Enhanced T cell responses against hepatitis C virus by ex vivo targeting of adenoviral particles to dendritic cells

• Published in: Hepatology (Baltimore, Md.) Vol. 54; no. 1; pp. 28 - 37
• Main Authors: Echeverria, Itziar, Pereboev, Alexander, Silva, Leyre, Zabaleta, Aintzane, Riezu‐Boj, José Ignacio, Bes, Marta, Cubero, María, Borras‐Cuesta, Francisco, Lasarte, Juan José, Esteban, Juan Ignacio, Prieto, Jesús, Sarobe, Pablo
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-07-2011; Wiley; Wiley Subscription Services, Inc
• Subjects: Adenoviridae; Adenoviridae - genetics; Adenoviridae - physiology; Adenovirus; Adenoviruses; Animals; Atoms & subatomic particles; Biological and medical sciences; CD40 Ligand - genetics; CD40 Ligand - physiology; Cells, Cultured; Dendritic cells; Dendritic Cells - metabolism; Dendritic Cells - pathology; Dendritic Cells - virology; Disease Models, Animal; Gastroenterology. Liver. Pancreas. Abdomen; Hepacivirus - immunology; Hepatitis; Hepatitis C; Hepatitis C - immunology; Hepatitis C - pathology; Hepatitis C - prevention & control; Hepatitis C virus; Humans; Interferon; Interferon-gamma - metabolism; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Lymphocytes; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - physiology; T cell receptors; T-Lymphocytes, Helper-Inducer - metabolism; T-Lymphocytes, Helper-Inducer - pathology; T-Lymphocytes, Helper-Inducer - physiology; Transduction, Genetic; Viral Hepatitis Vaccines - immunology; Viral Hepatitis Vaccines - therapeutic use; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - immunology; Viral Nonstructural Proteins - metabolism; Virion - physiology; Virus; Dendritic cell; Targeting; Ex vivo; Immunological investigation; Gastroenterology; T-Lymphocyte; Flaviviridae; Hepatitis C virus; Hepacivirus
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.24325

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. (HEPATOLOGY 2011;)