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Molecular Explanation For The Evolution Of Tamiflu Resistance
Date: 2010-06-15   Read: 146503

Molecular Explanation For The Evolution Of Tamiflu Resistance

Biologists at the California Institute of Technology (Caltech) have pinpointed molecular changes that helped allow the global spread of resistance to the antiviral medication Tamiflu (oseltamivir) among strains of the seasonal H1N1 flu virus.

The study - led by David Baltimore, Caltech's Robert Andrews Millikan Professor of Biology and recipient of the 1975 Nobel Prize in Physiology or Medicine, and postdoctoral scholar Jesse D. Bloom - appears in the June 4 issue of the journal Science.

Tamiflu and other antiviral drugs directly target viruses, unlike vaccines, which instead stimulate our body's immune system to respond to the pathogens after an infection is established.

In a flu infection, viruses bind to sialic acid on the surface of a host cell using a protein called hemagglutinin (the "H" in H1N1). The viruses then enter the cell and replicate. When the newly minted viruses exit the cell, they too bind to sialic acid. The viruses then use a protein called neuraminidase (the "N" in H1N1) to cut the sialic acid, freeing themselves to infect new cells.

This process, however, is blocked by Tamiflu, which prevents neuraminidase from cleaving the sialic acid. "It does this by binding in the 'active site' of the neuraminidase molecule, where neuraminidase normally cleaves sialic acid," Bloom says.

In general, for a virus to become resistant to Tamiflu, the neuraminidase protein has to be able to tell the difference between sialic acid (the thing it cleaves) and Tamiflu (the drug "decoy").

Such recognition is possible in viruses that have a mutation, known as H274Y, in the neuraminidase protein. The mutation swaps out one amino acid for another at a particular location on the neuraminidase protein, producing a slight conformational change in a crucial region of the protein's three-dimensional structure. "Once that happens," Bloom says, "the neuraminidase no longer strongly binds to Tamiflu, and it is still able to cleave sialic acid."

"People have known about this H274Y mutation for over a decade," he adds, "but the mutation seemed to interfere with the virus's ability to replicate and be transmitted. The molecular basis for that interference was not clear, but it seemed that the H274Y viruses weren't of great clinical significance."

However, during the 2007-2008 flu season, resistant H1N1 viruses with the H274Y mutation began cropping up all over the world. By the following year, essentially all seasonal H1N1 flu viruses suddenly were resistant to Tamiflu because of the mutation.

The only difference: They now were growing just as well as regular viruses.

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Adapted from materials provided by Medical News TODAY



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