Influenza Virus Reassortment Is Enhanced by Semi-infectious Particles but Can Be Suppressed by Defective Interfering Particles.

• Type of Material: Article
• Authors: Judith M. Fonville, University of Cambridge; Nicolle Marshall, Emory University; Hui Tao, Emory University; John Steel, Emory University; Anice Lowen, Emory University
• Language: English
• Date: 2015-10
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Fonville et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1005204
• Title of Journal or Parent Work: PLoS Pathogens
• ISSN: 1553-7366
• Volume: 11
• Issue: 10
• Start Page: e1005204
• End Page: e1005204
• Grant/Funding Information: National Institute of Allergy and Infectious Disease R01 AI099000 to ACL; National Institute of Allergy and Infectious Disease Centers of Excellence in Influenza Research and Surveillance (CEIRS), contract number HHSN272201400004C (to ACL and JS); Junior Research Fellowship from Homerton College Cambridge to JMF.; Award of a Fellowship in Biomedical Informatics from the Medical Research Council UK (MR/K021885/1) to JMF
• Research Categories: Biology, Virology; Health Sciences, Immunology

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.