title: Activation of refractory T cell responses against hepatitis C virus core protein by ablation of interfering hydrophobic domains.
abstract: Hepatitis C virus (HCV) is the major pathogen of chronic hepatitis and liver disease, but currently there are no prophylactic HCV vaccines available. The HCV core protein-encoding sequence is among the most conserved genes in the HCV genome, making it a prime candidate for a component of a vaccine. The core protein localizes to the endoplasmic reticulum (ER) through a C-terminal hydrophobic region that is cotranslationally inserted into the ER membrane. Here we show that removal of the C-terminal hydrophobic region confers nuclear localization and enhances proteasomal degradation of the core protein in mammalian cells. This efficient protein proteolysis induces enhanced core-specific CD8(+) T cell responses in BALB/c mice immunized with plasmids expressing C-terminal deletions of the HCV core protein. These results suggest that more potent HCV vaccines can be achieved by targeting the core protein for proteasomal degradation by deletion of its C-terminal hydrophobic domain.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine/Texas Children's Hospital/The Methodist Hospital, Baylor College of Medicine, Houston, 77030, USA.
authors.forename: Helen A
authors.initials: HA
authors.lastname: Andersson
authors.forename: Rana A K
authors.initials: RA
authors.lastname: Singh
authors.forename: Michael A
authors.initials: MA
authors.lastname: Barry
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D006367:HeLa Cells; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology / Q000517:prevention & control; D018936:Hepatitis C Antigens / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics*; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014758:Viral Core Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology*
chemical_list: D018936:Hepatitis C Antigens; D019444:Vaccines, DNA; D014758:Viral Core Proteins; C499352:core protein p22, Hepatitis C virus; D046988:Proteasome Endopeptidase Complex