Therapeutic interfering particles exploiting viral replication and assembly mechanisms show promising performance: a modelling study

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  Figure 1. Assembly and intracellular dynamics of vRNAs and tiRNAs. (a) The PS-mediated assembly paradigm: Multiple sequence/structure motifs called packaging signals (PSs), that are dispersed throughout the viral genome, promote virion assembly via sequence specific interactions with coat protein (Cp). (b) vRNA and tiRNA in comparison: tiRNA is similar to vRNA but is devoid of any genetic message. (c) Schematic representation of the mathematical model for vRNA (red) and tiRNA (blue) in an HCV infection: In step 1 and 2; vRNA in the cytoplasm binds to free ribosomes to form a translation complex, which synthesizes the viral polyprotein (PP). The latter is cleaved, leading to the production of structural proteins such as core protein (Cp) and nonstructural proteins, including NS3/4A, NS5A, and NS5B. In step 3; NS5B and NS5A bind to vRNA or tiRNA and host factor (HF), respectively. These two complexes are imported into the vesicular membranous structure (VMS). In step 4; the imported RNAs form double-strand RNAs (dsRNAs) and release NS5B and HF. In step 5; dsRNAs again bind to the NS5B and synthesise new vRNAs and tiRNAs. In step 6; these RNAs are either exported into the cytoplasm, or…

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  Figure 2. The impact of replication and assembly efficiencies on the treatment efficacy and cumulative number of released virus-like particles. (a) TIP design is defined by two parameters: assembly efficacy \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$b_a$$\end{document}ba, which can be changed by addition of PSs in the tiRNAs (blue) compared with vRNA (red), and replication efficacy \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$b_r$$\end{document}br, which can be improved by shortening of tiRNA with respect to vRNA. (b) The efficacy of tiRNAs (shown as the fraction indicating reduction in the number of released infectious virions) as a function of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek}…

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  Figure 3. Pie charts for the cumulative number of released virions and TIPs 100 days post infection. Increasing the MOI of tiRNA (T) increases the cumulative number of released TIPs and reduces the total number of released particles (virion+TIP) compared with the control. Red and blue indicate the number of virions and TIPs, respectively, while white shows the difference between the total number of released virions in the control (tiRNA-free) case with the number of released particles (virion+TIP) in the presence of treatment. This figure is plotted by averaging over 250 simulations using parameter values from Table 1 with \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$b_a=1$$\end{document}ba=1 and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$b_r=1$$\end{document}br=1. The initial condition for the MOIs of…

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  Figure 4. Starting treatment 24 h after cell infection has no significant impact even for high replication and assembly efficiencies and MOIs. The black curves indicate the average of efficacy over varying MOIs of vRNAs and tiRNAs from 1 to 10 (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$1\le \hbox {V} \le 10$$\end{document}1≤V≤10, \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$1\le \hbox {T}\le 10$$\end{document}1≤T≤10). Blue and red shaded areas show the regions of mean+std and mean-std, respectively. Blue and red dashed lines indicates the maximum and minimum efficacy of treatment over various MOIs, respectively.