title: Synthetic Vpr protein activates activator protein-1, c-Jun N-terminal kinase, and NF-kappaB and stimulates HIV-1 transcription in promonocytic cells and primary macrophages.
abstract: The human immunodeficiency virus (HIV) Vpr protein plays a critical role in AIDS pathogenesis, especially by allowing viral replication within nondividing cells such as mononuclear phagocytes. Most of the data obtained so far have been in experiments with endogenous Vpr protein; therefore the effects of extracellular Vpr protein remain largely unknown. We used synthetic Vpr protein to activate nuclear transcription factors activator protein-1 (AP-1) and NF-kappaB in the promonocytic cell line U937 and in primary macrophages. Synthetic HIV-1 Vpr protein activated AP-1, c-Jun N-terminal kinase, and MKK7 in both U937 cells and primary macrophages. Synthetic Vpr activated NF-kappaB in primary macrophages and to a lesser extent in U937 cells. Because synthetic Vpr activated AP-1 and NF-kappaB, which bind to the HIV-1 long terminal repeat, we investigated the effect of synthetic Vpr on HIV-1 replication. We observed that synthetic Vpr stimulated HIV-1 long terminal repeat in U937 cells and enhanced viral replication in chronically infected U1 promonocytic cells. Similarly, synthetic Vpr stimulated HIV-1 replication in acutely infected primary macrophages. Activation of transcription factors and enhancement of viral replication in U937 cells and primary macrophages were mediated by both the N-terminal and the C-terminal moieties of synthetic Vpr. Therefore, our results suggest that extracellular Vpr could fuel the progression of AIDS via stimulation of HIV-1 provirus present in such cellular reservoirs as mononuclear phagocytes in HIV-infected patients.
authors.affiliation: Department of Virology, EA3186, IFR133, Franche-Comté University, F-25030 Besançon, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Varin
authors.forename: Anne-Zélie
authors.initials: AZ
authors.lastname: Decrion
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Sabbah
authors.forename: Vincent
authors.initials: V
authors.lastname: Quivy
authors.forename: Joséphine
authors.initials: J
authors.lastname: Sire
authors.forename: Carine
authors.initials: C
authors.lastname: Van Lint
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Roques
authors.forename: Bharat B
authors.initials: BB
authors.lastname: Aggarwal
authors.forename: Georges
authors.initials: G
authors.lastname: Herbein
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000473:pathology / Q000821:virology; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D018450:Disease Progression; D004789:Enzyme Activation; D016336:Gene Products, vpr / Q000378:metabolism*; D017930:Genes, Reporter; D016655:HIV Core Protein p24 / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000821:virology; D048688:MAP Kinase Kinase 7 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology* / Q000201:enzymology; D009000:Monocytes / Q000166:cytology* / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism*; D010586:Phagocytes / Q000473:pathology / Q000821:virology; D010587:Phagocytosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic; D020298:U937 Cells; D054325:vpr Gene Products, Human Immunodeficiency Virus
chemical_list: D016336:Gene Products, vpr; D016655:HIV Core Protein p24; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D054325:vpr Gene Products, Human Immunodeficiency Virus; D048031:JNK Mitogen-Activated Protein Kinases; D048688:MAP Kinase Kinase 7; C482569:MAP2K7 protein, human