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Enhanced T cell responses against hepatitis C virus by ex vivo targeting of adenoviral particles to dendritic cells
Author(s) -
Echeverria Itziar,
Pereboev Alexander,
Silva Leyre,
Zabaleta Aintzane,
RiezuBoj José Ignacio,
Bes Marta,
Cubero María,
BorrasCuesta Francisco,
Lasarte Juan José,
Esteban Juan Ignacio,
Prieto Jesús,
Sarobe Pablo
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24325
Subject(s) - dendritic cell , immune system , virology , immunology , cd8 , t cell , cytotoxic t cell , adenoviridae , ns3 , biology , hepatitis c virus , medicine , virus , in vitro , genetic enhancement , gene , biochemistry
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. Conclusion: 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. (H EPATOLOGY 2011;)