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Abstract
Viruses are one of the major causes of 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 signaling pathways. A collective view of these multiple studies could advance our understanding of virus-host interactions 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.
Highlights
Viruses continue to be a major contributor to the global burden of disease through acute and chronic infections that cause substantial economic impact in addition to increased mortality and morbidity [1]
We considered two important parameters—relative betweenness centrality and degree of the host proteins targeted by each virus
We found that host targets from the hostvirus protein-protein interaction data (hvPPI) were spread across the spectrum of genes with proviral as well as antiviral phenotype (Figure S5), showing that targeting of the host protein by the virus could lead into any direction that favors the virus
Summary
Viruses continue to be a major contributor to the global burden of disease through acute and chronic infections that cause substantial economic impact in addition to increased mortality and morbidity [1]. Development of antiviral resistance of hepatitis C virus (HCV), influenza A virus (IAV), herpes simplex virus (HSV), human cytomegalovirus (HCMV), human immunodeficiency virus (HIV), and other viruses is a major concern [2,3,4]. One of the main reasons for increasing resistances is the accumulation of mutations in the viral genome caused by multiple factors including the polymerase infidelity [5, 6]. The World Health Organization (WHO) and the United Nations have urged for better control of viral diseases. This has led to turning the focus on the host for therapeutic intervention. Targeting the host factors has been proven to be useful for restricting viral infections [7, 8]. The small molecule CCR5 inhibitor Maraviroc and the anti-CD4 monoclonal antibody Ibalizumab are examples of successful use of host-directed therapies for combating HIV in clinic [9,10,11]
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