Molecular Epidemiology of H5N1 Avian Influenza Virus: Correlations between Antigenic Drift, Geographical Migration and Expansion of Viral Diversity

Abstract

Background: H5N1 highly pathogenic avian influenza virus (H5N1-HPAIV) has seriously impacted poultry industries. Nevertheless, the evolutionary and epidemiological dynamics of H5N1-HPAIV were not fully understood. Methods: Maximum likelihood (ML) phylogenetic tree was reconstructed using hemagglutinin (HA) genes of 1266 H5N1-HPAIV isolates in 1996—2007, to study the global viral epidemiology in avian population. By enforcing the molecular clock, an evolutionary time-scale for worldwide H5N1-HPAIV was established, and was utilized to estimate the rate of HA antigenic drift and viral migratory history in the last decade, using ML joint method and parsimony optimization method respectively. The viral genetic diversity over time was estimated using Bayesian coalescence method. Since all these estimations were grounded on the real time-scale, their temporal correlations could be assessed. Results: Our analyses suggest H5N1-HPAIV first emerged in China in 1995—1996. The occasions of viral dispersions from China to Thailand, Vietnam, Indonesia, and other Asian and European countries temporally coincided with the rapid expansion of global H5N1 viral genetic diversity which started in 2001—2002. The HA antigenic drift rate of H5N1-HPAIV circulating in China remained slow, at 0.1—0.2 amino acid substitutions on 25 antigenic sites per total amino acid substitutions (a.t.) throughout 1998—2007. In contrast, the drift rates were high (0.5—0.3 a.t.) when the H5N1-HPAIV initially emerged in Indonesia, Thailand and Vietnam in 2001—2003, but gradually declined to 0.1—0.2 a.t. when the virus progressed to endemic maintenance after 1—2 years following the invasion. Conclusions: The temporal coincidence of viral dispersions between countries and expansion of global H5N1 genetic diversity suggests the geographical spread might expand the ecological niche and species distribution for H5N1-HPAIV. Furthermore, our study suggests that the mutations on antigenic epitopes of H5N1-HPAIV are essential for their adaptation and immune evasion in bird populations, particularly at the early stage of invasion.