Critical Nodes of Virus–Host Interaction Revealed Through an Integrated Network Analysis

Korbinian Bösl; Aleksandr Ianevski; Thoa T. Than; Petter I. Andersen; Suvi Kuivanen; Mona Teppor; Eva Zusinaite; Uga Dumpis; Astra Vitkauskiene; Rebecca J. Cox; Hannimari Kallio-Kokko; Anders Bergqvist; Tanel Tenson; Valentyn Oksenych; Magnar Bjørås; Marit W. Anthonsen; David Shum; Mari Kaarbø; Olli Vapalahti; Marc P. Windisch; Giulio Superti-Furga; Berend Snijder; Denis Kainov; Richard K. Kandasamy

Our analyses pointed out that viral evasion mechanism observed in one virus could also be relevant for other viruses. Thus, we wanted to test if we could target viral replication of other viruses based on the results from the hvPPI analyses. To get an estimate of the druggability of the hvPPI, we obtained known drug-gene interactions from DGIdb (Cotto et al. 2018) . The data from DGIdb included drug-gene interactions for 48 drugs that were investigational/experimental/approved safe-in-human antivirals compounds (Ianevski et al. 2018 ). Among these 48 broad-spectrum-antivirals, 28 of them had targets that are part of the hvPPI. Based on this overlap, we performed a targeted drug re-purposing screen with 35 of these 48 compounds (Table S1) to check for antiviral activity against and HCV, which is part of the hvPPI and human metapneumovirus (HMPV) which is not in the hvPPI.. We tested 35 broadspectrum-antivirals against GFP-expressing HMPV NL/1/00 strain (de Graaf et al. 2007) . Seven different concentrations of the compounds were added to HMPV or mock-infected cells. Cell viability was controlled after 48 hours and HMPV-induced GFP expression was tested to determine compound efficiency. After the initial screening, we identified five compounds, which lowered GFP-expression without detectable cytotoxicity (with SI > 3). We repeated the experiment with these compounds. The experiment confirmed novel activity of azacytidine, lopinavir, nitazoxanide, itraconazole and oritavancin against HMPV ( Fig. 6A and Table 1 ). Similarly, we examined toxicity and antiviral activity of broad-spectrum-antivirals against GFP-expressing HCV in Huh-7.5 cells using previously described procedures ). Our test identified azithromycin, cidofovir, oritavancin, dibucaine, gefitinib, minocycline and pirlindole mesylate as novel anti-HCV agents with SI > 3 ( Fig. 6B and Table 1 ).