New Platform Technologies for Viral and Therapeutic Evolution Assays

From HIV to metastatic cancer, state-of-the-art therapeutics are static biological or pharmaceutical compounds—whose efficacy is inevitably lost once their evolving disease targets sufficiently mutate. We engineered the first adaptive therapeutics designed to co-adapt with adapting disease agents—to provide ‘resistance-proof’ disease control. Known as Therapeutic Interfering Particles (‘TIPs’), these therapeutics are viral deletion mutants engineered to be obligate molecular parasites of targeted diseases. Given this obligate parasitism, natural selection is predicted to drive the TIPs co-evolve with their changing disease targets to maintain parasitism and disease control. Yet, prior to our feasibility studies, no continuous-culture laboratory platform existed to test the possibility that TIPs could indefinitely co-evolve with rapidly evolving disease targets such as HIV. More generally, no laboratory system existed in which to assay long-term viral evolution under human-like (i.e., continuous-culture) conditions. Here we propose a 3-year effort to optimize and transition prototype TRL4+ HIV and HCMV Viroreactors into TRL7 technologies that assay disease evolution and therapeutic control under long-term, in vivo like conditions. Once combined with technologies under development in the DARPA Intercept Program, the ViroReactors will enable us to rapidly develop, test and optimize resistance-proof interventions in the time-scale required to halt an emerging pandemic.