UC San Diego

Recent theoretical work has proposed a new paradigm of infectious disease intervention through the spread of Therapeutic Interfering Particles (TIPs). Instead of solely focusing on treatment of individuals with a particular disease, TIPs inhibit spread of a pathogen at the population level and decreases prevalence of the pathogen over time. TIPs are degenerate viruses that can only replicate in the presence of wild-type virus, act to inhibit the growth of the wild-type virus, and can be transferred between individuals. They have no protein- coding capability and consist of only the necessary cis- acting elements for replication and mobilization. We used a rational design approach to synthesize a TIP against Human Immunodeficiency Virus Type-1 (HIV-1). Employing a joint computational-experimental methodology, we quantified the inhibition of HIV-1 replication by TIP in cell culture and the relative fold-increase of TIP genomic RNA expression compared to HIV-1 genomic RNA expression. Our results show that the presence of TIPs in a cell culture decreases HIV-1 spread by 67% by day 8 post- infection. Increased mobilization of TIP virions and cell- to-cell transfer correlated with greater control of HIV-1 replication within a cell culture. Although we did detect differences in packaging efficiency between TIP genomic RNA and HIV-1 genomic RNA, we proposed this could be compensated for through engineering even higher production values of TIP genomic RNA in the cell than our models originally predicted