title: Enhancement of cellular and humoral immune responses to hepatitis C virus core protein using DNA-based vaccines augmented with cytokine-expressing plasmids.
abstract: Development of a broad based cellular and humoral immune response to hepatitis C virus (HCV) structural proteins may be important for irradication of infection. DNA-based immunization is a promising approach to generate HCV-specific immune responses. Previous studies of DNA-based immunizations in mice using an HCV core DNA expression plasmid (pHCV2-2) demonstrated an efficient CTL response against HCV core epitopes; however, the humoral and Th cell proliferative responses were found to be weak. To enhance the immunogenicity of this nonsecreted viral structural protein at the B and T cell level, we coimmunized mice with pHCV2-2 and DNA expression constructs encoding for mouse IL-2, IL-4, and granulocyte-macrophage CSF proteins. Under these experimental conditions, a seroconversion frequency to anti-HCV core increased from 40 to 80% in immunized mice. The CD4+ inflammatory T cell proliferative responses as well as CD8+ CTL activity to HCV core protein were enhanced substantially after coimmunization with the IL-2 and granulocyte-macrophage CSF DNA expression constructs. In contrast, coimmunization with an IL-4-producing construct induced differentiation of Th cells toward a Th0 subtype and suppressed HCV core-specific CTL activity. Taken together, these studies emphasize that generation of antiviral immune responses using DNA-based immunization may be modified by local cytokine production at the site of Ag presentation.
authors.affiliation: Molecular Hepatology Laboratory, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown 02129, USA.
authors.forename: M
authors.initials: M
authors.lastname: Geissler
authors.forename: A
authors.initials: A
authors.lastname: Gesien
authors.forename: K
authors.initials: K
authors.lastname: Tokushige
authors.forename: J R
authors.initials: JR
authors.lastname: Wands
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000917:Antibody Formation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000008:administration & dosage / Q000276:immunology*; D004279:DNA, Viral / Q000276:immunology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology*; D018937:Hepatitis C Antibodies / Q000276:immunology; D007376:Interleukin-2 / Q000008:administration & dosage; D015847:Interleukin-4 / Q000008:administration & dosage; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D019251:Nucleocapsid / Q000276:immunology; D014758:Viral Core Proteins / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D004279:DNA, Viral; D018937:Hepatitis C Antibodies; D007376:Interleukin-2; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor