Antiviral activity of influenza A virus defective interfering particles against SARS-CoV-2 replicationin vitrothrough stimulation of innate immunity

Abstract

SARS-CoV-2 causing COVID-19 emerged in late 2019 and resulted in a devastating pandemic. Although the first approved vaccines were already administered by the end of 2020, vaccine availability is still limited. Moreover, immune escape variants of the virus are emerging against which the current vaccines may confer only limited protection. Further, existing antivirals and treatment options against COVID-19 only show limited efficacy. Influenza A virus (IAV) defective interfering particles (DIPs) were previously proposed not only for antiviral treatment of the influenza disease but also for pan-specific treatment of interferon (IFN)-sensitive respiratory virus infections. To investigate the applicability of IAV DIPs as an antiviral for the treatment of COVID-19, we conducted in vitro co-infection experiments with produced, cell culture-derived DIPs and the IFN-sensitive SARS-CoV-2. We show that treatment with IAV DIPs leads to complete abrogation of SARS-CoV-2 replication. Moreover, this inhibitory effect was dependent on janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling. These results suggest an unspecific stimulation of the innate immunity by IAV DIPs as a major contributor in suppressing SARS-CoV-2 replication. Thus, we propose IAV DIPs as an effective antiviral agent for treatment of COVID-19, and potentially also for suppressing the replication of new variants of SARS-CoV-2.

Cell culture-based production of defective interfering influenza A virus particles in perfusion mode using an alternating tangential flow filtration system

“…The DIP-induced inhibition of STV replication is causative for their antiviral potential, previously demonstrated in mice (Dimmock et al 2008). Additionally, the antiviral effect of IAV DIPs against influenza B, pneumovirus and SARS-CoV2 was shown, likely mediated by an unspecific stimulation of the innate immune response (Easton et al 2011; Rand et al 2021; Scott et al 2011).…”

Semi-continuous propagation of influenza A virus and its defective interfering particles: analyzing the dynamic competition to select candidates for antiviral therapy

“…Notably, in mouse and ferret models, the administration of DIPs resulted in a pronounced antiviral effect against IAV infection (13,14,(23)(24)(25)(26). Furthermore, IAV DIPs also showed protection against heterologous interferonsensitive respiratory viruses (27,28), including SARS-CoV-2 (29), by the ability to stimulate innate immunity.…”

Exploring the therapeutic potential of defective interfering particles in reducing the replication of SARS-CoV-2

“…To this end, we extended the model proposed by Grebennikov et al in Ref. [21], which focused on the intra-cellular replication kinetics of SARS-CoV-2, to include co-infection with defective interfering particles, given their therapeutic potential [59,60]. In particular, we investigated the ability of DIPs to reduce WT viral load by competing for resources required to replicate or encapsulate the viral genome to form new virions.…”

“…These molecules are associated with activation of anti-viral cell states, which in turn lead to inhibition of viral replication and eventual viral clearance [64]. Furthermore, innate immune responses have been shown to be induced by DIP binding to PRRs, providing additional stimuli and magnifying the anti-viral cellular response [59]. As a consequence, it would, therefore be ideal to extend the proposed model to consider the role of an innate immune response.…”