Document 0886
 DOCN  M9550886
 TI    Cytotoxic T lymphocyte response to hepatitis C virus-derived peptides
       containing the HLA A2.1 binding motif.
 DT    9505
 AU    Cerny A; McHutchison JG; Pasquinelli C; Brown ME; Brothers MA;
       Grabscheid B; Fowler P; Houghton M; Chisari FV; Scripps Research
       Institute, La Jolla, California 92037.
 SO    J Clin Invest. 1995 Feb;95(2):521-30. Unique Identifier : AIDSLINE
       MED/95164680
 AB    The HLA class I-restricted cytotoxic T lymphocyte (CTL) response is a
       major defense mechanism in viral infections. It has been suggested that
       the CTL response may contribute to viral clearance and liver cell injury
       during hepatitis C virus (HCV) infection. To test this hypothesis
       requires an understanding of the characteristics of HCV-specific
       cytotoxic effector cells and identification of the target antigens to
       which they respond. To begin this process we stimulated peripheral blood
       mononuclear cells (PBMC) from a group of HLA-A2 positive patients with
       chronic hepatitis C with a panel of 130 HCV-derived peptides containing
       the HLA-A2 binding motif. Effector cells were tested for their capacity
       to lyse HLA-A2-matched target cells that were either sensitized with
       peptide or infected with a vaccinia virus construct containing HCV
       sequences. Using this approach we have identified nine immunogenic
       peptides in HCV, three of which are derived from the putative core
       protein, three from the nonstructural (NS) 3 domain, two from NS4 and
       one from NS5. Selected responses were shown to be HLA-A2 restricted,
       mediated by CD8+ T cells and to recognize endogenously synthesized viral
       antigen. Unexpectedly, peptide-specific CTL responses could also be
       induced in sero-negative individuals, suggesting in vitro activation of
       naive CTL precursors. The precursor frequency of peptide-specific CTL
       was 10 to 100-fold higher in infected patients compared to uninfected
       controls, and the responses were greatly diminished by removal of CD45
       RO+ (memory) T cells. Further quantitative studies are clearly required
       to establish whether a correlation exists between the HCV-specific CTL
       response and the clinical course of this disease. Definition of the
       molecular targets of the human CTL response to HCV creates this
       opportunity, and may also contribute to the development of a T
       cell-based HCV vaccine.
 DE    Amino Acid Sequence  Antigens, CD45/IMMUNOLOGY  Antigens,
       Viral/BIOSYNTHESIS/*IMMUNOLOGY  Binding Sites  Clone Cells
       Cytotoxicity, Immunologic  CD8-Positive T-Lymphocytes/IMMUNOLOGY
       Hepatitis C Viruses/*IMMUNOLOGY  Human  HLA-A2 Antigen/*IMMUNOLOGY
       Lymphocyte Depletion  Molecular Sequence Data  Peptide
       Fragments/IMMUNOLOGY  Support, Non-U.S. Gov't  Support, U.S. Gov't,
       P.H.S.  T-Lymphocytes, Cytotoxic/*IMMUNOLOGY  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).