Diversity and complexity of internally deleted viral genomes in influenza A virus subpopulations with enhanced interferon-inducing phenotypes

Authors: GHORBANI, AMIR - The Ohio State University; NGUNJIRI, JOHN - The Ohio State University; RENDON, GLORIA - University Of Illinois; BROOKE, CHRISTOPHER - University Of Illinois; KENNEY, SCOTT - The Ohio State University; Lee, Chang

Submitted to: Viruses
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/13/2023
Publication Date: 10/17/2023
Citation: Ghorbani, A., Ngunjiri, J.M., Rendon, G., Brooke, C.B., Kenney, S.P., Lee, C.W. 2023. Diversity and complexity of internally deleted viral genomes in influenza A virus subpopulations with enhanced interferon-inducing phenotypes. Viruses. 15(10):2107. https://doi.org/10.3390/v15102107.
DOI: https://doi.org/10.3390/v15102107

Interpretive Summary: Influenza A virus (IAV) consists of a highly diverse collection of genetically and biologically different subpopulations of viral particles. These subpopulations collectively impact the virus's evolutionary fitness. In the past, most particles in IAV populations were considered biologically insignificant since they could not be quantified using typical infectivity assays. However,since the identification of defective-interfering (DI) particles, which are incomplete virus particles that impede the replication of fully functional virus particles, the DI particles have been widely observed in laboratory-grown viruses and clinical samples. Recently, there has been growing interest in the therapeutic and immunogenic properties of DI particles. In this study, the diversity and complexity of the internally deleted IAV genomes were investigated among a panel of IAV that shows different immunological phenotypes. The study identified a heightened occurrence of internally deleted genomes with distinct junctions in viral clones exhibiting enhanced interferon-inducing phenotypes. Computational analyses suggest the internally deleted IAV genomes can encode a broad range of proteins with variable lengths and amino acid composition. Further research is warranted to explore the potential of diverse internal deletions and resulting proteins for modulating the cellular processes and immunity which may also affect the safety and effectiveness of live attenuated influenza vaccines.

Technical Abstract: Influenza A virus (IAV) populations harbor large subpopulations of defective-interfering particles characterized by internally deleted viral genomes. These internally deleted genomes have demonstrated the ability to suppress infectivity and boost innate immunity, rendering them promising for therapeutic and immunogenic applications. In this study, we aimed to investigate the diversity and complexity of the internally deleted IAV genomes within a panel of plaque-purified avian influenza viruses selected for their enhanced interferon-inducing phenotypes. Our findings unveiled that the abundance and diversity of internally deleted viral genomes were contingent upon the viral subculture and plaque purification processes. We observed a heightened occurrence of internally deleted genomes with distinct junctions in viral clones exhibiting enhanced interferon-inducing phenotypes, accompanied by additional truncation in the nonstructural 1 protein linker region (NS1D76-86). Computational analyses suggest the internally deleted IAV genomes can encode a broad range of carboxy-terminally truncated and intrinsically disordered proteins with variable lengths and amino acid composition. Further research is imperative to unravel the underlying mechanisms driving the increased diversity of internal deletions within the genomes of viral clones exhibiting enhanced interferon-inducing capacities and to explore their potential for modulating cellular processes and immunity.