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apbc2011_HIV

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Comparative analysis of protein interaction networks revealsthat conserved pathways are susceptible to HIV-1 intercep-tionXiaoning Qian∗ 1, Byung-Jun Yoon∗ 21Department of Computer Science and Engineering, University of South Florida, Tampa, FL, USA2Department of Electrical and Computer Engineering, Texas A&M University, College Station, TX, USAEmail: Xiaoning Qian∗- [email protected]; Byung-Jun Yoon∗- [email protected];∗Corresponding authorAbstractBackground: Human immunodeficiency virus type one (HIV-1) is the major pathogen that causes the acquiredimmune deficiency syndrome (AIDS). With the availability of large-scale protein-protein interaction (PPI)measurements, comparative network analysis can provide a promising way to study the host-virus interactionsand their functional significance in the pathogenesis of AIDS. Until now, there have been a large number of HIVstudies based on various animal models. In this paper, we present a novel framework for studying the host-HIVinteractions through comparative network analysis across different species.Results: Based on the proposed framework, we test our hypothesis that HIV-1 attacks essential biologicalpathways that are conserved across species. We selected the Homo sapiens and Mus musculus PPI networkswith the largest coverage among the PPI networks that are available from public databases. By using a localnetwork alignment algorithm based on hidden Markov models (HMMs), we first identified the pathways that areconserved in both networks. Next, we analyzed the HIV-1 susceptibility of these pathways, in comparison withrandom pathways in the human PPI network. Our analysis shows that the conserved pathways have asignificantly higher probability of being intercepted by HIV-1. Furthermore, Gene Ontology (GO) enrichmentanalysis shows that most of the enriched GO terms are related to signal transduction, which has beenconjectured to be one of the major mechanisms targeted by HIV-1 for the takeover of the host cell.1Conclusions: This proof-of-concept study clearly shows that the comparative analysis of PPI networks acrossdifferent species can provide important insights into the host-HIV interactions and the detailed mechanisms ofHIV-1. We expect that comparative multiple network analysis of various species that have different levels ofsusceptibility to similar lentiviruses may provide a very effective framework for generating novel, andexperimentally verifiable, hypotheses on the mechanisms of HIV-1. We believe that the proposed framework hasthe potential to expedite the elucidation of the important mechanisms of HIV-1, and ultimately, the discovery ofnovel anti-HIV drugs.BackgroundAcquired immune deficiency syndrome (AIDS), one of the most destructive pandemics in recorded historyaccording to the statistics from the World Health Organization (WHO) [1], has killed more than 25 millionpeople since it was first recognized in 1981. Human immunodeficiency virus type one (HIV-1) has beenfound to be the causative pathogen of AIDS [2, 3]. HIV-1 is a lentivirus, a slow retrovirus that isresponsible for long-duration illness with a long incubation period. HIV-1 has 9 genes which encode up to19 proteins due to post-translational cleavage [4]. By reverse transcription from viral RNA tohost-integrable DNA, the virus can become active and replicate to cause rapid T cell depletion, immunesystem collapse, and opportunistic infections that mark the advent of AIDS [5].Although advances in antiviral therapy and management of opportunistic infection for AIDS haveremarkably improved the general health, the expensive cost and adverse effects of the available drugs havemotivated many researchers to explore novel avenues to anti-HIV-1 drug discovery. With the increasingcoverage of HIV-1 and human protein interactions in the literature [6–11], a human/HIV-1 interactome hasbeen created [12], which can play a critical role in better understanding the virology and pathology of thisinfectious disease and developing new therapeutics. In addition to this, the availability of large-scalebiological networks, including protein-protein interaction (PPI) networks, has led to the introduction ofsystems biology approaches for novel HIV-1 drug discovery [13, 14]. In [13], Balakrishnan et al. proposed tofind alternative pathways to circumvent the HIV-1 intercepted pathways based on the efficiency androbustness of biological processes. The main goal was to generate new hypotheses regarding HIV-12targeted pathways and their effects on various molecular functions, which will help us better understandthe mechanisms of HIV-1 takeover of the host cell and find ways to circumvent it. The study was based oncurated signal transduction pathways obtained from multiple pathway databases. One practical problem ofthis pathway-based approach is that the currently known pathways cover only a limited number of humanproteins, hence it may exclude important HIV-1 targets from the analysis. Moreover, many curatedpathways in public databases overlap with each other, which may introduce bias in the analysis. On theother hand, Lin et al. [14] proposed comparative studies of host-virus protein interactions across human(Homo sapiens) and other animal models that may be invaded by similar lentiviruses that causeimmunosuppression or immunoproliferation, including three mammalian species: chimpanzee (Pantroglodyte), rhesus macaque (Macaca mulatta), and mouse (Mus musculus). All these animal models havebeen extensively studied to understand the HIV-1 host-virus interplay [15, 16]. Comparative studies ofhost-virus interactions may provide new insights into why different species have different susceptibility toHIV-1, which may lead to the development of potential therapeutics in the long run.Motivated by these works, we propose a novel framework for studying human/HIV-1 interactions, based oncomparative analysis of the human PPI network and the PPI network of other species that are susceptibleto lentivirus invasion. It has been shown that the comparative analysis of PPI networks of different speciescan identify conserved pathways that carry essential cellular functionalities [17–36]. Furthermore, HIV-1has to be a “minimalist” in order to survive, and for this reason, it has been believed to target theseessential pathways that are conserved across species [13, 37]. As a result, the comparative analysis of PPInetworks may be used to generate new hypotheses that will be useful in


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