Autonomous Targeting of Infectious Superspreaders Using Engineered Transmissible Therapies

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

This efficacy and robustness of TIP intervention arises from the unique and defining ability of TIPs to transmit between hosts. Analysis of TIPs that generate a 0.5-1.5 Log decrease in viral load, but do not transmit between hosts, shows only a minimal decrease in population-level disease burden ( Figure S3 in Text S1)-in agreement with the projected impact of acyclovir treatment which also generates a ,0.5 Log decrease in HIV viral load [33] . Accordingly, we have paid particular attention to ensuring that our results are robust with respect to changes in basic model assumptions about transmission biology and robust under parameter sensitivity analysis (see Text S1). We also consider two competing models of HIV transmission biology-infection by either a single 'founder' virus that enters the new host individual or 'bottlenecking' where multiple viruses enter and replicate locally but are then winnowed down by competition within the host [35, 36, 37] -and we provide arguments that our treatment of TIP transmission is consistent with either transmission mode and that TIPs could transmit efficiently in either case (see Text S1 section [12] ). Boldness of figures represents transmission rate, size of figures represents size of sexual activity class. Smallest but boldest figures represent the superspreaders (the least in number but the highest transmission rate). Largest but lightest figures represent individuals with the lowest transmission rates (the greatest in number). Infection by TIP alone (blue) converts susceptible individuals to into latent 'carriers' of integrated TIP genomes [22] . Infection by HIV converts susceptible individuals to individuals who progress to disease in ,10 yrs. Dual infection generates individuals who progress to disease more slowly. Disease progression and transmission rates are proportional to in vivo viral loads [25] . doi:10.1371/journal.pcbi.1002015.g001 entitled: ''Considerations for TIP transmission to uninfected hosts''). To be completely sure that our model results are robust to changes in assumptions about TIP transmission, we repeated the simulations under the worst-case assumption that TIPs are completely unable to transmit in the absence of HIV, and found results that are qualitatively unchanged from Figure 2 (see Text S1 section: ''Sensitivity of model to removal of independent transmission of TIPs (i.e. removal of S T individuals)''). This somewhat surprising result arises because TIPs autonomously target the highest-risk groups, which are highly likely to be already infected with HIV due to their highrisk status, and thus the majority of the TIP infection 'flow' occurs through the already infected individuals. In summary, while there is physiological basis to support that TIPs could transmit efficiently to HIV-uninfected persons, the efficacy of TIP intervention is largely independent of this assumption (i.e. TIPs need not convert susceptible individuals into 'TIP carriers' for population-level efficacy to be retained).