HIV protein sequence signatures for crosstalk with host proteins

Abstract

The HIV virus targets the immune system cells and suppresses immunity. The topology and connectivity of the signalling networks in host cells infected with the HIV virus are altered and redirected toward the synthesis of the virus. HIV proteins interact with host cell DNA and proteins in modulating cell signalling and metabolic pathways. Recent experimental studies involving immunoprecipitation and other binding assays have already identified a large number of host proteins as interacting with HIV virus proteins. Similarly, experiments with site-directed mutagenesis and HIV protein segments provided information on viral sequence sites potentially responsible for crosstalk with host proteins. Nevertheless, these experiments were not performed systematically and as a result much remains unknown about the HIV sequence hotspots for binding to host proteins.My Ph.D. thesis focuses on the identification of HIV sequence hotspots, identities of their target proteins hotspots are used as binding interfaces, and the identities of host proteins outcompeted by viral proteins in these binding interactions. For this purpose I use bioinformatics databases containing large numbers of copies of viral sequences, previously annotated HIV-host protein interactions, and the host protein interactome.The large-scale datasets on sequences and interactomes are integrated with motif discovery, statistical enrichment, and network construction tools in a computer code to reveal information on the details of binding interactions between HIV and host proteins.This dissertation has produced a system wide portrayal of how HIV virus proteins interact with host hub proteins and the resulting changes in the host network. My work has also identified Nef sequence hotspots potentially initiating binding interactions with thirty or more host proteins. My findings are largely consistent with existing experimental data and suggest new experiments on binding interfaces as well as identify HIV virus sequence targets for drug discovery. In this thesis I have also illustrated the use of network analysis in constructing medically relevant cellular pathways such as the one depicting HIV virus interactions with host cell iron ion binding protein pathways. Taken together, my work produces bioinformatics and computational biology techniques specially designed to investigate crosstalk between a virus and the host.%%%%Ph.D., Biomedical Engineering – Drexel University, 2010