Hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide (1) and is the major indication for liver transplantation in the United States (2, 3). While therapy with PEGylated Interferon-alpha (PEG-IFN) plus ribavirin (RBV) provides sustained virologic response (SVR) in 40-50% of patients overall, the SVR rate is only about 20% in African Americans and Hispanics, who have a higher frequency of single nucleotide polymorphisms associated with poor response (4, 5). Addition of direct-acting antivirals (DAAs) targeting the HCV NS3/4A protease increases SVR rates to 68-75% in previously untreated patients, but such regimens still suffer from the limitations of PEG-IFN/RBV. Thus, drug developers are seeking combinations of DAAs that will reduce or eliminate the need for PEG-IFN and/or RBV while providing an adequate barrier to resistance. It was recently reported that a small number of genotype 1a and 1b patients achieved SVR following treatment with a combination of two DAAs targeting NS3/4A and NS5A. While these results provide proof of concept for SVR without use of PEG-IFN/RBV, biological data to inform the selection of such DAA combinations are limited. The preponderance of preclinical characterization of DAAs and combinations has been obtained using subgenomic HCV replicons in Huh-7 hepatoma-derived cell lines, a recombinant system that omits important features of the viral life cycle. Systems have been developed that recapitulate the complete HCV life cycle in hepatoma lines and primary human hepatocytes/hepatoblasts. This study proposes to interrogate the effects of DAAs in cell systems that support the complete HCV life cycle. These studies will deepen our understanding of key biological processes involved in viral replication and provide new insights into DAA mechanisms of action that will be translatable to clinical studies.

Public Health Relevance

Hepatitis C virus (HCV) is a major public health burden, with approximately 130 million people infected worldwide, and HCV-associated liver disease is the main indication for liver transplant in the United States. We propose to characterize direct-acting antiviral agents and identify combinations with the greatest ability to eliminate infection by usin state of the art analytical methods and cell culture systems that reproduce the complete HCV life cycle in primary human hepatocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI099284-01
Application #
8283684
Study Section
Special Emphasis Panel (ZAI1-LG-M (J2))
Program Officer
Koshy, Rajen
Project Start
2012-05-01
Project End
2017-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$735,361
Indirect Cost
$202,493
Name
Rockefeller University
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Michailidis, Eleftherios; Huber, Andrew D; Ryan, Emily M et al. (2014) 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) inhibits HIV-1 reverse transcriptase with multiple mechanisms. J Biol Chem 289:24533-48
Adedeji, Adeyemi O; Sarafianos, Stefan G (2014) Antiviral drugs specific for coronaviruses in preclinical development. Curr Opin Virol 8:45-53
Adedeji, Adeyemi O; Singh, Kamalendra; Kassim, Ademola et al. (2014) Evaluation of SSYA10-001 as a replication inhibitor of severe acute respiratory syndrome, mouse hepatitis, and Middle East respiratory syndrome coronaviruses. Antimicrob Agents Chemother 58:4894-8
Sheldon, Julie; Beach, Nathan M; Moreno, Elena et al. (2014) Increased replicative fitness can lead to decreased drug sensitivity of hepatitis C virus. J Virol 88:12098-111
Anggakusuma; Colpitts, Che C; Schang, Luis M et al. (2014) Turmeric curcumin inhibits entry of all hepatitis C virus genotypes into human liver cells. Gut 63:1137-49
Muftuoglu, Yagmur; Sohl, Christal D; Mislak, Andrea C et al. (2014) Probing the molecular mechanism of action of the HIV-1 reverse transcriptase inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) using pre-steady-state kinetics. Antiviral Res 106:1-4
de Jong, Ype P; Dorner, Marcus; Mommersteeg, Michiel C et al. (2014) Broadly neutralizing antibodies abrogate established hepatitis C virus infection. Sci Transl Med 6:254ra129
Singh, Kamalendra; Flores, Jacqueline A; Kirby, Karen A et al. (2014) Drug resistance in non-B subtype HIV-1: impact of HIV-1 reverse transcriptase inhibitors. Viruses 6:3535-62
Shlomai, Amir; de Jong, Ype P; Rice, Charles M (2014) Virus associated malignancies: the role of viral hepatitis in hepatocellular carcinoma. Semin Cancer Biol 26:78-88
Huber, Andrew D; Michailidis, Eleftherios; Schultz, Megan L et al. (2014) SAMHD1 has differential impact on the efficacies of HIV nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 58:4915-9

Showing the most recent 10 out of 18 publications