By Kilian Robinson
Amidst the coronavirus pandemic many people have looked towards vaccines to gain some hope that one day we may be able to control this disease. Yet, there may be other potential ways of treating and preventing coronavirus. One such potential solution is the antiviral action of interferons and how they can be utilised in the fight against COVID-19.
Interferons are categorised as cytokines which are a small group of proteins that are used in cell signalling and immune responses. One example of a group of cytokines are interleukins which promote the proliferation and differentiation of T, B and other hematopoietic cells, thus playing important roles in immunity (Fitzgerald & Bryant, 2009). However, we will be focusing on another group of cytokines concerned with the defence against viruses: Type 1 Interferons (α & β).
(Figure 1 – IFN-β from humans. It consists of a dimer with molecules A and B are held together by metal coordination involving Zinc. The molecule also possesses significant glycolisation (Karpusas et al, 1997))
Following translation, interferons activate Jak-STAT pathways, which can also be used by a variety of other cytokines and growth factors (Sen,2001). These pathways are named due to their incorporation of Janus kinases (Jak), signal transducers and activators of transcription (STAT) (Biomart, 2020). Type 1 interferons bind to interferon receptors in the cell membrane causing a subsequent cascade which eventually results in the phosphorylation of STAT1 and other transcription factors which are used to express Interferon stimulated genes (ISGS). The proteins produced then interfere with viral replication (Lam, 2020).
Interferons themselves can block viral replication in two other ways: prevention of the initiation of translation and the induced deterioration of viral mRNA (Voet and Voet, 2020). The prevention of translation happens as follows: Interferons induce the production of ‘eIF2α dsRNA activated protein kinase’ (aka PKR) which, on binding to dsRNA (which is only present due to viral infection), dimerizes and phosphorylates itself (Voet and Voet, 2012). Consequently, PKR is activated and phosphorylates the initiation factor eIF2α which inhibits subsequent ribosomal translation due to a confirmational change (Ashwathi,2020).
Interferons also activate another enzyme named 2’-5’ oligoadenylate synthetase which is, like PKR, activated by the binding of viral dsRNA. When this synthetase is activated, it activates yet another preexisting endonuclease, namely RNase L. Production of RNAse L facilitates the degradation of viral mRNA preventing viral protein synthesis (Voet and Voet, 2020).
Viruses have evolved various mechanisms in order to protect themselves from the inherent antiviral function of mammalian cells. Transcriptomic evaluation of SARS-CoV-2 in infected bronchial epithelial cells showed a reduced IFN1 (Interferon type 1) response perhaps implying that this pathway has a significant impact on SARS-CoV-2 proliferation. Indeed, more studies seem to confirm that IFN-1 responses are heavily impaired within individuals with severe COVID-19 (Lee,2020). Although the use of type 1 interferons may therefore seem promising, conflicting studies hinder its projection to be used as a drug. Experiments done by Lee (2020) suggest a robust IFN1 response is still exhibited during infection. The current interpretation of these contradictory data is that the presence of the IFN-1 response is dependent on the stage of infection and sampling at different points of infection may clarify this (Lee, 2020).
We have previously used other antiviral drugs in conjunction with interferon β in the treatment of past coronaviruses such as MERS and SARS. A combination of lopinavir/ritonavir and ribavirin presented a ‘modest’ antiviral response in vitro against SARS (Cheng,2004). Additionally, investigation into the use of the same combination in marmosets implied that Lopinavir/ritonavir may work synergistically with interferon β (Chan, 2015). Consequently, it may seem sensible then to use similar treatments due to their close phylogenetic relationship. However, SARS-CoV 2 is still very different to SARS and MERS. For example, the peak viral load is reached at significantly different times for each virus: SARS-COV 2 reaches its peak viral load at the occurrence of symptoms, whereas SARS and MERS show theirs at approximately 7-10 days in from initial infection (To, 2020). This has implications for therapeutics as the timing of antiviral treatment is critical in the attempt to reduce viral load (Goncalves, 2020). Infact, the use of IFNα against SARS-CoV-2 at a late stage of infection actually increased mortality and delayed recovery (Wang,2020). Variability in the time to reach peak viral load is best opposed by using a multitude of drugs in unison. A study in the lancet showed that early treatment with a triple combination of lopinavir-ritonavir, ribavirin and IFN β was ‘highly effective’ in reducing viral load in patients with mild to moderate COVID-19, with emphasis on the fact that the triple combination with IFN β was ‘superior’ to lopinavir-ritonavir alone (Hung,2020).
As with any experiment there were several limitations to this study. Critically ill patients were absent and since timing of antiviral treatment is paramount, this study doesn’t exactly explain whether interferon β is effective against covid-19 in general, just that a notable reduction in viral load was recorded in mild-moderate patients. Moreover, upon peer review the effectiveness of Lopinavir/ritonavir is questionable as they seem to assume its effective as a result of close relation to other coronaviruses and ribavirin induces quite significant adverse effects.
In conclusion, we can deduce that interferon β does influence coronaviruses and this too applies to SARS-CoV2, yet due to the lack of data justifying the use of interferon β we cannot deduce that its combination with lopinavir/ritonavir and ribavirin, would be effective. Investigation into the use of interferon β will need to be explored and scrutinized further by many scientists before we can make any judgements on whether interferon β can truly be used against SARS-COV2.
Karpusas et al. (1997) Schematic representation of the crystallographic dimer of huIFN-β. Available at: The crystal structure of human interferon β at 2.2-Å resolution | PNAS [Accessed 22/11/2020]
Bryant, C. Fitzgerald, K. A. (2009) Molecular mechanisms involved in inflammasome activation. Trends in Cell Biology.Volume 19, Issue 9, Pages 455-464, ISN 0962-8924. Available at: http://www.sciencedirect.com/science/article/pii/S096289240900138X [Accessed 19/11/2020]
Sen, G. C. (2001) Viruses and Interferons. Annual Review of Microbiology. Volume 55, Page 255-281. Available at: Viruses and Interferons | Annual Review of Microbiology (annualreviews.org) [Accessed 19/11/2020]
Ashwathi P. (n.d) Interferons: Meaning, Production and Applications. Available at: Interferons: Meaning, Production and Applications (biologydiscussion.com) [Accessed 19/11/2020]
Biomart (n.d) Interferon JAK/STAT Signaling Pathway Available at: Interferon JAK/STAT Signaling Pathway – Creative BioMart [Accessed 19/11/2020]
Hung et al. (2020) Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Available at: Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial – The Lancet [Accessed 19/11/2020]
Lee, J. S., Shin, E. C. (2020) The type 1 interferon response in COVID-19: implications for treatment. Available at: The type I interferon response in COVID-19: implications for treatment | Nature Reviews Immunology [Accessed 21/11/2020]
Melo et al. (2020) Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. Volume 181, Issue 5, Pages 1036-1045, ISN 0092-8674. Available at: Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19 – ScienceDirect [Accessed 20/11/2020]
Lam, S., Lombardi, A., Ouanonunou COVID-19: A review of the proposed pharmacological treatments. European Journal of Pharmacology. Volume 886, 2020, 173451, ISN 0014-2999. Available at: COVID-19: A review of the proposed pharmacological treatments – ScienceDirect [Accessed 21/11/2020]
Chan et al. (2015) Treatment With Lopinavir/Ritonavir or Interferon- β1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset. The Journal of Infectious Diseases, Volume 212, Issue 12, Pages 1904-1913. Available at: Treatment With Lopinavir/Ritonavir or Interferon-β1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset | The Journal of Infectious Diseases | Oxford Academic (oup.com) [Accessed 20/11/2020]
Chu, C. M., Cheng, V. C. C., Hung I. F. N. et al. (2004) Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. Volume 59, Issue 3, Pages 252 – 256. Available at: Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings | Thorax (bmj.com) [Accessed 20/11/2020]
Gonçalves, A. et al. (2020) Timing of Antiviral Treatment Initiation is Critical to Reduce SARS-CoV-2 Viral Load. CPT: Pharmacometrics & Systems Pharmacology. Volume 9, Issue 9, Pages 509-514. Available at: Timing of Antiviral Treatment Initiation is Critical to Reduce SARS‐CoV‐2 Viral Load – Gonçalves – 2020 – CPT: Pharmacometrics & Systems Pharmacology – Wiley Online Library [Accessed 21/11/2020]
Voet, D., Voet, J. G. (2020) Biochemistry 4th edition. John Wiley & Sons, Inc.
RIKEN (2019) How phosphorylation of eIF2 reduces protein synthesis. Available at: How phosphorylation of eIF2 reduces protein synthesis | RIKEN [Accessed 20/11/2020]
Wang, N. et al. (2020) Retrospective Multicenter Cohort Study Shows Early Interferon Therapy Is Associated with Favorable Clinical Responses in COVID-19 Patients. Cell Host & Microbe. Volume 28, Issue 3, Pages 455-464.Available at: Retrospective Multicenter Cohort Study Shows Early Interferon Therapy Is Associated with Favorable Clinical Responses in COVID-19 Patients: Cell Host & Microbe [Accessed 22/11/2020]
To, K. K-W. (2020) Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. The Lancet – Infectious Diseases. Volume 20, Issue 5, Pages 565-574. Available at:Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study – The Lancet Infectious Diseases [Accessed 22/11/2020]
Dunning, J. et al. (2014) Antiviral combinations for severe influenza. The Lancet – Infectious Diseases. Volume 14, Issue 12, Pages 1259-1270. Available at: Antiviral combinations for severe influenza – The Lancet Infectious Diseases [Accessed 22/11/2020]