Broad-Spectrum Antiviral Activity of Influenza A Defective Interfering Particles against Respiratory Syncytial, Yellow Fever, and Zika Virus Replication In Vitro

Abstract

New broadly acting and readily available antiviral agents are needed to combat existing and emerging viruses. Defective interfering particles (DIPs) of influenza A virus (IAV) are regarded as promising options for the prevention and treatment of IAV infections. Interestingly, IAV DIPs also inhibit unrelated viral infections by stimulating antiviral innate immunity. Here, we tested the ability of IAV DIPs to suppress respiratory syncytial, yellow fever and Zika virus infections in vitro. In human lung (A549) cells, IAV DIP co-infection inhibited the replication and spread of all three viruses. In contrast, we observed no antiviral activity in Vero cells, which are deficient in the production of interferon (IFN), demonstrating its importance for the antiviral effect. Further, in A549 cells, we observed an enhanced type-I and type-III IFN response upon co-infection that appears to explain the antiviral potential of IAV DIPs. Finally, a lack of antiviral activity in the presence of the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib was detected. This revealed a dependency of the antiviral activity on the JAK/signal transducers and activators of transcription (STAT) signaling pathway. Overall, this study supports the notion that IAV DIPs may be used as broad-spectrum antivirals to treat infections with a variety of IFN-sensitive viruses, particularly respiratory viruses.

Generation of “OP7 chimera” defective interfering influenza A particle preparations free of infectious virus that show antiviral efficacy in mice

“…For instance, mice were rescued from a lethal dose of influenza B virus and pneumonia virus of mice by DIP co-administration 38 , 41 . In addition, we demonstrated a pronounced antiviral effect against SARS-CoV-2 37 and against respiratory syncytial, yellow fever and Zika virus replication in vitro 42 . Such broad protective immunity against many different unrelated viruses was also observed for dengue and poliovirus DIPs 24 , 56 .…”

“…DIP co-infections also result in a strong induction of the interferon (IFN) system 35 – 38 , and it was shown that this stimulation of the innate immunity also contributes to their antiviral effect 25 , 26 , 35 , 37 . As a consequence, IAV DIPs display a broad-spectrum antiviral activity that is not only directed against a wide range of IAV strains 16 , 21 , 25 , 39 , 40 , but even against unrelated viruses, including SARS-CoV-2 37 , 38 , 41 , 42 .…”

Defective viral genomes: advances in understanding their generation, function, and impact on infection outcomes

“…Deletion DVGs identified from dengue ( Flaviviridae ), Sindbis ( Togaviridae ), and influenza virus ( Orthomyxovidae ) DIPs all showed potent IFN stimulation ( 105 – 107 ). One engineered deletion DVG from poliovirus ( Picornaviridae ) also induced strong IFN responses ( 108 ).…”

Production of antiviral “OP7 chimera” defective interfering particles free of infectious virus

“…Simultaneously, they strongly stimulate the interferon (IFN)-induced antiviral activity against IAV infections (Frensing et al 2014 ; Huo et al 2020 ; Penn et al 2022 ). Furthermore, this unspecific innate immune response stimulation can also suppress replication of unrelated viruses including severe acute respiratory syndrome coronavirus (SARS-CoV-2) (Easton et al 2011 ; Pelz et al 2023 ; Rand et al 2021 ; Scott et al 2011 ). Previously, we discovered a new type of IAV DIP named “OP7”.…”