Understanding the determinants of resistance to type I interferons and IFITMs in HIV-1 envelope and SARS-CoV-2 spike
Aligned with our mission to advance the understanding and impact of microbiology, the Society reached out to our community of microbiologists to share their experiences in responding to SARS-CoV-2. We aim to showcase the perspective of scientists during the COVID-19 pandemic and the variety of roles adopted to mitigate the global crisis.
This case study is written by Helena Winstone, a PhD Candidate at King’s College London. She gives a research student’s perspective of how a project can be quickly derailed by worldwide events and can pivot to explore new avenues, as well as the frustrations involved with studying a readily mutating virus and the associated mental health effects.
How did you respond to SARS-CoV-2 during the COVID-19 pandemic? Was this response related to your work prior to the outbreak?
At the start of the pandemic, our Principal Investigator divided the lab across different aspects of the COVID-19 response, ranging from diagnostics and testing to research. Before COVID-19, my PhD project was based on understanding determinants of resistance in the HIV entry protein envelope to interferon-induced transmembrane (IFITM) proteins. These are antiviral proteins which inhibit the cellular entry of a range of enveloped viruses that are upregulated by interferons (IFN). The entry protein of SARS-CoV-2, spike, has a polybasic cleavage site insertion compared to ancestral viruses, which at the time was postulated to affect the cleavage of spike and affect how SARS-CoV-2 enters cells.
In the time it took to set up the experimental tools we needed to work on SARS-CoV-2 viral entry, there were some data early on in the pandemic from other labs suggesting that the Wuhan SARS-CoV-2 strain was very sensitive to IFN. Given that IFN upregulates IFITMs, we wanted to understand the sensitivity of SARS-CoV-2 to IFITMs and if this was related to the polybasic cleavage site in spike. Further into the pandemic, with the emergence of variants of concern (VOCs) containing mutations which appeared to enhance transmission, we worked on testing these different variants for their relative sensitivity to IFNs and IFITMs and postulated that the increased transmissibility of some of these variants was related to their ability to evade IFITM restriction.
What were some of the challenges that you faced during this time?
I had just started the second year of my PhD, so starting a project entirely from scratch with no preliminary data or expertise on the virus in the lab was challenging. Additionally, I don’t think there’s anyone for whom the pandemic was not a struggle in terms of mental health – although I was lucky to not be working from home in a tiny London flat all day. However, working long hours in the lab combined with living alone still took a toll on my mental health and by the end of 2020 I was burnt out.
Further into the pandemic it became challenging in a different way, as new variants emerged every other month. It was frustrating when it felt like we had just started to make progress with one variant, then another one would emerge and it would feel like it made a few months of work essentially obsolete and that we were starting over again.
How did your experience throughout the response aid in your development?
Presenting our SARS-CoV-2 work at the virtual Annual Conference in 2021 was a great opportunity to get some different questions and perspectives on our work. The COVID-19 pandemic has highlighted the role and importance of basic molecular virology in understanding emerging viruses, however it has arguably highlighted the need for more effective science communication and policy.
References
Winstone, H., Lista, M. J., Reid, A., Bouton, C., Pickering, S., Ribeiro Galao, R. P., Kerridge, C., Doores, K., Swanson, C. & Neil, S. 'The Polybasic Cleavage Site in SARS-CoV-2 Spike Modulates Viral Sensitivity to Type I Interferon and IFITM2', Journal of virology, 2021, 95(9), e02422-20.
About the author
Helena Winstone is a PhD candidate supervised by Professor Stuart Neil. Her research focuses on understanding the determinants of resistance to type I interferons and IFITMs in HIV-1 envelope and SARS-CoV-2 spike.