title: Hepatitis C virus NS3/NS4A DNA vaccine induces multiepitope T cell responses in rhesus macaques mimicking human immune responses [corrected].
abstract: Numerous studies have suggested that an effective hepatitis C virus (HCV) vaccine must induce a strong T helper 1 (Th1) T cell response. While several therapeutic vaccine candidates have shown promise in clinical trials, response rates have been low suggesting that further optimization is important. However, such optimization has been hindered by a lack of a benchmark animal model in which to test vaccine-induced immune responses before clinical evaluation. The goal of this study was to analyze the utility of the rhesus macaque vaccination model in assessing HCV vaccine-induced T cell responses. To test this, we employed the use of a novel HCV genotype 1a/1b consensus DNA vaccine encoding both HCV nonstructural protein 3 (NS3) and nonstructural protein 4A (NS4A) proteins. Following immunization, rhesus macaques mounted HCV-specific responses strikingly similar to those reported in resolving patients, including strong NS3-specific interferon-γ (IFN-γ) responses, robust CD4(+) and CD8(+) T cell proliferation, and induction of polyfunctional T cells. Additionally, fine epitope mapping revealed one animal that mounted a T cell response against a known HCV NS3 human leukocyte antigen A2 (HLA-A2) epitope previously identified in humans. Taken together our findings suggest that the rhesus macaque vaccination model is a useful tool in the evaluation of immune responses induced by HCV immunogens.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Krystle A
authors.initials: KA
authors.lastname: Lang Kuhs
authors.forename: Arielle A
authors.initials: AA
authors.lastname: Ginsberg
authors.forename: Jian
authors.initials: J
authors.lastname: Yan
authors.forename: Roger W
authors.initials: RW
authors.lastname: Wiseman
authors.forename: Amir S
authors.initials: AS
authors.lastname: Khan
authors.forename: Niranjan Y
authors.initials: NY
authors.lastname: Sardesai
authors.forename: David H
authors.initials: DH
authors.lastname: O'Connor
authors.forename: David B
authors.initials: DB
authors.lastname: Weiner
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005805:Genes, MHC Class I; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008253:Macaca mulatta; D013601:T-Lymphocytes / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology*; D014761:Viral Hepatitis Vaccines / Q000235:genetics / Q000276:immunology*; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000276:immunology*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D019444:Vaccines, DNA; D014761:Viral Hepatitis Vaccines; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases