title: Inhibition of herpesvirus-induced HIV-1 replication by cyclopentenone prostaglandins: role of IkappaB kinase (IKK).
abstract: OBJECTIVE
  Herpes simplex virus (HSV) infections have been associated with reactivation of HIV-1 replication and increases of HIV-1-load in plasma of co-infected individuals. The present authors have previously reported that in epithelial cells HSV-1 induces the IkappaB-kinase (IKK) causing persistent activation of NF-kappaB, a critical regulator of HIV-1 replication. The present study was performed to investigate whether HSV-1-infection could induce IKK-mediated NF-kappaB activation and enhance HIV-1 expression in human T cells, and to analyze the effect of the IKK-inhibitor prostaglandin A1 (PGA1) and other prostanoids on the NF-kappaB-mediated HSV-HIV interaction.
  
  
  METHODS
  Induction of IKK and NF-kappaB activity was determined in lymphoblastoid Jurkat cells and HIV-1 chronically-infected H9 and ACH-2 cells by kinase assay and electrophoretic mobility shift assay, respectively. The effect of HSV-1 and different prostanoids on HIV-1 expression and replication was determined in Jurkat cells transfected with HIV-1-LTR-driven reporter genes, and in H9 and ACH-2 cells by p24-antigen level evaluation. The role of NF-kappaB in HSV-1-induced HIV-1 expression was investigated by using the IkappaBalpha dominant-negative IkappaBalpha-AA in co-transfection experiments.
  
  
  RESULTS
  In human T lymphoblastoid cells HSV-1 potently induces IKK activity, causing a persistent induction of NF-kappaB. HSV-1-induced IKK and NF-kappaB function results in transactivation of HIV-1-LTR-regulated genes and induction of HIV-1 replication in chronically-infected T cells. The cyclopentenone PGA1 inhibits HSV-1-induced IKK and NF-kappaB activities, blocking HIV-1-LTR-driven expression and preventing HSV-1-induced HIV-1 replication in co-infected cells.
  
  
  CONCLUSIONS
  The results indicate that IKK is a key factor in triggering HSV-1-induced HIV-1 transcription in chronically-infected cells and identify cyclopentenone prostanoids as potent inhibitors of HSV-1-induced HIV-1 reactivation.
authors.affiliation: Department of Biology, University of Rome Tor Vergata, 00133 Rome.
authors.forename: Carla
authors.initials: C
authors.lastname: Amici
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Belardo
authors.forename: Carmela
authors.initials: C
authors.lastname: Rozera
authors.forename: Daniela
authors.initials: D
authors.lastname: Bernasconi
authors.forename: M Gabriella
authors.initials: MG
authors.lastname: Santoro
mesh_terms: D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D024202:Electrophoretic Mobility Shift Assay; D016655:HIV Core Protein p24 / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006561:Herpes Simplex / Q000378:metabolism / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D051550:I-kappa B Kinase; D019169:Jurkat Cells; D016328:NF-kappa B / Q000378:metabolism; D011454:Prostaglandins A / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology; D014158:Transcription, Genetic; D014709:Vero Cells; D019562:Viral Load; D014775:Virus Activation / Q000187:drug effects
chemical_list: D016655:HIV Core Protein p24; D016328:NF-kappa B; D011454:Prostaglandins A; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C100573:prostaglandin A1