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

Abstract

Viruses are one of the major causes of various acute and chronic infectious diseases and thus a major contributor to the global burden of disease. Several studies have shown how viruses have evolved to hijack basic cellular pathways and evade innate immune response by modulating key host factors and signalling pathways. A collective view of these multiple studies could advance our understanding of viral evasion mechanisms and provide new therapeutic perspectives for the treatment of viral diseases. Here, we performed an integrative meta-analysis to elucidate the 17 different host-virus interactomes. Network and bioinformatics analyses showed how viruses with small genomes efficiently achieve the maximal effect by targeting multifunctional and highly connected host proteins with a high occurrence of disordered regions. We also identified the core cellular process subnetworks that are targeted by all the viruses. Integration with functional RNA interference (RNAi) datasets showed that a large proportion of the targets are required for viral replication. Furthermore, we performed an interactome-informed drug re-purposing screen and identified novel activities for broad-spectrum antiviral agents against hepatitis C virus and human metapneumovirus. Altogether, these orthogonal datasets could serve as a platform for hypothesis generation and follow-up studies to broaden our understanding of the viral evasion landscape. author/funder. All rights reserved. No reuse allowed without permission.

Selected nucleos(t)ide-based prescribed drugs and their multi-target activity

“…Experimental studies have shown that azacitidine is a potent, broadspectrum antiviral agent. The range of viruses against which it shows activity includes AdV (Alexeeva et al, 2001(Alexeeva et al, , 2015, human metapneumovirus (HMPV) (Bösl et al, 2019), HIV-1 (Dapp et al, 2009;Rawson et al, 2016a), HIV-2 (Beach et al, 2014), Rift Valley fever virus (RVFV) (Ianevski et al, 2018, human T-lymphotropic virus (HTLV-1) (Diamantopoulos et al, 2012), HSV-1, and FLUAV (Ianevski et al, 2018). A study of azacytidine activity against HIV-1 and HIV-2 revealed that it primarily targets reverse transcription (in the form of 5azacytidine-triphosphate or 5-aza-2′-deoxycytidine triphosphate).…”

“…Myelodysplastic syndrome (2004) AdV (Alexeeva et al (2001); (Alexeeva et al, 2015) HMPV (Bösl et al, 2019) HIV-1 (Dapp et al, 2009;Rawson et al, 2016a) HIV-1 -synergy in combination with resveratrol (Rawson et al, 2016b) HIV-2 (Beach et al, 2014) RVFV ( (Clouser et al, 2012) HIV-1 -synergy in combination with decitabine (Clouser et al, 2010) MuLV (Clouser et al, 2012) HIV-2 (Beach et al, 2014) ZIKV (Kuivanen et al, 2017) Enteroviruses including poliovirus (Kang et al, 2015;Zhang et al, 2017) Enteroviruses -synergy with ribavirin (Kang et al, 2015) Rhinoviruses (Song et al, 2017) HCV (Beran et al, 2012) Coronaviruses (Dyall et al, 2014) SINV, HSV-1, FLUAV (Denisova et al, 2012) Gram-positive bacteria (Jordheim et al, 2012;Sandrini et al, 2007;…”

Discovery and Development of Safe-in-Man Broad-Spectrum Antiviral Agents

“…Other cell death assays include LDH enzyme leakage assays, membrane impermeable dye-based assays, and apoptosis assays, such as Annexin V, TUNEL, and caspase assays (19). For example, the Cell Titer Glo (CTG) assay quantifies ATP, an indicator of metabolically active living cells, whereas Cell Tox Green assay uses fluorescent asymmetric cyanine dye that stains the DNA of dead cells (13,(20)(21)(22).…”

“…For example, TZM-bl cells expressing firefly luciferase under control of HIV-1 LTR promoter allowed quantitation of BSAA action on HIV-1 infection (tat-protein expression by integrated HIV-1 provirus) using firefly luciferase assay (23,24). RFP-expressing RVFV, nanoLucexpressing CHIKV and RRV, as well as GFP-expressing FLUAV, HCV and HMPV also allowed identification of novel activities of several BSAAs (13,21,(25)(26)(27)(28)(29)(30)(31). In addition, qPCR/RT-qPCR, RNA/DNA sequencing, RNA/DNA hybridization, immuno-and plaque assays as well as CRISPR-CAS9 systems could be used for detection of inhibitory effects of BSAAs (32)(33)(34)(35)(36)(37)(38)(39).…”

“…A counterpoint to this is "one drug, multiple viruses" paradigm, which came with the discovery of broad-spectrum antiviral agents (BSAAs), small-molecules that inhibit a wide range of human viruses (7)(8)(9)(10)(11)(12). This paradigm was based on the observation that different viruses utilize similar pathways and host factors to replicate inside a cell (13). Although the concept of BSAAs has been around for almost 50 years, the field received a new impetus with recent outbreaks of Ebola, Zika, Dengue, influenza and other viral infections, the discovery of novel host-directed agents as well as development of drug repositioning methodology.…”