CDC guidelines for antiviral therapy for swine flu infection:
This swine influenza A (H1N1) virus is sensitive (susceptible) to the neuraminidase inhibitor antiviral medications zanamivir and oseltamivir. It is resistant to the adamantane antiviral medications, amantadine and rimantadine. (CDC)
What are these antiviral drugs and how do they work? Over the years here we’ve discussed this pretty often, so I went back and retrieved one of our older posts (from 2007). I’ve done some editing but it’s pretty much the same as when I wrote it about bird flu. Same principles.
Oseltamivir (which we will call by its trade name, Tamiflu) belongs to a class of flu antivirals called neuraminidase inhibitors. Neuraminidase (NA) is a protein that acts like an enzyme (it catalyzes a specific biochemical reaction) and it is present on the virus in the form of a glycoprotein, one of the two glycoproteins that stud the viral surface (for more on the basics of glycoproteins in lay language see our series that starts here). The other glycoprotein is hemagglutinin (HA). There are 9 immunologically distinct classes of NA and 16 of HA and the specific HA/NA combination of these types are what distinguish the various influenza A subtypes named for them (e.g., H1N1, H3N2 or H5N1). These are also the main elements that our own immune systems recognize and it is the HA glycoprotein that is the basis for the current seasonal influenza vaccines (some newer experimental vaccines are now using other viral proteins).
The HA protein plays an important role at two critical points in viral infection of a host cell. The first comes when it binds to a host cell receptor of the right kind. Currently we believe the main receptor is something called a sialylglycan (we have discussed details in the glycoprotein series linked above). Once docked to the receptor the virus is “taken into” the cell by being enveloped by the cell’s membrane in a process called endocytosis. Think of a closed bag of liquid you push a small stone into the side of, making an indented pocket with a sort of “neck” to the outside. Now pinch off the neck part so that the stone is now inside the bag surrounded by its own little piece of the bag wall. It still isn’t really inside the bag yet because of the surrounding coating of bag wall, but if it could get through that it would be bathed by the liquid in the bag and truly “inside.” That’s what the virus needs to do because it requires to give its genetic material access to the cell’s genetic and protein-making machinery so it can make copies of itself, its only real function. HA takes part in this process, too, helping the virus “fuse” with the surrounding little bit of bag wall and exit from its internal bubble into the cell proper. In addition, there is a viral protein (M2, called an ion channel protein) that allows the virus to “uncoat” and release the genetic material in more or less naked form (I say more or less because the genetic material is complexed with three other proteins but free of its viral coat). An older class of viral drugs, the adamantane class (amantadine and rimantadine) works by inhibiting the M2 protein and preventing the internalized virus from exposing its genetic material for us by the host cell’s protein making and replication machinery. The current swine flu virus is completely resistant to the adamantane drugs.
But it is sensitive the the neuraminidase inhibitors that involve NA, not HA. After the virus makes copies of its genetic material and its various parts all is fully assembled again at the inside cell surface and then budded from the outside surface of the host cell. But it is stuck to the service by the same HA that enabled its entrance, so it has to be cut loose from the same sialylglycans it used to attach, on entry. That is what NA does. Neuraminidase inhibitors like Tamiflu work by decreasing NA function, making it hard for them to exit after budding at the surface (I’m simplifying, so see the original post if you want more gory details about the complications; for most people this is already too much).
Antiviral drugs like Tamiflu and Relenza (generic name zanamivir) work because they look like the sialylglycan the virus is trying to find for its initial attachment, acting like decoy host cell receptors. The drugs bind in a chemical recognition site, a sort of “pocket” on the NA glycoprotein. In order for the drug to bind, there must be a fairly specific set of attachment points in the pocket and this is determined by the sequence of amino acids that make up the NA protein. which in turn is determined by the genetic sequence in the viral RNA. So if that genetic material changes (a mutation) it can alter the attachment points the drug needs and produce an NA that no longer binds the drug.
That’s the back story of antiviral drug resistance. The bottom line, as published officially by CDC last night is this:
Since April 21, 2009, CDC has reported cases of respiratory infection with a swine-origin influenza A (H1N1) virus (S-OIV) that is being spread via human-to-human transmission (1). As of April 28, the total number of confirmed S-OIV cases in the United States was 64; these cases occurred in California (10 cases), Kansas (two), New York (45), Ohio (one), and Texas (six). The viruses contain a unique combination of gene segments that had not been reported previously among swine or human influenza viruses in the United States or elsewhere (1). Viruses from 13 (20%) of 64 patients have been tested for resistance to antiviral medications. To date, all tested viruses are resistant to amantadine and rimantadine but are susceptible to oseltamivir and zanamivir. (Morbidity and Mortality Weekly Report Dispatch, Update: Drug Susceptibility of Swine-Origin Influenza A (H1N1) Viruses, April 2009)
Now you know a little more what this means.