Evolvable "resistance-proof" therapies

11 October 2013

Leor Weinberger
Gladstone Institute of Virology and Immunology
UC San Francisco


From common Staph infection to tuberculosis, our most powerful antimicrobials are rapidly becoming non-protective. The fundamental problem with our current therapies is that pathogens are dynamic – they mutate and transmit – while our therapies are static, neither mutating nor transmitting. This mismatch necessarily selects for drug-resistant escape variants, which arise far quicker than current platforms can identify and develop new antimicrobials. Faced with dynamic pathogens, my lab engineers dynamic, evolvable therapies. For viruses, these dynamic therapies are based on synthetic molecular parasites that can only replicate using the molecular machinery of the virus (ie: they "piggyback"). In the case of HIV, these molecular parasites are pared-down HIV vectors where the essential protein products have been ablated, forcing the vectors to intracellularly compete for viral replication and packaging resources, thereby generating Therapeutic Interfering Particles (TIPs) from HIV-infected cells. By starving HIV of its own essential elements, TIPs act as therapy, reducing viral loads in the patient. The fundamental departure from traditional therapies is that TIPs harness the inherent biology of the pathogen, replicating with equal speed and with the same evolutionary adaptive potential as the pathogen. TIPs are under strong evolutionary selection to maintain their parasitic relationship with the pathogen and natural selection pushes the molecular parasite to co-evolve and keep pace with the pathogen (ie: establishing a co-evolutionary "arms race" between therapy and pathogen). I will discuss the theory and the first generation of synthetically engineered TIPs that can transmit and interfere with HIV to lower viral transmission and protect cells. While the TIP concept is a departure from conventional approaches, it could apply broadly and has the potential to overcome the universal barriers to disease control by transforming disease control from static to dynamic, evolvable interventions.

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