Abstract

This proposal concerns the relationship between hepatitis C virus (HCV) and cytotoxic T lymphocytes (CTL) during the evolution of chronic persistent HCV infection in humans. Although it is known that a polyclonal CTL response to HCV proteins is elicited in this disease, there is no understanding of why these cells fail to clear the virus, as would normally be expected from such effector cells. Several distinct hypotheses are presented for investigation of the molecular and cellular basis for this phenomenon, and will be addressed in four specific aims.
Specific aim 1 will determine whether the strength of the CTL response is a major determinant of the capacity to clear HCV infection.
Specific aim 2 will address whether mutations in viral CTL epitopes are involved in the initiation and maintenance of persistent infection. The third specific aim is to determine whether HCV proteins, in particular, the E1 glycoprotein can inhibit Class I antigen presentation and also whether viral infection can render hepatocytes resistant to CTL-mediated killing. The fourth and final aim is to establish whether hepatocytes can anergize or delete CTL responses as a result of suboptimal antigen presentation.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076403-02
Application #
2837781
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1997-12-12
Project End
2002-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Wieland, S F; Asabe, S; Engle, R E et al. (2014) Limited hepatitis B virus replication space in the chronically hepatitis C virus-infected liver. J Virol 88:5184-8
Asabe, Shinichi; Wieland, Stefan F; Chattopadhyay, Pratip K et al. (2009) The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J Virol 83:9652-62
Sidney, John; Peters, Bjoern; Moore, Carrie et al. (2007) Characterization of the peptide-binding specificity of the chimpanzee class I alleles A 0301 and A 0401 using a combinatorial peptide library. Immunogenetics 59:745-51
Sakai, Akito; Takikawa, Shingo; Thimme, Robert et al. (2007) In vivo study of the HC-TN strain of hepatitis C virus recovered from a patient with fulminant hepatitis: RNA transcripts of a molecular clone (pHC-TN) are infectious in chimpanzees but not in Huh7.5 cells. J Virol 81:7208-19
Sidney, John; Asabe, Shinichi; Peters, Bjoern et al. (2006) Detailed characterization of the peptide binding specificity of five common Patr class I MHC molecules. Immunogenetics 58:559-70
Guidotti, Luca G; Chisari, Francis V (2006) Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol 1:23-61
Wieland, Stefan F; Chisari, Francis V (2005) Stealth and cunning: hepatitis B and hepatitis C viruses. J Virol 79:9369-80
Neumann-Haefelin, C; Blum, H E; Chisari, F V et al. (2005) T cell response in hepatitis C virus infection. J Clin Virol 32:75-85
Kapadia, Sharookh B; Chisari, Francis V (2005) Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids. Proc Natl Acad Sci U S A 102:2561-6
Wieland, Stefan; Thimme, Robert; Purcell, Robert H et al. (2004) Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci U S A 101:6669-74

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