Abstract
Vpr, a HIV-1 accessory protein, was believed to be present in the plasma of HIV-1-positive patients, and our previous work demonstrated the presence of plasma Vpr in 20 out of 52 patients. Interestingly, our data revealed that patients' viral titer was correlated with the level of Vpr detected in their plasma. Here, we first show that rVpr, when incubated with human monocytes or MDMs, caused viral production from latently infected cells, and IL-6 was identified as a responsible factor. The induction of IL-6 by rVpr was dependent on signaling through TLR4 and its adaptor molecule, MyD88. We next provide evidence that rVpr induced the formation of OxPC and that a mAb against OxPC blocked rVpr-induced IL-6 production with the concomitant attenuation of MAPK activation. Moreover, the addition of NAC, a scavenger of ROS, abrogated the rVpr-induced formation of OxPC, the phosphorylation of C/EBP-beta, a substrate of MAPK, and IL-6 production. As rIL-6 reactivated viral replication in latently infected cells, our data indicate that rVpr-induced oxidative stress triggers cell-based innate immune responses and reactivates viral production in latently infected cells via IL-6 production. Our results suggest that Vpr should be monitored based on the viral titer, and they provide the rationale for the development of novel, anti-AIDS therapeutics targeting Vpr.
MeSH terms
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Blotting, Western
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CCAAT-Enhancer-Binding Protein-beta / antagonists & inhibitors
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CCAAT-Enhancer-Binding Protein-beta / genetics
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CCAAT-Enhancer-Binding Protein-beta / metabolism
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Cells, Cultured
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Humans
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Immunity, Innate
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Interleukin-6 / genetics
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Interleukin-6 / metabolism*
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MAP Kinase Signaling System
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Monocytes / cytology
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Monocytes / metabolism
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Myeloid Differentiation Factor 88 / antagonists & inhibitors
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / metabolism*
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Oxidation-Reduction
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Phospholipids / chemistry
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Phospholipids / metabolism
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Promoter Regions, Genetic / genetics
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Protein Array Analysis
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / pharmacology
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Reactive Oxygen Species / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Toll-Like Receptor 4 / antagonists & inhibitors
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / metabolism*
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Virus Activation*
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Virus Latency*
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Virus Replication
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vpr Gene Products, Human Immunodeficiency Virus / genetics
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vpr Gene Products, Human Immunodeficiency Virus / metabolism*
Substances
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CCAAT-Enhancer-Binding Protein-beta
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CEBPB protein, human
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Interleukin-6
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MYD88 protein, human
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Myeloid Differentiation Factor 88
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NF-kappa B
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Phospholipids
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RNA, Messenger
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RNA, Small Interfering
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Reactive Oxygen Species
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TLR4 protein, human
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Toll-Like Receptor 4
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vpr Gene Products, Human Immunodeficiency Virus