Understanding Human-Virus Protein-Protein Interactions Using a Human Protein Complex-Based Analysis Framework

Abstract

Computational analysis of human-virus protein-protein interaction (PPI) data is an effective way toward systems understanding the molecular mechanism of viral infection. Previous work has mainly focused on characterizing the global properties of viral targets within the entire human PPI network. In comparison, how viruses manipulate host local networks (e.g., human protein complexes) has been rarely addressed from a computational perspective. By mainly integrating information about human-virus PPIs, human protein complexes, and gene expression profiles, we performed a large-scale analysis of virally targeted complexes (VTCs) related to five common human-pathogenic viruses, including influenza A virus subtype H1N1, human immunodeficiency virus type 1, Epstein-Barr virus, human papillomavirus, and hepatitis C virus. We found that viral targets are enriched within human protein complexes. We observed in the context of VTCs that viral targets tended to have a high within-complex degree and to be scaffold and housekeeping proteins. Complexes that are essential for viral propagation were simultaneously targeted by multiple viruses. We characterized the periodic expression patterns of VTCs and provided the corresponding candidates that may be involved in the manipulation of the host cell cycle. As a potential application of the current analysis, we proposed a VTC-based antiviral drug target discovery strategy. Finally, we developed an online VTC-related platform known as VTcomplex (http://zzdlab.com/vtcomplex/index.php or http://systbio.cau.edu.cn/vtcomplex/index.php). We hope that the current analysis can provide new insights into the global landscape of human-virus PPIs at the VTC level and that the developed VTcomplex will become a vital resource for the community. IMPORTANCE Although human protein complexes have been reported to be directly related to viral infection, previous studies have not systematically investigated human-virus PPIs from the perspective of human protein complexes. To the best of our knowledge, we have presented here the most comprehensive and in-depth analysis of human-virus PPIs in the context of VTCs. Our findings confirm that human protein complexes are heavily involved in viral infection. The observed preferences of virally targeted subunits within complexes reflect the mechanisms used by viruses to manipulate host protein complexes. The identified periodic expression patterns of the VTCs and the corresponding candidates could increase our understanding of how viruses manipulate the host cell cycle. Finally, our proposed conceptual application framework of VTCs and the developed VTcomplex could provide new hints to develop antiviral drugs for the clinical treatment of viral infections.

Keywords: antiviral drug discovery; human-virus interaction; network; protein complex; protein-protein interaction.

FIG 1

Landscape of VTCs related to the five viruses. (A) Flowchart of experimental design. (B) Numbers of human-virus PPIs with the corresponding targets within and outside complexes. (C) Sizes of the VTCs related to the five viruses. (D) Jaccard indices corresponding to the target and VTC level for each virus. The corresponding Jaccard index of each virus was calculated using data from two high-throughput human-virus PPI studies.

FIG 2

Comparison of the topological and functional characteristics between viral targets and nontargets within VTCs. (A) Within-complex degree distributions of the proteins. (B) Within-complex degree distributions of the proteins targeted by single and multiple viruses. (C) Proportions of scaffold proteins. (D) Proportions of housekeeping proteins. (E) d_N/d_S distribution of the proteins. Values that are significantly different (P < 0.001) are indicated by three asterisks. Values that are not significantly different (P > 0.05) are indicated (NS). The P values in panels A, B, and E were calculated by one-tailed Wilcoxon rank sum test, and the P values in panels C and D were calculated by one-tailed two-proportion z-test.

FIG 3

Functional annotations of the VTCs. (A) Venn diagram shows the number of common and specific VTCs (VT_significance < 0.05). Representative complex names are labeled; an example of VTCs with similar functions but that are comprised of different subunits is shown in red. (B) Overlap between all viruses’ VTCs and complexes containing innate immune-related proteins. (C) Overlap between HIV-1 VTCs and complexes containing HDFs. Three asterisks denote a P value of <0.001, and NS (not significantly different) denotes a P value of >0.05.

FIG 4

VTCs responding to viral infection. (A) Overlap between HIV-1 VTCs and DECs. (B) Numbers of different classes of HIV-1-targeted DECs. The gray region represents DECs with a VT_significance of <0.05. (C) Selected HIV-1 significantly targeted DECs (VT_significance < 0.05). A total of 81 upregulated or downregulated DECs are ranked according to the fraction of DEGs they contain. In addition, network representations of two DECs are provided. Nodes in purple represent upregulated genes, while nodes in blue represent downregulated genes. Circles represent human proteins, and V shapes represent viral proteins.

FIG 5

Temporal mapping of VTCs during the host cell cycle. (A) Overlap between VTCs and periodic complexes. (B) Proportions of virally targeted periodic complexes at different cell cycle phases. The colors indicate different cell cycle phases. For comparison, all periodic complexes were used as the background, and the PCC values between the proportions of virally targeted periodic complexes and the periodic complexes at different cell cycle phases were labeled for each virus. (C) Network representation of two experimentally validated periodic complexes involved in the manipulation of the host cell cycle. (D) Overlap among viral significantly targeted periodic complexes (VT_significance < 0.05 and Periodic_ratio > 0.2) related to five viruses. (E) Periodic complexes targeted by multiple viruses during the G₁, G₁-S, S, S-G₂, G₂-M, or M-G₁ phase (VT_significance < 0.05 and Periodic_ratio > 0.2). The color scheme of nodes in panel B is also used in panels C and E.

FIG 6

Network representation of the identified anti-HIV-1 druggable complexes as well as the potential druggable targets and drugs. For the associated subnetworks (VTCs), the corresponding complex IDs and names are shown. Circles represent human proteins, V shapes represent viral proteins, and squares represent druggable targets. Nodes in purple represent upregulated genes, while nodes in blue represent downregulated genes.