The role of cellular RNA editing in human respiratory syncytial virus and influenza virus biology.

Influenza A virus (IAV) and human respiratory syncytial virus (HRSV) are two very important respiratory viruses of major significance for global health. Both viruses cause infections in winter months in the UK with IAV also having the potential to cause major pandemics. Both viruses can infect the adult population with HRSV also infecting all children under the age of two. Whilst there are effective vaccines to seasonal IAV and also anti-viral drugs that can be taken there are no equivalent therapies for HRSV. Likewise, pandemic IAV can go global very quickly and therefore effective therapeutic countermeasures are always needed. Thus there is an urgent and unmet healthcare need to ensure robust strategies to lower the current and future disease burden caused by these viruses.

For both viruses they rely critically on the cell they infect to mount productive and efficient infections. However, these cells resemble a battleground with the virus attacking the cell and the cell trying to sabotage and reduce the impact of virus infection. Certain host cell proteins are key players in the balance between these processes and sometime this is referred to as an 'evolutionary arms race'. We have identified a group of similar cellular proteins that we propose are one of these key proteins that can tip the favour in the balance of virus infection. Collectively they are known as Adenosine Deaminase Acting on RNA (ADAR), and their function is to change the sequence of the viral genetic material. Originally it was thought this worked for the benefit of the cell by causing the buildup of harmful mutations that prevent the virus from working. However, our preliminary and published data combined with that from other research groups suggests that for a number of medically important viruses, including IAV and HRSV and viruses such as HIV-1 and herpesviruses that these are actually pro-viral and the viruses use them to promote virus infection and the expense of the host cell.

Our proposal is to investigate how and why the interaction with ADAR achieves this pro-viral activity for IAV and HRSV and we have all the expert ease necessary to conduct this research. We want to determine where on the virus genetic material ADAR works, where in the cell this occurs and how this causes beneficial effect for virus biology and diversity of the genetic material. This latter point is very important because as ADAR is used by many viruses as a positive pro-viral factor, the ability to therapeutically manipulate ADAR activity would be of medical benefit as it could provide the potential for a generic therapy against many different viruses.

The proposal will focus on IAV at the Roslin Institute and HRSV at the University of Leeds. However, we propose that undertaking this as a combined project will allow the efficient sharing of many different reagents are more important identify and investigate common mechanisms of ADAR activity for both respiratory viruses.

Influenza A virus (IAV) and human respiratory syncytial virus (HRSV) are globally important negative stranded RNA virus pathogens responsible for a large disease burden. Whilst there is an effective vaccine to IAV and selective anti-viral chemotherapy, the rapid emergence of IAV pandemics and the build up and spread of drug resistance can lead to current strategies becoming ineffective. No effective therapeutic strategy exists for HRSV. Thus there is an urgent and unmet healthcare need to ensure robust strategies to lower the current and future disease burden caused by these viruses.

This proposal focuses on the interaction between IAV and HRSV and the cellular Adenosine Deaminase Acting on RNA (ADAR) pathway, a system whose importance to human disease (both infectious and genetic) is becoming increasingly apparent. Our research will define the interactions of these two important human respiratory pathogens with the ADAR system, furthering our understanding of their replication and potentially leaving us well placed to take advantage of future advances in chemotherapeutic modification of ADAR activity. ADAR activity catalyses adenosine (A) to inosine (I) changes on both viral and cellular mRNAs. For many medically relevant viruses, including IAV, HRSV, HIV-1 and herpesviruses this is thought to be pro-viral, although the mechanisms are not understood.

This proposal brings together expertise in both viruses and the necessary technologies to investigate the activity of ADAR on IAV and HRSV to investigate two primary hypotheses. (1). That both IAV and HRSV co-opt the cellular ADAR pathway for pro-viral purposes and (2) that ADAR activity contributes to virus diversity. To achieve this we propose to define which isoforms of ADAR are involved in the IAV and HRSV life cycles, where these activities occur inside the virus infected cells and how this modification process is important for viral fitness and sequence diversity.

Influenza A virus (IAV) and human respiratory syncytial virus (HRSV) are globally important negative stranded RNA virus pathogens responsible for a large disease burden across all age groups in the developed and developing world. Whilst there is an effective vaccine to IAV and selective anti-viral chemotherapy, the rapid emergence of IAV pandemics and the build up and spread of drug resistance can lead to current strategies becoming ineffective. No effective therapeutic strategy exists for HRSV. Thus there is an urgent and unmet healthcare need to ensure robust strategies to lower the current and future disease burden caused by these viruses. Our proposal is rooted in basic science and the primary beneficiaries in the short term will be the academic community of virologists and cell biologists, who will be able to build on our data studying cellular induced RNA editing. We anticipate this will be after year one of the proposal when our initial results are presented at national and international meetings and published in appropriate journals. In the longer term, a better understanding of the biology behind IAV and HRSV replication and evolution will aid control measures; if our research suggests that the ADAR pathway as a viable drug target for anti-viral therapy then the pharmaceutical sector would benefit and ultimately, the general population. This will be achieved and pursued through our established links with public health bodies and UK-based industry.