug so that secondary fitness-restoring mutations must
occur to enable the large-scale spread of resistance. More puzzling,
drug resistance can also occur in the absence of the main agent of
selection -- the widespread use of antiviral drugs. Both of these
evolutionary conundrums are apparent in one of the most important
cases of antiviral resistance in recent years -- the global spread of
resistance to oseltamivir in seasonal H1N1 influenza A virus. Bloom et
al. (above) show that in a "permissive" genetic background, seasonal
H1N1 virus avoids the fitness costs normally associated with
oseltamivir resistance."

The mutations which have favoured the spread of oseltamivir resistance
in seasonal (H1N1) influenza virus fortunately have yet to appear in
the pandemic strain of H1N1 influenza virus (or any other N1 type
influenza virus as far as is known), but their recognition may
encourage a more cautious approach to the use of Tamiflu and Relenza.
- Mod.CP]

[see also:
Influenza A (H1N1) - worldwide (85): Tamiflu resistance, Japan 20090706.2429
Influenza A (H1N1) - worldwide (84): Tamiflu resistance, China (HK)
Influenza A (H1N1) - worldwide (78): Tamiflu resistance, DK 20090630.2359
Influenza A(H1N1) virus, oseltamivir resistance (02): N.Hemisphere
Influenza A(H1N1) virus, oseltamivir resistance: Korea 20090113.0136
Influenza virus, oseltamivir resistance (06): Japan 20080228.0812
Influenza A (H1N1) virus, oseltamivir resistance (05): China (HK)
Influenza A (H1N1) virus, oseltamivir resistance (03): corr. 20080203.0430
Influenza A (H1N1) virus, oseltamivir resistance (04): CA, USA 20080202.0428
Influenza A (H1N1) virus, oseltamivir resistance (03): Europe 20080201.0399
Influenza A (H1N1) virus, oseltamivir resistance (02): Europe 20080129.0371
Influenza A (H1N1) virus, oseltamivir resistance - Norway 20080128.0361
Avian influenza, human (162): oseltamivir resistance 20061010.2907
Avian influenza, human (155): Thailand, Indonesia 20060927.2757 2005]
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