Implications of segment mismatch for influenza A virus evolution

Abstract

Influenza A virus (IAV) is an RNA virus with a segmented genome. These viral properties allow for the rapid evolution of IAV under selective pressure, due to mutation occurring from error-prone replication and the exchange of gene segments within a co-infected cell, termed reassortment. Both mutation and reassortment give rise to genetic diversity, but constraints shape their impact on viral evolution: just as most mutations are deleterious, most reassortment events result in genetic incompatibilities. The phenomenon of segment mismatch encompasses both RNA- and protein-based incompatibilities between co-infecting viruses and results in the production of progeny viruses with fitness defects. Segment mismatch is an important determining factor of the outcomes of mixed IAV infections and has been addressed in multiple risk assessment studies undertaken to date. However, due to the complexity of genetic interactions among the eight viral gene segments, our understanding of segment mismatch and its underlying mechanisms remain incomplete. Here, we summarize current knowledge regarding segment mismatch and discuss the implications of this phenomenon for IAV reassortment and diversity.

Keywords: evolution; evolutionary constraint; influenza A virus; packaging; reassortment; segment mismatch.

Fig. 1.

The influenza A virus genome. (a) Schematic diagram of the IAV genome, with the eight RNA genomic segments organized according to size from largest to smallest. (b) Arrangement of the IAV genome within a virus particle, demonstrating the ‘7+1’ pattern of the eight viral segments as observed via transmission electron microscopy performed by Noda et al. One central segment is surrounded by seven outer segments. However, the identity of the segments arranged in this pattern, as well as the precise interaction network between the segments, remains unknown. The glycoproteins present on the viral membrane have been removed for clarity.

Fig. 2.

Reassortant influenza A viruses can have suboptimal RNA and/or protein interactions. During IAV evolution, the genomes and proteins of an individual strain co-evolve alongside one another, resulting in optimal interactions (a and b). During reassortment, the genomes of the two co-infecting strains are mixed. This can result in suboptimal interactions between the genomic segments and/or encoded proteins, leading to viruses that are less fit compared to the parental strains (c).

Fig. 3.

Manifestations of segment mismatch during the influenza A virus life cycle. When two different IAVs co-infect the same cell, their genomes mix, resulting in the genomic assembly of viral ribonucleoprotein complexes (vRNPs) from either the same virus (as shown in blue) or from different viruses (as shown in blue and orange). The interactions that occur between segments, most likely at the packaging signal regions (dotted lines between coloured rectangles), might be optimal when segments originate from the same parental virus, thus facilitating packaging. Conversely, these interactions might be suboptimal or non-existent (black x’s) between heterologous segments due to nucleotide differences, and thus formation of these progeny genotypes would be restricted due to RNA mismatch. Protein mismatch manifests later, after reassortant viruses have budded from the host cell and go on to infect new cells. Incompatibilities between polymerase subunits or HA-NA proteins, among others, can prevent the successful formation of progeny viruses, resulting in an abortive infection. Proteins and RNAs are shown with the same colour for clarity; however, in co-infected cells, proteins derived from co-infecting viruses are thought to mix.