Autonomous Targeting of Infectious Superspreaders Using Engineered Transmissible Therapies

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

The TIP concept capitalizes upon and extends the phenomenon of interfering particles that occur naturally in many viruses, spread along with the viral pathogen [15] , and have demonstrated potential therapeutic efficacy against HIV [16, 17, 18, 19] . TIPs are minimal versions of the pathogen engineered to lack the virulent replication and structural genes of the wild-type pathogen and instead encode therapeutic elements that target key host or viral processes. Since a TIP genome is significantly shorter than the wild-type virus genome, TIP genomes are synthesized at a faster rate, resulting in increased numbers of TIP genomes compared to wild-type virus genomes in the infected cell (see Text S1 and [15] ). Specifically, for HIV, the proposed TIP is a lentiviral gene-therapy vector that lacks all structural and envelope genes required to selfreplicate, but retains HIV's genomic packaging signals. The TIP can mobilize out of the infected cell only by co-opting wild-type HIV capsid and envelope gene-products [16] . By parasitizing a pathogen's resources, TIPs mobilize from cell to cell [16, 18] and, in a recent clinical trial, this mobilization of a gene-therapy vector against HIV did not appear to be detrimental to patient health [17] . Due to their ability to mobilize and reproduce within hosts, TIPs have the potential to decrease wild-type pathogen levels in vivo by many orders of magnitude [19] .