Autonomous Targeting of Infectious Superspreaders Using Engineered Transmissible Therapies

Metzger, Vincent T.; Lloyd-Smith, James O.; Weinberger, Leor S.

The TIP approach carries unique safety concerns [41] and ethical concerns associated with introducing an intervention that transmits and evolves, even in the TIP's limited fashion, within the population. Importantly, clear ethical precedents for transmissible therapies exist in the use of live-attenuated vaccines. Regarding safety, one major concern is that the TIP may recombine with (i.e. acquire) an element that 'upregulates' pathogen production and in turn upregulates its own production from the cell. To explore this concern, we examine HIV viral load and population prevalence in the regime where TIP encodes HIV inhibition and in the regime where TIP encodes potential upregulation of HIV gene expression within a single cell. (Figure 6a ). As expected, at the single-cell level upregulation of HIV generates increased HIV and TIP production. However, at the individual patient level upregulation of HIV leads to increased TIP viral loads (Figure 6a , inset) which actually generate even lower HIV viral loads (Figure 6a ) and HIV population prevalence (Figure 6b) . Interestingly, at the population level, there is an optimal value of TIP-encoded inhibition, which yields a maximum in TIP prevalence (Figure 6b, inset) . Thus, the TIP appears to be subject to competing selection pressures at multiple scales which may limit the potential for evolutionary breakdown of TIP therapies, echoing recent proposals for antivirals that resist viral escape [42] and 'evolution-proof' malaria insecticides [43] .