The role of genomics in tracking the evolution of influenza A virus

Abstract

Influenza A virus causes annual epidemics and occasional pandemics of short-term respiratory infections associated with considerable morbidity and mortality. The pandemics occur when new human-transmissible viruses that have the major surface protein of influenza A viruses from other host species are introduced into the human population. Between such rare events, the evolution of influenza is shaped by antigenic drift: the accumulation of mutations that result in changes in exposed regions of the viral surface proteins. Antigenic drift makes the virus less susceptible to immediate neutralization by the immune system in individuals who have had a previous influenza infection or vaccination. A biannual reevaluation of the vaccine composition is essential to maintain its effectiveness due to this immune escape. The study of influenza genomes is key to this endeavor, increasing our understanding of antigenic drift and enhancing the accuracy of vaccine strain selection. Recent large-scale genome sequencing and antigenic typing has considerably improved our understanding of influenza evolution: epidemics around the globe are seeded from a reservoir in East-Southeast Asia with year-round prevalence of influenza viruses; antigenically similar strains predominate in epidemics worldwide for several years before being replaced by a new antigenic cluster of strains. Future in-depth studies of the influenza reservoir, along with large-scale data mining of genomic resources and the integration of epidemiological, genomic, and antigenic data, should enhance our understanding of antigenic drift and improve the detection and control of antigenically novel emerging strains.

Figure 1. Schematic representation of an influenza A virion.

Three proteins, hemagglutinin (HA, a trimer of three identical subunits), neuraminidase (NA, a tetramer of four identical subunits), and the M2 transmembrane proton channel (a tetramer of four identical subunits), are anchored in the viral membrane, which is composed of a lipid bilayer. The large, external domains of hemagglutinin and neuraminidase are the major targets for neutralizing antibodies of the host immune response. The M1 matrix protein is located below the membrane. The genome of the influenza A virus is composed of eight individual RNA segments (conventionally ordered by decreasing length, bottom row), which each encode one or two proteins. Inside the virion, the eight RNA segments are packaged in a complex with nucleoprotein (NP) and the viral polymerase complex, consisting of the PA, PB1, and PB2 proteins.

Figure 2. Generation of genetic diversity and antigenic drift in the evolution of human influenza A viruses.

Blue and yellow viruses depict two antigenically similar strains of the same subtype circulating in the human population. The genetic diversity of the circulating viral population increases through mutation and reasssortment. Single white arrows indicate relationships between ancestral and descendant viruses. White marks on the segments indicate neutral mutations and red marks indicate mutations that affect the antigenic regions of the surface proteins. Incoming pairs of orange arrows indicate the generation of reassortants with segments from two different ancestral viruses. As these viruses continue to circulate, immunity against them builds up in the host population, represented here by the narrowing of the bottleneck. In parallel, viruses with mutations affecting the antigenic regions of the surface proteins accumulate in the viral population. At some point a novel antigenic drift variant, indicated by a red colored virus, which is less affected by immunity in the human population, is generated. This variant is able to cause widespread infection and founds a new cluster of antigenically similar strains.