The hepatitis C virus (HCV) poses a public health threat. It is important to identify viral factors that thwart natural defenses and contribute to treatment failure. In a cross sectional study, we recently found an inverse relationship between viral replication and the presence of antibodies directed against HCV's novel alternate reading frame proteins (ARFPs). ARFPs were discovered previously by our group. The spike of anti-ARFP antibodies suggests that production of ARFPs is increased when HCV replication is inhibited. HCV RNAs of patients with anti-ARFP antibodies have mutations in a putative cis regulatory element (CRE) called the Terminal Stem-loops, an RNA structure we also discovered previously. Our recent results suggest that ARFPs may help HCV survive adverse conditions, and indicate that CREs may control the production of ARFPs. The proposed studies are based on our recent data, and on data of others showing that HCV RNAs of patients with advanced cirrhosis and liver cancer have mutations in the Terminal Stem-loops. Experiments in Aim I test the hypothesis that effective anti-viral responses induced by IFN/ribavirin treatment are marked by a rise in immune responses to ARFPs. HCV RNA and anti-ARFP antibody levels, and the stimulation index (SI) and phenotype of peripheral blood mononuclear cells will be compared before, during, and after treatment. Experiments in Aim 2 test the hypothesis that mutations in the Terminal Stem-loops element accumulate during IFN/ribavirin treatment and during progression to advanced liver disease and liver cancer, modulating its function and increasing production of ARFPs. New software will be developed and applied to an expanded dataset of mutations, and the structure/function relationships of the Terminal Stem-loops will be defined. New information about HCV's adaptive mechanisms and pathways of gene expression will emerge from these studies and will advance the development of new drugs and vaccines for HCV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK066939-02
Application #
6881285
Study Section
Special Emphasis Panel (ZRG1-GMA-2 (50))
Program Officer
Doo, Edward
Project Start
2004-04-01
Project End
2009-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
2
Fiscal Year
2005
Total Cost
$398,325
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Martel-Laferrière, V; Michel, A; Schaefer, S et al. (2015) Clinical characteristics of human immunodeficiency virus patients being referred for liver transplant evaluation: a descriptive cohort study. Transpl Infect Dis 17:527-35
El-Shamy, Ahmed; Eng, Francis J; Doyle, Erin H et al. (2015) A cell culture system for distinguishing hepatitis C viruses with and without liver cancer-related mutations in the viral core gene. J Hepatol 63:1323-33
Vachon, Marie-Louise C; Factor, Stephanie H; Branch, Andrea D et al. (2011) Insulin resistance predicts re-treatment failure in an efficacy study of peginterferon-?-2a and ribavirin in HIV/HCV co-infected patients. J Hepatol 54:41-7
Gutierrez, Julio A; Klepper, Arielle L; Garber, John et al. (2011) Cross-genotypic polyclonal anti-HCV antibodies from human ascitic fluid. J Virol Methods 171:169-75
Branch, Andrea D; Rice, Charles M (2010) Antisense gets a grip on miR-122 in chimpanzees. Sci Transl Med 2:13ps1
Childs, Kathryn E; Fishman, Sarah L; Constable, Catherine et al. (2010) Short communication: Inadequate vitamin D exacerbates parathyroid hormone elevations in tenofovir users. AIDS Res Hum Retroviruses 26:855-9
Chang, Theresa L; Klepper, Arielle; Ding, Jian et al. (2010) Human peritoneal macrophages from ascitic fluid can be infected by a broad range of HIV-1 isolates. J Acquir Immune Defic Syndr 53:292-302
Eng, Francis J; Walewski, Jose L; Klepper, Arielle L et al. (2009) Internal initiation stimulates production of p8 minicore, a member of a newly discovered family of hepatitis C virus core protein isoforms. J Virol 83:3104-14
Cox, Andrea L; Page, Kimberly; Bruneau, Julie et al. (2009) Rare birds in North America: acute hepatitis C cohorts. Gastroenterology 136:26-31
Fishman, Sarah L; Branch, Andrea D (2009) The quasispecies nature and biological implications of the hepatitis C virus. Infect Genet Evol 9:1158-67

Showing the most recent 10 out of 16 publications