CELL-MEDIATED IMMUNITY IN HEPATITIS C VIRUS INFECTION
Principal Investigator: Bruce Walker
Affiliation: Massachusetts General Hospital
Abstract: Hepatitis C virus (HCV) infection is a major cause of post-transfusion and community acquired hepatitis, and results in significant morbidity due to chronic hepatitis in an estimated 50-80% of cases. Attempts to control infection with antiviral agents have met with limited success, and the need for an effective vaccine to prevent continued spread of this infection remains paramount. Central to the development of such a vaccine is an understanding of the virus-specific immune responses which confer protection. Cytotoxic T lymphocytes (CTL) have been shown to be an important component of protective immunity in a number of viral infections. CTL may also mediate tissue damage in the infected host under certain conditions, and have been postulated to contribute to liver damage in viral hepatitis. Characterization of the CTL response to HCV is an important step in determining the role of these cells in disease pathogenesis. During the initial period of support provided by AI31563, our laboratory established a method to detect HCV-specific, HLA class I restricted CTL among liver infiltrating lymphocytes from persons with chronic HCV hepatitis. Our initial studies indicate that a) both structural and nonstructural proteins of HCV are targets of CTL in infected persons; b) these CTL are predominantly compartmentalized in the liver i persons with chronic HCV hepatitis; c) the CTL response is HLA class I restricted and directed at multiple 8-10 amino acid epitopes, and can be directed at multiple epitopes simultaneously; d) CTL epitopes exist in regions which tolerate sequence variation. We have recently established method for expanding HCV-specific memory T cells from peripheral blood will allow us to evaluate the CTL response not only in persons in different stages of acute and chronic infection, but will also facilitate longitudinal studies of CTL and their relationship to disease course. Specifically, we propose to a) Evaluate liver biopsy-derived lymphocytes and peripheral blood lymphocytes from HCV-seropositive persons with symptomatic and asymptomatic chronic HCV infection for the presence of HCV-specific CTL, and characterize the cells mediating this cytotoxicity as well as the dominant viral antigens and epitopes targeted by this response; b) Determine the magnitude and specificity of the HCV-specific CTL response in persons in different stages of infection, including acute infection, chronic infection before and after treatment with interferon, and those with acute flares of hepatitis in order to determine whether a correlation exists between the HCV-specific CTL response and the course of disease; c) Evaluate the potential role of sequence variation as a means of escape from detection by HCV-specific CTL; and d) Determine the HCV-specific CTL response to autologous viruses in infected persons. These studies will provide a detailed understanding of the role of the host cellular immune response in HCV infection, and should facilitate rational vaccine design as well as help to guide immunotherapeutic interventions.
Funding Period: 1991-08-01 - 2001-02-28
more information: NIH RePORT
- Broad repertoire of the CD4+ Th cell response in spontaneously controlled hepatitis C virus infection includes dominant and highly promiscuous epitopesJulian Schulze zur Wiesch
Partners AIDS Research Center and Infectious Disease Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA
J Immunol 175:3603-13. 2005..This comprehensive characterization of CD4(+) T cell epitopes in resolved HCV infection provides important information to facilitate studies of immunopathogenesis and HCV vaccine design and evaluation...
- Full-breadth analysis of CD8+ T-cell responses in acute hepatitis C virus infection and early therapyGeorg M Lauer
Partners AIDS Research Center and Infectious Disease Division, Massachusetts General Hospital and Harvard Medical School, Charlestown, 02129, USA
J Virol 79:12979-88. 2005..These data suggest that broad CD8(+) T-cell responses alone may be insufficient to contain HCV replication, and also that early therapy is effective independent of such responses...
- Acute hepatitis C virus infection in incarcerated injection drug usersBarbara H McGovern
Lemuel Shattuck Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Clin Infect Dis 42:1663-70. 2006....
- Impaired hepatitis C virus-specific T cell responses and recurrent hepatitis C virus in HIV coinfectionArthur Y Kim
Partners AIDS Research Center and Infectious Disease Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
PLoS Med 3:e492. 2006..Here we examined the effect of a lymphotropic virus, HIV-1, on the ability of coinfected patients to maintain spontaneous control of HCV infection...
- Characterization of full-length hepatitis C virus genotype 4 sequencesJ Timm
Partners AIDS Research Center, Infectious Disease Division, Massachusetts General Hospital, Boston, MA, USA
J Viral Hepat 14:330-7. 2007..Here we describe seven unique HCV genotype 4a full genomes, in addition to a single genotype 4d genome, and characterize their sequence diversity in relation to other more closely characterized HCV genotypes...
- Immunologic evidence for lack of heterologous protection following resolution of HCV in patients with non-genotype 1 infectionJulian Schulze zur Wiesch
Partners AIDS Research Center, Infectious Disease Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Blood 110:1559-69. 2007....
- High level of PD-1 expression on hepatitis C virus (HCV)-specific CD8+ and CD4+ T cells during acute HCV infection, irrespective of clinical outcomeVictoria Kasprowicz
Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA
J Virol 82:3154-60. 2008..Our results suggest that an analysis of PD-1 expression alone is not sufficient to predict infection outcome or to determine T-cell functionality in HCV infection...
- Defining the directionality and quality of influenza virus-specific CD8+ T cell cross-reactivity in individuals infected with hepatitis C virusVictoria Kasprowicz
Partners AIDS Research Center and Infectious Disease Division, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
J Clin Invest 118:1143-53. 2008..Further studies are needed to relate affinity and functionality of cross-reactive T cells...