Mutations I117V and I117M and Oseltamivir Sensitivity of Pandemic (H1N1) 2009 Viruses

Aeron C. Hurt

, Sook Kwan Leang, David J. Speers, Ian G. Barr, and Sebastian Maurer-Stroh

Author affiliations: World Health Organization Collaborating Centre for Reference and Research on Influenza, North Melbourne, Victoria, Australia (A.C. Hurt, S.K. Leang, I.G. Barr); PathWest Laboratory Medicine, Nedlands, Western Australia, Australia (D.J. Speers); Agency for Science, Technology and Research, Singapore (S. Maurer-Stroh); Ministry of Health, Singapore (S. Maurer-Stroh); Nanyang Technological University, Singapore (S. Maurer-Stroh)

Abstract

Analysis of mutations I117V and I117M in the neuraminidase of influenza A pandemic (H1N1) 2009 viruses showed that I117V confers a mild reduction in oseltamivir sensitivity and has a synergistic effect of further increasing resistance when combined with H275Y. Contrary to recent reports, the I117M mutation does not alter oseltamivir sensitivity.

The neuraminidase inhibitors (NAIs) oseltamivir and zanamivir have been widely used in many countries to treat infection with influenza A pandemic (H1N1) 2009 virus. Since the start of the pandemic, >27,000 strains have been tested for oseltamivir resistance, of which 383 (1.4%) have contained the H275Y neuraminidase (NA) mutation, the same mutation that was found in oseltamivir-resistant prepandemic seasonal subtype H1N1 viruses that emerged in 2007–08. Apart from the H275Y mutation, a small number of other NAI resistance mutations have been detected in the NA of pandemic (H1N1) 2009 viruses, such as S247N (1), I223V (2), and I223R (3). Another NA mutation, I117M, has also recently been associated with oseltamivir resistance in pandemic (H1N1) 2009 viruses (4,5). The I117M NA mutation was detected in a virus from South Korea that was isolated from a patient before oseltamivir treatment and then was detected, with the H275Y mutation, in the same patient after oseltamivir treatment, although the dual mutations were not conclusively shown in the same virus (4,5). In both studies, neither the I117M variant nor the dual I117M + H275Y strain were specifically tested for oseltamivir resistance. Instead, the viruses were assumed to be resistant on the basis of previous studies that described a reduction in oseltamivir sensitivity in influenza A (H5N1) viruses because of an I117V amino acid substitution (6,7), rather than the I117M substitution detected in their studies.
Other studies have documented that different amino acid substitutions at key NA residues can cause considerably different effects on NAI susceptibility and that these mutations can have a variable effect in different NA backgrounds (8). Therefore, we tested the assumption that the I117M mutation confers oseltamivir resistance and investigate the role of the I117M and the I117V mutations with and without the H275Y mutation in pandemic (H1N1) 2009 viruses.