The Global Emergence and Evolution of Adamantane Resistant A/H3N2 Influenza Viruses

Session I – Nelson, Martha, Young Investigator Applicant

Title of Contribution: The Global Emergence and Evolution of Adamantane Resistant A/H3N2 Influenza Viruses
Author(s): Martha Nelson1, Lone Simonsen2, Mark A. Miller1, Edward C. Holmes1,3, Cecile Viboud1
Affiliation(s): 1. Fogarty International Center, National Institutes of Health, 2. George Washington University, 3. The Pennsylvania State University

Abstract:
Resistance to the adamantane class of antiviral drugs by human A/H3N2 influenza viruses has increased dramatically in recent years, from a global prevalence of < 2% prior to 2002 to 12.3% in 2004, and currently > 90% in the United States and multiple Asian countries (Deyde et al. 2007).  In most cases, adamantane resistance is associated with a single amino acid change (S31N) in the M2 gene, which encodes for the viral ion channel.  Increasing resistance to adamantane drugs was first observed in Asia, with the prevalence in China rising from ~8% in 2002 to ~74% in 2004, but resistance quickly spread worldwide in 2005 in association with a major reassortment event (Simonsen et al. 2007).   However, the genesis and evolution of influenza viruses carrying the S31N mutation prior to the 2005 reassortment event has not been characterized to date, particularly in South-East Asia.  To understand the emergence of adamantane resistance within the context of the global evolutionary dynamics of the influenza A virus and the evolution of the key antigenic proteins, we conducted a large-scale phylogenetic analysis of the HA, NA, and M segments of viral isolates collected from 1997-2007 from three localities that are broadly representative of the global ecology of influenza:  temperate localities in the Northern hemisphere (New York State, 505 isolates) and Southern hemisphere (New Zealand/Australia, 624 isolates) and a tropical locality in South-East Asia (Hong Kong, 281 isolates).  Although we find that the S31N mutation was independently introduced multiple times in all three locations between 1997-2007, the vast majority of resistant viruses all descend from a single introduction that was first detected in Hong Kong in the summer of 2003.  Whereas all other S31N introductions exhibited little spread, this critical introduction persisted in Hong Kong throughout 2003-2004, allowing for its reassortment with a novel HA in the early spring of 2005 and its rapid global dissemination.  In demonstrating how adamantane resistance first emerged in Hong Kong and persisted throughout a period when adamantane sensitive viruses were dominant globally, this study further supports the proposed sink-source model of global influenza virus evolution, in which South-East Asia supports continuous viral activity and greater genetic diversity that repeatedly seeds epidemics in temperate areas (Russell et al. 2008; Rambaut et al. 2008).  Additional sequencing of influenza viruses from South-East Asia is greatly needed to further understand the genesis of adamantane resistance in this critical region, as well as role of South-East Asia in the evolutionary dynamics of seasonal influenza A virus in general.