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Will Tamiflu save the world from the avian flu?

 

Joe Magliocca

Joe Magliocca

No one wants to catch the flu! At the very least, it will put you out of commission for a week, and it can also cause ResearchBlogging.org life-threatening infections – pneumonia is the most common, although other bacterial diseases like bronchitis are common too. Most people don’t think about problems with secondary infections after catching the flu, but a deadly form of the flu could be just around the corner.

The H5N1 “avian” flu is highly deadly among birds, and it has occurred in humans. Most people who contract the avian flu have had direct contact with infected birds. Fortunately, H5N1 does not appear to spread from human to human, but what if mutations occur in the virus that allow this to happen?

The 2009 H1N1 “swine” flu reminded us of the potential for flu pandemics that cross over to humans from other animals.

Based on its severity in birds and in the humans who have been infected, an H5N1 pandemic could be far more deadly than the H1N1 pandemic; it could kill a significant percentage of the world’s population! For example, in the 1918 flu pandemic, about 5% of the world’s population died. Based on the virulence of H5N1 in birds, it’s predicted that a higher percentage of humans would die as a result of a H5N1 human pandemic, although this is, of course, conjecture. In support of this conjecture, however, is the fact that 63% of the humans who have been infected with H5N1 have died (Hurt et al.).

antiviral compounds

Antiviral compounds

Fortunately Tamiflu (Oseltamivir) and a related drug, Relenza (Zanamivir), reduce the severity of the flu if they are given when the flu symptoms initially appear. But will the drugs be effective forever?

Seventy years ago, antibiotics such as penicillin seemed like miracle drugs. But now bacteria are evolving to become resistant to antibiotics, in part because the antibiotics have been overprescribed. Could the same thing occur with antivirals as they become used more frequently? It is a possibility.

Mutations, changes in the genetic code of an organism, occur rapidly in the influenza virus. Most mutations are harmful to the virus, but a few are beneficial (and, therefore, potentially harmful to humans). A mutation could occur in an influenza virus that allows it to resist the effects of Tamiflu and Relenza. Such a virus would then grow much more rapidly than a nonresistant form in the presence of the drugs.

To understand how Tamilflu and Relenza function and how the virus might become resistant to them, we need a little background on the life cycle of the flu virus. When an unsuspecting victim inhales a flu virus, a protein on the surface of the virus called hemagglutinin (the ‘H’ in H1N1, for example) binds to a receptor called sialic acid on the surface of cells in the respiratory tract (see structure of sialic acid in picture above).

Influenza life cycle

Influenza life cycle

The cell takes in the virus, which then replicates inside the host cell. The newly formed viruses leave the cell by budding off the surface. The hemagglutinin on the new viruses can then bind to the sialic acid on the surface of other host cells, thus infecting new cells. For this to occur, however, the viruses need to escape the host cells. Another viral surface protein, neuraminidase (the ‘N’ in H1N1, for example), breaks down the sialic acid receptors so the viruses can escape.

Tamiflu and Relenza are structurally similar to sialic acid and will bind to the neuraminidase, but they cannot be broken down. Therefore, neuraminidase cannot bind to sialic acid on the cell surface when it has Tamiflu or Relenza bound to it. Because they prevent neuraminidase from functioning, the two drugs are collectively referred to as neuraminidase inhibitors (NAIs). When NAIs are present, some of the newly produced virus will get stuck to the original host cell and will not be able to infect other cells.  Some viruses will still escape, so NAIs don’t cure the flu but rather reduce its severity.

Are NAI-resistant viral mutants forming? Studies have identified a few flu viruses that are resistant to these drugs. A very dedicated (and patient) group of scientists (Monto et al.) grew up a whopping 2287 samples of flu virus that were collected from all over the world during the first three years (1999-2002) the drugs were prescribed. They grew these samples in the presence of each of the two NAIs. While the vast majority of the viruses were not resistant to the drugs, a few samples were. Resistance was determined by measuring the concentration of the drug needed to inactivate each virus. These results were concerning; however, another team of scientists (Yen et al.) studied two NAI-resistant flu mutants and found that they were not as contagious nor as fit as the non-resistant strains.

Ferrets

Ferrets used in nasal washes

Yen et al. (2005) also showed that the virus didn’t grow as well in vitro, and they measured how well the virus grew in an in vivo model. In those studies, three ferrets were infected with the virus: two with the mutant strains and one with a wild type (not mutated) virus.

After two days, each ferret was put into close contact with two other ferrets. Each day after exposure, the researchers took nasal washes of each ferret and quantified the amount of virus in the wash. (I wonder if there is a neti pot for ferrets.)

Neti Pot

Net pot for sinus infection

The washes showed that less virus was produced by the two resistant mutants. In fact, one of the ferrets exposed to a mutant virus was less contagious. Other studies have found this to be the case with the most resistant flu virus mutants. That is, the more resistant the flu virus is to an NAI, the less virulent is the virus.

However, exceptions were found in a further study by Yen et al. in 2006, where they found two mutants that were resistant to the drugs but still grew relatively well, which is more concerning. While these mutants did not appear naturally (they were designed by the lab) they could, in principle, occur in nature.

None of these studies looked at the H5N1 avian flu directly, but because the drug-resistant viruses were found over a wide variety of strains, there is potential for an H5N1 mutant that is resistant to Tamiflu and Relenza. Fortunately the drug-resistant mutants are usually less fit, so an H5N1 NAI-resistant mutant might not be as deadly. It appears that Tamiflu and Relenza would help reduce the impact of an H5N1 pandemic. However, we must monitor the virus for resistant mutants.

References:

Silver, G. (2003) The treatment of influenza with antiviral drugs. Canadian Medical Association Journal 168 (1), 49–57.

Monto, A., McKimm-Breschkin, J., Macken, C., Hampson, A., Hay, A., Klimov, A., Tashiro, M., Webster, R., Aymard, M., Hayden, F., & Zambon, M. (2006). Detection of Influenza Viruses Resistant to Neuraminidase Inhibitors in Global Surveillance during the First 3 Years of Their Use Antimicrobial Agents and Chemotherapy, 50 (7), 2395-2402 DOI: 10.1128/AAC.01339-05

Yen, H., Herlocher, L., Hoffmann, E., Matrosovich, M., Monto, A., Webster, R., & Govorkova, E. (2005). Neuraminidase Inhibitor-Resistant Influenza Viruses May Differ Substantially in Fitness and Transmissibility Antimicrobial Agents and Chemotherapy, 49 (10), 4075-4084 DOI: 10.1128/AAC.49.10.4075-4084.2005

Hurt, A., Holien, J., & Barr, I. (2009). In Vitro Generation of Neuraminidase Inhibitor Resistance in A(H5N1) Influenza Viruses Antimicrobial Agents and Chemotherapy, 53 (10), 4433-4440 DOI: 10.1128/AAC.00334-09

Yen, H., Hoffmann, E., Taylor, G., Scholtissek, C., Monto, A., Webster, R., & Govorkova, E. (2006). Importance of Neuraminidase Active-Site Residues to the Neuraminidase Inhibitor Resistance of Influenza Viruses Journal of Virology, 80 (17), 8787-8795 DOI: 10.1128/jvi.00477-06