Abstract
A high particle to infectivity ratio is a feature common to many RNA viruses, with ~90–99% of particles unable to initiate a productive infection under low multiplicity conditions. A recent publication by Brooke et al. revealed that, for influenza A virus (IAV), a proportion of these seemingly non-infectious particles are in fact semi-infectious. Semi-infectious (SI) particles deliver an incomplete set of viral genes to the cell, and therefore cannot support a full cycle of replication unless complemented through co-infection. In addition to SI particles, IAV populations often contain defective-interfering (DI) particles, which actively interfere with production of infectious progeny. With the aim of understanding the significance to viral evolution of these incomplete particles, we tested the hypothesis that SI and DI particles promote diversification through reassortment. Our approach combined computational simulations with experimental determination of infection, co-infection and reassortment levels following co-inoculation of cultured cells with two distinct influenza A/Panama/2007/99 (H3N2)-based viruses. Computational results predicted enhanced reassortment at a given % infection or multiplicity of infection with increasing semi-infectious particle content. Comparison of experimental data to the model indicated that the likelihood that a given segment is missing varies among the segments and that most particles fail to deliver ≥1 segment. To verify the prediction that SI particles augment reassortment, we performed co-infections using viruses exposed to low dose UV. As expected, the introduction of semi-infectious particles with UV-induced lesions enhanced reassortment. In contrast to SI particles, inclusion of DI particles in modeled virus populations could not account for observed reassortment outcomes. DI particles were furthermore found experimentally to suppress detectable reassortment, relative to that seen with standard virus stocks, most likely by interfering with production of infectious progeny from co-infected cells. These data indicate that semi-infectious particles increase the rate of reassortment and may therefore accelerate adaptive evolution of IAV.
Highlights
The influenza A virus (IAV) genome comprises eight segments of negative sense RNA, each of which encode at least one essential viral protein [1,2]
It has long been known that a large proportion of the virus particles that influenza and many other RNA viruses produce are not fully infectious, but the biological significance of these particles has remained unclear
Despite their limited potential to produce progeny viruses, these incomplete particles may play an important role in viral evolution
Summary
The influenza A virus (IAV) genome comprises eight segments of negative sense RNA, each of which encode at least one essential viral protein [1,2]. This genome structure supports the generation of viral diversity through two major mechanisms: genetic drift due to an error prone viral polymerase, and exchange of gene segments between viruses through reassortment [3]. Reassortment is highly prevalent among avian and swine IAVs and has been implicated repeatedly in the emergence of epidemically significant human strains [reviewed in 4]. The potential for reassortment to purge the viral genome of deleterious changes and bring together multiple beneficial mutations makes it a powerful catalyst of viral evolution [12]
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