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Will the D225G Mutation Herald More Severe Illness in Patients with 2009 H1N1 Influenza?

By Amesh A. Adalja, MD, December 11, 2009

To date, the H1N1 influenza A pandemic has been one of the mildest on record. Although millions of people have been infected, relatively few have become severely ill or died. Nonetheless, scientists have been looking for evidence of a mutation that might cause the virus to become more lethal. Recently, a mutation was found in a few isolates.

D225G Mutation Detected

On November 20, 2009, officials in Norway announced the discovery in 3 patients of isolates that contained a mutation in the hemagglutinin gene, which resulted in a change from aspartic acid to glycine at the 225 amino acid position of the hemagglutinin surface glycoprotein. This D225G mutation (also referred to as D222G using a different numbering system) affects host binding site specificity of the virus and is worrisome because of its potential for causing severe disease.1,2 This mutation was also present in the virus that caused the 1918 H1N1 pandemic.

Altered Binding Specificity May Cause More Severe Disease

Influenza viruses bind to respiratory cells via sialic acid molecules that are on cell surfaces. Most human influenza viruses preferentially bind to sialic acid residues linked by alpha 2,6 bonds—the predominant type found in the upper respiratory tract. Alpha 2,3 bonds, which are the target of avian influenza viruses, are located primarily in the lower respiratory tract of humans, which explains the high incidence of severe pneumonia in patients with H5N1 avian influenza. The D225G mutation confers the ability of an influenza virus to bind to the alpha 2,3-containing cells in the lower respiratory tract, which would be expected to lead to a more serious infection. However, it is believed that this heightened ability to bind to lower respiratory tract cells may diminish the transmissibility of the virus, even as it may cause more severe disease, as is the case with H5N1 infection.2,3

Some Viruses Containing D225G Have Caused Fatal and Severe Illness in Norway

The Norwegian isolates first reported to contain the D225G mutation were discovered in specimens taken from 2 fatal cases and 1 severe case of influenza. There appears to be no epidemiological link among the 3 Norwegian patients, suggesting that each isolate represents an independent mutation. There has been no evidence of transmission of the mutated virus.1

D225G Mutations Have Been Found in Other Countries

A number of severe cases of respiratory disease in Ukraine have been reported by the World Health Organization (WHO), and the D225G mutation was found in isolates from some of these cases.4,5 WHO reports that this mutation also has been observed in Brazil, China, Chinese Taipei, Finland, France, Italy, Japan, Mexico, Spain, and the U.S.. Interestingly, though, the mutation has been found in patients with both mild and severe cases of influenza.6

Tracking D225G and Confirming Associated Disease Manifestations Is Crucial

The presence of the D225G mutation has been noted in several different geographic areas—including the U.S.—presumably due to independent spontaneous mutations.7 As the current pandemic continues, case control studies of patients with this mutation will be essential to confirm the severity of associated clinical disease. While still rare, this mutation, like the mutation associated with oseltamivir resistance, and the Shanghai mutation [see CBN Report for July 17, 2009], illustrates the constantly changing nature of the influenza virus, which always has the potential to mutate into a more severe pathogen.


  1. ProMED-mail. Influenza pandemic (H1N1) 2009 (111): Norway, mutants. November 11, 2009.
    . Accessed December 5, 2009.

  2. Stevens J, Blixt O, Tumpey TM, et al. Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Science 2006;312:404-410.

  3. Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus. Update on avian influenza A (H5N1) virus infection in humans. N Engl J Med 2008;358:261–273.

  4. WHO. Pandemic (H1N1) 2009, Ukraine. November 1, 2009. Accessed December 6, 2009.

  5. Recombinomics. All fatal Ukraine cases at GISAID have RBD D225G. November 19, 2009. Accessed December 6, 2009.

  6. WHO. Pandemic (H1N1) 2009-update 77. Accessed December 8, 2009.

  7. Recombinomics. 1918 RBD D225G in lung cases in the United States. November 23, 2009. Accessed December 6, 2009.