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    HIV-1 Vpr Modulates Macrophage Metabolic Pathways: A SILAC-Based Quantitative Analysis

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    HIV-1 Vpr modulates macrophage ...
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    Genre
    Journal Article
    Date
    2013-07-12
    Author
    Barrero, CA
    Datta, PK
    Sen, S
    Deshmane, S
    Amini, S
    Khalili, K
    Merali, S
    Subject
    Blotting, Western
    Computational Biology
    Glycolysis
    Humans
    Isotope Labeling
    Macrophages
    Metabolic Networks and Pathways
    Models, Biological
    Protein Interaction Maps
    Proteome
    Proteomics
    Reproducibility of Results
    Transduction, Genetic
    U937 Cells
    vpr Gene Products, Human Immunodeficiency Virus
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    Permanent link to this record
    http://hdl.handle.net/20.500.12613/5387
    
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    DOI
    10.1371/journal.pone.0068376
    Abstract
    Human immunodeficiency virus type 1 encoded viral protein Vpr is essential for infection of macrophages by HIV-1. Furthermore, these macrophages are resistant to cell death and are viral reservoir. However, the impact of Vpr on the macrophage proteome is yet to be comprehended. The goal of the present study was to use a stable-isotope labeling by amino acids in cell culture (SILAC) coupled with mass spectrometry-based proteomics approach to characterize the Vpr response in macrophages. Cultured human monocytic cells, U937, were differentiated into macrophages and transduced with adenovirus construct harboring the Vpr gene. More than 600 proteins were quantified in SILAC coupled with LC-MS/MS approach, among which 136 were significantly altered upon Vpr overexpression in macrophages. Quantified proteins were selected and clustered by biological functions, pathway and network analysis using Ingenuity computational pathway analysis. The proteomic data illustrating increase in abundance of enzymes in the glycolytic pathway (pentose phosphate and pyruvate metabolism) was further validated by western blot analysis. In addition, the proteomic data demonstrate down regulation of some key mitochondrial enzymes such as glutamate dehydrogenase 2 (GLUD2), adenylate kinase 2 (AK2) and transketolase (TKT). Based on these observations we postulate that HIV-1 hijacks the macrophage glucose metabolism pathway via the Vpr-hypoxia inducible factor 1 alpha (HIF-1 alpha) axis to induce expression of hexokinase (HK), glucose-6-phosphate dehyrogenase (G6PD) and pyruvate kinase muscle type 2 (PKM2) that facilitates viral replication and biogenesis, and long-term survival of macrophages. Furthermore, dysregulation of mitochondrial glutamate metabolism in macrophages can contribute to neurodegeneration via neuroexcitotoxic mechanisms in the context of NeuroAIDS. © 2013 Barrero et al.
    Citation to related work
    Public Library of Science (PLoS)
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    PLoS ONE
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    ae974a485f413a2113503eed53cd6c53
    http://dx.doi.org/10.34944/dspace/5369
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