Epidemiologic study of human influenza virus infection in South Korea from 1999 to 2007: origin and evolution of A/Fujian/411/2002-like strains

Abstract

Influenza epidemics arise through the accumulation of viral genetic changes, culminating in a novel antigenic type that is able to escape host immunity. Following an outbreak of the A/Fujian/411/2002-like strains in Asia, including China, Japan, and South Korea, in 2002, Australia and New Zealand experienced substantial outbreaks of the same strains in 2003, and subsequently worldwide outbreaks occurred in the 2003-2004 season. The emergence of A/Fujian/411/2002-like strains coincided with a higher level of influenza-like illness in South Korea than what is seen at the peak of a normal season, and there was at least a year's difference between South Korea and the United States. Genetic evolution of human influenza A/H3N2 viruses was monitored by sequence analysis of hemagglutinin (HA) genes collected in Asia, including 269 (164 new) HA genes isolated in South Korea from 1999 to 2007. The Fujian-like influenza strains were disseminated with rapid sequence variation across the antigenic sites of the HA1 domain, which sharply distinguished between the A/Moscow/10/1999-like and A/Fujian/411/2002-like strains. This fast variation, equivalent to approximately 10 amino acid changes within a year, occurred in Asia and would be the main cause of the disappearance of the reassortants, although the reassortant and nonreassortant Fujian-like strains circulated simultaneously in Asia.

FIG. 1.

Weekly influenza epidemic time series. (A) Influenza virus isolates in South Korea over the period from 2000 to 2007. Different subtypes are shown in different gray shades. (B) Epidemics in South Korea and United States. The y axis shows influenza-like illness over the period from 2000 to 2007. (C) Proportions of influenza viruses A/H1N1, A/H3N2, and B in South Korea (KOR) and the United States in each season. Unsubtyped influenza A viruses of the United States were assumed to have proportions identical to those of subtyped ones.

FIG. 2.

Phylogenetic analysis and amino acid substitutions of HA of influenza A/H3N2 viruses circulating in South Korea from 1999 to 2007. (A) The maximum parsimony tree. Reference vaccine strains are highlighted in gray. Six 2009 strains from the United States and the Philippines are combined. Amino acid substitutions in major clades are described under the internal branches, and the substitutions to extant lineage are highlighted in bold. Only one representative strain is presented (in bold) along with the number of identical strains when there were more than two strains having identical amino acid sequences. Numbers in parentheses under group names indicate the number of isolates in that group. (B) Locations of the amino acid substitutions that were found in major clades on an HA structure model (Protein Data Bank [PDB] identification no. 1HA0).

FIG. 3.

Maximum likelihood (ML) phylogenies reconstructed by PhyML program to identify the Fujian reassortants in Asia from 2002 to 2004. The clade A strains shown in Fig. 1 of reference were used for the reference sequences of reassortants. The closely related nonreassorted strain of clade A, A/NewYork/406/2002, is marked as a gray dot on the ML trees. The node support values for reassortant clades were estimated using an approximate likelihood ratio test incorporated in PhyML (1). (A) ML tree of HA1 nucleotide sequences of 637 Asian strains, 30 New York strains, and A/Moscow/10/1999 as a phylogenetic root. The Fujian/411 clade is shown, and the branch marked by a circle indicates a reassortant clade. (B) The reassortant clade shown in panel A. (C) ML tree of neuraminidase (NA) nucleotide sequences of 161 Asian strains, 30 New York strains, and two outgroup strains (A/NewYork/313/1998 and A/NewYork/328/1998). (D) The reassortant clade shown in panel C.

FIG. 4.

Maximum likelihood (ML) trees and timeline of the emergence of the A/Fujian/411/2002 strain. Both trees are rooted by A/Moscow/10/1999. (A) The ML tree of HA1 domain nucleotide sequences of 521 human influenza A/H3N2 virus strains isolated worldwide from 2001 to 2002. The circle indicates the locations of the strains for the further analysis shown in panel B. (B) The ML tree of 53 strains around the emergence of the Fujian/411 strain. Two vaccine strains isolated in 2004 and A/Moscow/10/1999 as a root were included. The earliest isolates of the clades are highlighted in bold. The amino acid changes are described under the internal branches. (C) Timeline of the appearance of A/Fujian/411/2002 in Asia. The earliest day of each clade is described under the timeline.