title: Mechanisms involved in stimulation of human immunodeficiency virus type 1 replication by aminooxypentane RANTES.
abstract: Aminooxypentane (AOP)-RANTES is a potent inhibitor of nonsyncytium-inducing (NSI), CCR5-tropic (R5) human immunodeficiency virus type 1 (HIV-1) isolates. Although classical chemotactic responses are not induced in primary leukocytes by AOP-RANTES, recent studies suggest that a remnant of cell signaling occurs upon binding of receptor to this compound. We have detected a breakthrough of NSI/R5 replication from the inhibitory effects of high AOP-RANTES concentrations (<100 nM). A stimulation of different primary syncytium-inducing (SI), CXCR4-tropic (X4) HIV-1 isolates was also observed in the presence of AOP-RANTES. This stimulation was also observed after 110 h in PCR and RT-PCR for minus-strand strong-stop DNA and unspliced and multiply spliced RNA, respectively. However, there was significant variability between different SI/X4 or NSI/R5 HIV-1 isolates with regard to this AOP-RANTES-mediated stimulation or breakthrough, respectively. To further define the mechanism(s) responsible for this AOP-RANTES effect, we performed detailed retroviral replication studies with an NSI/R5 (B-92BR021) and SI/X4 (D-92UG021) HIV-1 isolate in the presence of the drug. Treatment of peripheral blood mononuclear cells with 125 nM AOP-RANTES and virus did not alter coreceptor expression, HIV-1 entry, reverse transcription, or mRNA transcription from the long terminal repeat, but it did result in increased HIV-1 integration. This AOP-RANTES-mediated increase in HIV-1 integration was diminished by treatment with pertussis toxin. Phosphorylation of the mitogen-activated protein kinase (MAPK) isoforms, extracellular signal-regulated kinase 1 (ERK1) and ERK2, was increased in a CD4(+) CCR5(+) U87 cell line treated with AOP-RANTES or with an NSI/R5 HIV-1 isolate. These findings suggest that AOP-RANTES may induce a MAPK/ERK signal transduction pathway upon binding to a G-protein-coupled receptor. MAPK/ERK1 and -2 appear to phosphorylate the HIV-1 preintegration complex, a step necessary for nuclear translocation and successful integration.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Marozsan
authors.forename: V S
authors.initials: VS
authors.lastname: Torre
authors.forename: M
authors.initials: M
authors.lastname: Johnson
authors.forename: S C
authors.initials: SC
authors.lastname: Ball
authors.forename: J V
authors.initials: JV
authors.lastname: Cross
authors.forename: D J
authors.initials: DJ
authors.lastname: Templeton
authors.forename: M E
authors.initials: ME
authors.lastname: Quiñones-Mateu
authors.forename: R E
authors.initials: RE
authors.lastname: Offord
authors.forename: E J
authors.initials: EJ
authors.lastname: Arts
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D018946:Chemokine CCL5 / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000821:virology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011533:Proviruses / Q000235:genetics; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D014158:Transcription, Genetic; D016662:Virus Integration; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D018946:Chemokine CCL5; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C111989:aminooxypentane-RANTES; D020928:Mitogen-Activated Protein Kinases