Evans, James P
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Publication Modeling Virus-Host Networks(2010-12-22) Evans, James PVirus-host interactions are being cataloged at an increasing rate using protein interaction assays and small interfering RNA screens for host factors necessary for infection. These interactions can be viewed as a network, where genes or proteins are nodes, and edges correspond to associations between them. Virus-host interac- tion networks will eventually support the study and treatment of infection, but first require more data and better analysis techniques. This dissertation targets these goals with three aims. The first aim tackles the lack of data by providing a method for the computational prediction of virus-host protein interactions. We show that HIV-human protein interactions can be predicted using documented human peptide motifs found to be conserved on HIV proteins from different subtypes. We find that human proteins predicted to bind to HIV proteins are enriched in both documented HIV targeted proteins and pathways known to be utilized by HIV. The second aim seeks to improve peptide motif annotation on virus proteins, starting with the dock- ing site for protein kinases ERK1 and ERK2, which phosphorylate HIV proteins during infection. We find that the docking site motif, in spite of being suggestive of phosphorylation, is not present on all HIV subtypes for some HIV proteins, and we provide evidence that two variations of the docking site motif could explain phos- phorylation. In the third aim, we analyze virus-host networks and build on the observation that viruses target host hub proteins. We show that of the two hub types, date and party, HIV and influenza virus proteins prefer to interact with the latter. The methods presented here for prediction and motif refinement, as well as the analysis of virus targeted hubs, provide a useful set of tools and hypotheses for the study of virus-host interactions.Publication Prediction of HIV-1 virus-host protein interactions using virus and host sequence motifs(2009-05-18) Evans, Perry; Ungar, Lyle; Dampier, William; Tozerin, AydinBackground Host protein-protein interaction networks are altered by invading virus proteins, which create new interactions, and modify or destroy others. The resulting network topology favors excessive amounts of virus production in a stressed host cell network. Short linear peptide motifs common to both virus and host provide the basis for host network modification. Methods We focused our host-pathogen study on the binding and competing interactions of HIV-1 and human proteins. We showed that peptide motifs conserved across 70% of HIV-1 subtype B and C samples occurred in similar positions on HIV-1 proteins, and we documented protein domains that interact with these conserved motifs. We predicted which human proteins may be targeted by HIV-1 by taking pairs of human proteins that may interact via a motif conserved in HIV-1 and the corresponding interacting protein domain. Results Our predictions were enriched with host proteins known to interact with HIV-1 proteins ENV, NEF, and TAT (p-value < 4.26E-21). Cellular pathways statistically enriched for our predictions include the T cell receptor signaling, natural killer cell mediated cytotoxicity, cell cycle, and apoptosis pathways. Gene Ontology molecular function level 5 categories enriched with both predicted and confirmed HIV-1 targeted proteins included categories associated with phosphorylation events and adenyl ribonucleotide binding. Conclusion A list of host proteins highly enriched with those targeted by HIV-1 proteins can be obtained by searching for host protein motifs along virus protein sequences. The resulting set of host proteins predicted to be targeted by virus proteins will become more accurate with better annotations of motifs and domains. Nevertheless, our study validates the role of linear binding motifs shared by virus and host proteins as an important part of the crosstalk between virus and host.