Spumaviruses

Loh, Philip C.

doi:10.1007/978-1-4899-1627-3_6

Cited by 12 publications

(4 citation statements)

References 88 publications

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“…51,52 The drug targets from STITCH were used as predictors and the differentially expressed genes were used as a response variable. GUIDE constructed regression trees that correlate the drug targets to the expressed genes.…”

Section: Investigation Of the Statistical Significance Of The Ilp Prementioning

confidence: 99%

Identification of drug-specific pathways based on gene expression data: application to drug induced lung injury

et al. 2015

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Identification of signaling pathways that are functional in a specific biological context is a major challenge in systems biology, and could be instrumental to the study of complex diseases and various aspects of drug discovery. Recent approaches have attempted to combine gene expression data with prior knowledge of protein connectivity in the form of a PPI network, and employ computational methods to identify subsets of the protein-protein-interaction (PPI) network that are functional, based on the data at hand. However, the use of undirected networks limits the mechanistic insight that can be drawn, since it does not allow for following mechanistically signal transduction from one node to the next. To address this important issue, we used a directed, signaling network as a scaffold to represent protein connectivity, and implemented an Integer Linear Programming (ILP) formulation to model the rules of signal transduction from one node to the next in the network. We then optimized the structure of the network to best fit the gene expression data at hand. We illustrated the utility of ILP modeling with a case study of drug induced lung injury. We identified the modes of action of 200 lung toxic drugs based on their gene expression profiles and, subsequently, merged the drug specific pathways to construct a signaling network that captured the mechanisms underlying Drug Induced Lung Disease (DILD). We further demonstrated the predictive power and biological relevance of the DILD network by applying it to identify drugs with relevant pharmacological mechanisms for treating lung injury. Insight, innovation, integrationIn this manuscript we introduce a novel approach for the identification of signaling pathways that are functional in a specific biological context, by leveraging gene expression data and prior knowledge of protein connectivity. In more detail, we introduce a linear programming formulation to model signal transduction from one node to the next in a Prior Knowledge Network (PKN), and by minimizing the mismatch between model predictions and experimental data, we are able to identify subsets of the PKN that are most probably functional in the specific biological context. More specifically, we address the problem of identifying the modes of action of drugs that have been reported to induce respiratory side effects, based on their gene expression profiles, and subsequently, merge the drug specific pathways together to construct a signaling network that captures the signaling mechanisms underlying Drug Induced Lung Disease (DILD). Moreover, to demonstrate the predictive power and biological relevance of the DILD network, we use it to suggest potential drug repositioning for treating lung injury.

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Section: Investigation Of the Statistical Significance Of The Ilp Prementioning

confidence: 99%

Identification of drug-specific pathways based on gene expression data: application to drug induced lung injury

et al. 2015

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“…Foamy viruses (FV) are ubiquitous in bovines, felines and non-human primates, but are not associated with any diseases (Loh, 1993 ;Schweizer et al, 1995). Zoonotic infections of humans exposed to primates occur without any recognized clinical sequelae (Schweizer et al, 1995(Schweizer et al, , 1997Goepfert et al, 1996 ;Neumann-Haefelin & Schweizer, 1997 ;Weiss, 1998 ;Heneine et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Comparative sequence analysis and predictions for the envelope glycoproteins of foamy viruses.

Wang

Mulligan

1999

Journal of General Virology

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The foamy viruses (FVs) are a genus of complex retroviruses that has recently been found to possess several novel molecular features. There is increasing interest in the development of FVs as novel vectors for gene delivery. As there are remarkably few published studies of FV proteins, these recent findings prompted us to predict the structural features of FV glycoproteins with the aid of computer programs. We analysed all seven available FV Env sequences, a greater number of sequences than in previously published analyses. The relative rates of change for FV structural proteins were Pol Env Gag in increasing order, which differs from all other retroviruses. We determined that this difference is primarily caused by a higher relative rate of change for FV Gag proteins. We analysed the functional domains of FV glycoproteins and found that their structural organization was generally similar to other retroviruses. Putative structures were identified for the signal peptide, cleavage site, fusion peptide, membrane-spanning domain and the unique endoplasmic reticulum retrieval signal. Based on the predicted secondary structure of the transmembrane glycoprotein (TM) subunit, gp47, we also identified a unique prolonged central ' sheets and loops ' region as the dominant feature of an unusually lengthy TM ectodomain. This lengthy central domain was flanked at each end by α-helices. The predictions reported here will stimulate and facilitate experimental approaches to better understand the structure and function of FV glycoproteins, and should assist in the planning and development of FV vectors.

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“…Foamy viruses (FVs) (Spumavirinae) represent a unique genus of retrovirus, endemic in a number of mammalian species, including nonhuman primates, cats, rodents, and cows (20,25,36). Extremely cytopathic in vitro, FVs have yet to be associated with any disease pathology in their natural hosts.…”

mentioning

confidence: 99%

Persistent Zoonotic Infection of a Human with Simian Foamy Virus in the Absence of an Intactorf-2Accessory Gene

Callahan

Switzer

Matthews

et al. 1999

J Virol

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Although foamy viruses (FVs) are endemic among nonhuman primates, FV infection among humans is rare. Recently, simian foamy virus (SFV) infection was reported in 4 of 231 individuals occupationally exposed to primates (1.8%). Secondary transmission to spouses has not been seen, suggesting that while FV is readily zoonotic, humans may represent dead-end hosts. Among different simian species, SFV demonstrates significant sequence diversity within the U3 region of the long terminal repeat (LTR) and 3′ accessory open reading frames (ORFs). To examine if persistent human SFV infection and apparent lack of secondary transmission are associated with genetic adaptations in FV regulatory regions, we conducted sequence analysis of the LTR, internal promoter, ORF-1, and ORF-2 on a tissue culture isolate and peripheral blood mononuclear cell samples from a human infected with SFV of African green monkey origin (SFV-3). Compared to the prototype SFV-3 sequence, the LTR, internal promoter, and FV transactivator (ORF-1) showed sequence conservation, suggesting that FV zoonosis is not dependent on host-specific adaptation to these transcriptionally important regions. However, ORF-2 contains a number of deleterious mutations predicted to result in premature termination of protein synthesis. ORF-2 codes in part for the 60-kDa Bet fusion protein, proposed to be involved in the establishment of persistent cellular SFV infections. These results suggest that persistent human infection by SFV and reduced transmissibility may be influenced by the absence of a functional ORF-2.

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Spumaviruses

Cited by 12 publications

References 88 publications

Identification of drug-specific pathways based on gene expression data: application to drug induced lung injury

Identification of drug-specific pathways based on gene expression data: application to drug induced lung injury

Comparative sequence analysis and predictions for the envelope glycoproteins of foamy viruses.

Persistent Zoonotic Infection of a Human with Simian Foamy Virus in the Absence of an Intactorf-2Accessory Gene

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