Autonomous Targeting of Infectious Superspreaders Using Engineered Transmissible Therapies

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

To examine how HIV might respond in such an arms race resulting from TIP intervention, we consider the multi-scale dynamics across a range of parameter values for the molecularlevel properties used to design a TIP. Specifically, we consider the interplay of HIV and TIP levels as a function of both the strength of TIP-encoded inhibition of HIV and the engineered TIP genomic abundance within a dually infected cell. For HIV, the TIP design encodes an inherent evolutionary tradeoff that generates conflicting selection pressures at different scales ( Figure 5 ). On the one hand, inhibition of HIV replication by TIP-encoded therapy genes inevitably limits TIP productionsince any TIP-encoded antiviral that inhibits HIV will compromise the TIP's ability to mobilize. However, due to the diploid nature of retroviral genomes, high concentrations of TIP genomic mRNA alone will inhibit HIV production by wasting the majority of HIV genomes in virions containing one HIV RNA and one TIP RNA, and these heterozygous-diploid virions are not viable [18, 23] . Thus, the lowest TIP-mediated inhibition generates the highest production of TIPs from an infected cell (Figure 5a) . The increased numbers of TIP virions then compete more effectively against HIV for target cells which generates a greater reduction in HIV viral-load at the patient-level (Figure 5b) , and the lowest HIV/AIDS prevalence in the population (Figure 5c) . These results suggest a non-intuitive design criterion for a TIP against HIV: TIPs lacking an inhibitory factor for HIV will be most effective in reducing HIV levels, both in individual patients and at the population level. Similarly, the cellular-scale selective pressure for HIV to escape from TIP-encoded inhibition would point in the same direction (toward zero TIP inhibitory effect) and would lead to increased TIP production (Figure 5a) . So, counter-intuitively, HIV escape from TIP-mediated inhibition (at the molecular scale within cells) would reduce HIV viral load and HIV population prevalence to lower levels (Figure 5b-c) .