Deanery of Biomedical Sciences
The overall aim of this project will be to identify innate immune antiviral cellular factors that regulate both, the pandemic lentivirus HIV-1, and LINE-1 endogenous retroelements that are the only autonomously active Transposable Element in our genome. Given the functional and evolutionary relationship between extant retroviruses like HIV-1 and genome embedded retroelements such as Long Interspersed Nuclear Element-1 (LINE-1), both are often controlled by similar cellular antiviral factors. Both use a Reverse Transcriptase and an intermediate RNA in their life cycle, but their mechanism of insertion in genomes are largely different. Yet common regulatory factors have been identified, including several members of the APOBEC3 family of cytidine deaminases, several host factors mutated in the rare genetic disorder Aicardi Goutieres Syndrome (SAMHD1, Trex1 and ADAR1), and the HUSH complex to name a few. Although we and others have identified and characterised antiviral factors to both HIV-1 and LINE-1, our understanding of their regulation is still incomplete. However, an emerging hypothesis suggest that factors used to control endogenous retroelements can be recycled to control exogenous viruses, including HIV-1, but also other RNA viruses such as SARS-CoV-2.
Using Crispr-based Gene Expression Knockout (GeCKO) and other screens for both HIV-1 and LINE-1, previously conducted in our laboratories, as well as using existing datasets, we will be able to identify common inhibitory cellular antiviral factors involved in both innate immune responses to viral infection and genome regulation. Indeed, our preliminary analyses have identified several genes related to the innate immune response to HIV-1 as LINE-1 regulators. By identifying shared antiviral factors between distinct elements in comparative screens, we will be able to more confidently identify genuine antiviral factors that target the shared features of the HIV-1 and LINE-1 replication cycles. Identified targets will be validated and prioritised for further functional characterisation, and this will also include testing for broader efficacy against a panel of RNA viruses including SARS-CoV-2.
By identifying antiviral factors that target both LINE-1 and HIV-1 in common systems, we will be able to more stringently identify genuine antiviral factors and understand the relationship between genomic regulation and antiviral immunity. In sum, this work will allow new insights in regard immunity to viral infections as well as Transposable Element-mediated autoimmune disease and will help understand the relationship between them.
This project is based on recent innovative reverse genetics methods, Crispr-based screening approaches, and will exploit a range of molecular and cellular techniques with particular emphasis on viral infections and retroelement mobility assays. Full training will be given in multiple experimental approaches including cell culture, working in BSL3 laboratory environment, RNA-seq, qPCR, and flow cytometry.
This 4 year PhD project is part of a competition funded by
EASTBIO BBSRC Doctoral Training Partnership. This opportunity is open to UK and international students and provides funding to cover stipend and UK level tuition fees. The UoE covers the difference between home and international fees. There is a cap on the number of international students the DTP can recruit so it is important to know in which fees status category applicants fall under when applying.
Refer to UKRI
website and Annex B of the
UKRI Training Grant Terms and Conditions for full eligibility criteria.
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