Immunologic and Virologic Correlates of Liver Fibrosis

Investigators:

Study Co-Chairs: Karen Lindsay and Chihiro Morishima

Immunology Principal Investigators: Margaret Koziel, Alan Rothman, Chihiro Morishima, Ranjit Ray

Virology Principal Investigators: David Gretch, Stephen Polyak, Daniel Sullivan, and Raymond T. Chung

Clinical Center and Data Coordinating Center Principal Investigators: Adrian Di Bisceglie, Herbert Bonkovsky, Savant Mehta, William Lee, Karen Lindsay, Elizabeth Wright

Hypotheses/Aims

Primary Hypothesis: The hypothesis to be tested in these studies is that HCV-specific immune responses protect against fibrosis and that interferon (IFN) acts to enhance these HCV-specific immune responses.

  1. Virologic studies hypotheses:
    1. that quasispecies diversity at baseline will correlate with disease progression and response to therapy.
    2. disease non-progressors will have higher rates of HCV quasispecies evolution than disease progressors.
    3. treated patients will have higher rates of HCV quasispecies evolution than non-treated controls.
    4. and that high rates of quasispecies evolution will positively correlate with strong immune responses.
  2. Replication study hypothesis:
    1. that the HCV nonstructural proteins made in the HCV replication-active cells serve as antigens, which activate cytotoxic T cells.

Specific Aims:

  1. Define HCV quasispecies diversity and complexity in baseline sera.
  2. Track HCV quasispecies in the major variant evolution over time in serum for 400 patients.
  3. Perform nucleotide sequencing and phylogenetic analysis of E1, E2 and NS5A genetic regions over time for 100 patients.
  4. Correlate the progression of liver disease in study subjects with the presence and magnitude of HCV-specific immune responses (lymphoproliferative responses, intrahepatic CTL, and neutralizing antibody) before, during and after therapy in the treated cohort and at similar time points in the observation cohort.
  5. Determine if a favorable response to IFN therapy is associated with enhancement of HCV-specific immune responses during therapy.
  6. Evaluate the percentage of hepatocytes containing HCV genomic and replicative intermediate RNAs in 100 patients' pre-treatment biopsies, 40 treated and 40 untreated patients' biopsies at years 1 and 2 by in situ hybridization.