Abstract
Rapidly evolving viruses are a major threat to human health. Such viruses are often highly pathogenic (e.g., influenza virus, HIV, Ebola virus) and routinely circumvent therapeutic intervention through mutational escape. Error-prone genome replication generates heterogeneous viral populations that rapidly adapt to new selection pressures, leading to resistance that emerges with treatment. However, population heterogeneity bears a cost: when multiple viral variants replicate within a cell, they can potentially interfere with each other, lowering viral fitness. This genetic interference can be exploited for antiviral strategies, either by taking advantage of a virus’s inherent genetic diversity or through generating de novo interference by engineering a competing genome. Here, we discuss two such antiviral strategies, dominant drug targeting and therapeutic interfering particles. Both strategies harness the power of genetic interference to surmount two particularly vexing obstacles—the evolution of drug resistance and targeting therapy to high-risk populations—both of which impede treatment in resource-poor settings.
Highlights
RNA viruses, such as influenza virus, HIV, and dengue virus, are dynamic, rapidly evolving pathogens that evade most therapeutic interventions
Provided that therapeutic interfering particle (TIP) can be engineered, theoretical models predict that for HIV/AIDS, TIPs could piggyback on wild-type HIV-1 replication (Fig 2B) to produce substantially greater reductions in disease prevalence compared to conventional interventions
While there are safety risks associated with live-attenuated vaccines such as oral poliovirus vaccine (OPV), TIPs exhibit far greater safety in this regard, as they can only recombine to become virulent if they have mobilized
Summary
Evolving viruses are a major threat to human health. Such viruses are often highly pathogenic (e.g., influenza virus, HIV, Ebola virus) and routinely circumvent therapeutic intervention through mutational escape. Population heterogeneity bears a cost: when multiple viral variants replicate within a cell, they can potentially interfere with each other, lowering viral fitness. This genetic interference can be exploited for antiviral strategies, either by taking advantage of a virus’s inherent genetic diversity or through generating de novo interference by engineering a competing genome. We discuss two such antiviral strategies, dominant drug targeting and therapeutic interfering particles Both strategies harness the power of genetic interference to surmount two vexing obstacles— the evolution of drug resistance and targeting therapy to high-risk populations—both of which impede treatment in resource-poor settings
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