title: Enhanced T cell responses against hepatitis C virus by ex vivo targeting of adenoviral particles to dendritic cells.
abstract: Injection of dendritic cells (DCs) presenting viral proteins constitutes a promising approach to stimulate T cell immunity against hepatitis C virus (HCV). Here we describe a strategy to enhance antigen loading and immunostimulatory functions of DCs useful in the preparation of therapeutic vaccines. Incubation of murine DCs with CFm40L, an adapter molecule containing the coxsackie-adenovirus receptor fused to the ecto-domain of murine CD40L-induced DC maturation, produced high amounts of interleukin-12 and up-regulation of molecules associated with T helper 1 responses. Accordingly, targeting of an adenovirus encoding HCV NS3 protein (AdNS3) to DCs with CFm40L strongly enhanced NS3 presentation in vitro, activating interferon-γ-producing T cells. Moreover, immunization of mice with these DCs promoted strong CD4 and CD8 T cell responses against HCV NS3. CFh40L, a similar adapter molecule containing human CD40L, enhanced transduction and maturation of human monocyte-derived DCs. Comparison of DCs transduced with AdNS3 and CFh40L from patients with chronic HCV infection and healthy donors revealed similar maturation levels. More importantly, DCs from the patients induced NS3-specific responses when transduced with AdNS3 and CFh40L but not with AdNS3 alone.
  
  
  CONCLUSIONS
  DCs transduced with AdNS3 and the adapter molecule CFm/h40L exhibit enhanced immunostimulatory functions, induce robust anti-HCV NS3 immunity in animals, and can induce antiviral immune responses in subjects with chronic HCV infection. This strategy may serve as therapeutic vaccination for patients with chronic hepatitis C.
authors: Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors: Itziar
authors: I
authors: Echeverria
authors: Alexander
authors: A
authors: Pereboev
authors: Leyre
authors: L
authors: Silva
authors: Aintzane
authors: A
authors: Zabaleta
authors: José Ignacio
authors: JI
authors: Riezu-Boj
authors: Marta
authors: M
authors: Bes
authors: María
authors: M
authors: Cubero
authors: Francisco
authors: F
authors: Borras-Cuesta
authors: Juan José
authors: JJ
authors: Lasarte
authors: Juan Ignacio
authors: JI
authors: Esteban
authors: Jesús
authors: J
authors: Prieto
authors: Pablo
authors: P
authors: Sarobe
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D000818:Animals; D023201:CD40 Ligand / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D004195:Disease Models, Animal; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D014161:Transduction, Genetic; D014761:Viral Hepatitis Vaccines / Q000276:immunology / Q000627:therapeutic use; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014771:Virion / Q000502:physiology*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D023201:CD40 Ligand; D007371:Interferon-gamma; D011993:Recombinant Fusion Proteins; D014761:Viral Hepatitis Vaccines; D017361:Viral Nonstructural Proteins; C494066:CFm40L fusion protein; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases