Dynamics of Influenza A Virus Defective Interfering Particle Replication
Influenza and other respiratory viral diseases constitute a major threat to human health. Besides vaccination strategies, this threat is handled by the use of antivirals which inhibit virus replication and spread. However, protection against IAV is compromised by rapid resistance development, and by vaccines that need to be reformulated on an annual basis and do not protect against pandemic strains.
The observation that defective (IAV particles, a natural byproduct of their replication, interfere with the spread of influenza viruses and other respiratory agents by competing for cellular resources and by inducing antiviral responses, opens an exciting possibility for new therapeutic and preventive approaches. Nevertheless, important roadblocks need to be removed before defective interfering particles (DIP) for therapeutic use (TIP) can be used for treatment of humans. In particular, i) save and efficient production systems for TIP need to be established, ii) the full antiviral potential of TIPs needs to be explored by generating and testing TIPs other than the prototype particles such as DI244 established by Dimmock’s group [Dimmock and Easton, 2014], iii) antiviral activity and safety of optimized TIPs need to be assessed in state-of-the-art cell culture [Frensing, Heldt et al., 2013 and Frensing et al., 2014] and animal models and iv) mathematical models for TIP/IAV co-infection [Laske, Heldt, et al., 2016] need to be further developed which will pave the way for rational design and optimization of TIPs. The interdisciplinary joint research project DIA_TIP funded by the DARPA (https://www.darpa.mil/news-events/2016-04-07a) will use a systems biology approach to meet these challenges
Aim of the project
The DIA_TIP project will provide a pipeline for generation of safe and efficacious TIPs as antivirals and for preventive approaches. We will establish a novel, cell culture-based production platform for TIP, which allows generation of well-defined TIP preparations without use of infectious helper virus. Moreover, we will explore the full therapeutic potential of TIPs using genetic engineering and a unique funnel for assessing of TIP safety and antiviral activity: TIP/IAV coinfections will be investigated in state-of-the-art cell culture systems, including bioreactors and cultures of respiratory epithelium, and animal models for IAV infection, including mice and ferrets. These tools, jointly with highly sensitive methods for detection of viral spread, including IAV/TIP with reporter genes, will allow us to track IAV/TIP spread at unprecedented resolution and to identify TIsP with optimal therapeutic activity. Finally, the high resolution of quantitative data, the parallel assessment of cells, tissues and entire organisms plus the analysis of IAV/TIP-induced innate responses will allow us to generate and validate mathematical models able to simulate TIP spread in humans, which will be instrumental to the design and testing of safe, next generation TIPs. Collectively, DIA_TIP will generate novel and safe TIPs for therapeutic use and will provide the theoretical framework for understanding their antiviral action. This will be achieved within a highly collaborative approach of partners with strong expertise in molecular virology, cell culture and animal models of IAV infection and mathematical models for IAV replication and interference by TIPs.