Induction of intrahepatic HCV NS4B, NS5A and NS5B-specific cellular immune responses following peripheral immunization

PLoS One. 2012;7(12):e52165. doi: 10.1371/journal.pone.0052165. Epub 2012 Dec 21.

Abstract

Numerous studies have suggested that an effective Hepatitis C Virus (HCV) vaccine must induce strong cytotoxic and IFN-γ+ T cell responses targeting the non-structural region of the virus. Most importantly, these responses must be able to migrate into and remain functional within the liver, an organ known to cause T cell tolerance. Using three novel HCV DNA vaccines encoding non-structural proteins NS4B, NS5A and NS5B, we assessed the ability of peripheral immunization to induce functional intrahepatic immunity both in the presence and absence of cognate HCV antigen expression within the liver. We have shown that these constructs induced potent HCV-specific CD4+ and CD8+ T cell responses in the spleen of C57BL/6 mice and that these responses were detected within the liver following peripheral immunization. Additionally, using a transfection method to express HCV antigen within the liver, we showed that intrahepatic HCV-specific T cells remained highly functional within the liver and retained the ability to become highly activated as evidenced by upregulation of IFN-γ and clearance of HCV protein expressing hepatocytes. Taken together, these findings suggest that peripheral immunization can induce potent HCV-specific T cell responses able to traffic to and function within the tolerant environment of the liver.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / metabolism
  • Cells, Cultured
  • Female
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Hepacivirus / immunology
  • Immunity, Cellular / immunology*
  • Liver / immunology*
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Confocal
  • Viral Nonstructural Proteins / immunology*

Substances

  • NS-5 protein, hepatitis C virus
  • NS4B protein, flavivirus
  • Viral Nonstructural Proteins

Grant support

This manuscript was supported by the Commonwealth Universal Research Enhancement (CURE) competitive grant program funded through Pennsylvania's share of the 2009-2010 national tobacco settlement (RFA 08-07-07). The title of the grant is “Development of a DNA Vaccine Strategy for Hepatitis C Virus” (SAP 4100051718). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.