Developing Transmissible Antivirals by Exploiting Gene-Expression Circuitry

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DESCRIPTION (Provided by the applicant) Abstract: Emerging and established viral diseases take an enormous toll on human health. Current treatment approaches are unlikely to halt epidemic spread of many viruses, notably HIV-1, due to prohibitive costs of treatment (i.e. access), compliance issues, rapid viral mutation, and the influence of hard-to-reach high-risk viral 'superspreaders'. We propose to shift the treatment paradigm toward developing Therapeutic Infectious Pseudoviruses (TIPs) that require the pathogen to replicate. TIPs would transmit along a pathogen's normal transmission route, reaching precisely those high-risk populations that most require therapy. TIPs co-opt wild-type virus packaging elements, decreasing disease-progression in vivo and reducing disease transmission on a population scale. We have demonstrated that an anti-HIV TIP could mutate with equal speed and under evolutionary selection to maintain its parasitic relationship with wild-type virus, thereby overcoming viral mutational escape. Since TIPs replicate conditionally (i.e. piggyback) treatment compliance and cost issues are eliminated. A precedent for the safety of TIPs exists in the oral polio vaccine (a live-attenuated vaccine) which exhibits limited spread and is being used in the polio eradication campaign. To develop candidate TIPs we will capitalize upon our expertise in HIV-1 transcriptional circuitry. We discovered that HIV-1 exploits stochastic gene-expression to control entry into a dormant state (proviral latency). By targeting a cellular gene (SirT1) essential for viral feedback, we have biased HIV-1 toward dormancy and diminished reactivation. We will exploit this innovative strategy of forcing viruses into dormancy by utilizing our single-cell imaging methods to conduct high-throughput imaging screens for therapeutic candidates that promote viral latency. Next, these candidate TIPs will be analyzed in novel microfluidic chemostats that maintain homeostatic infection and allow viral evolution in an in vivo-like setting. By integrating these approaches with predictive models, we will develop a revolutionary therapy to halt the spread of HIV/AIDS and other infectious diseases. Public Health Relevance: Emerging and established viral diseases are major health concerns. Many viral diseases lack effective treatments or preventative vaccines and even when available these treatments are unable to halt epidemic spread due to viral mutational escape and the presence of infectious superspreader individuals. Clearly, new and more effective antiviral strategies are needed and this proposal presents a multi-pronged approach to identify and develop an innovative new antiviral approach.