Hepatitis C virus (HCV) is the leading cause of liver disease in the United States. With no specific anti-HCV therapies, the cun-ently employed interferon-based treatment is inadequate, as it has severe side effects and is only effective in half of the major genotype infected individuals. The research proposed in this application is aimed at furthering the understanding the HCV replication mechanisms, with the ultimate goal of . . uncovering novel antiviral targets. In the past, I have studied how HCV replication is regulated, how viral proteins interact with each other and cellular factors, and helped establish systems to study HCV in cell culture. Currently, my research is focused on the earliest events in the viral life cycle involving entry into the host cell, which are poorly understood processes. In particular, although several host factors have been implicated as involved in HCV entry, litt|e is know as to how they are utilized by the virus. Our recent identification ofthe tight junction protein, claudin-1 (CLDN1), as essential for this process was a major development in this field. This discovery has opened-up a whole new view of HCV cell entry, as the involvement of CLDN1 in cell polarity strongly suggests that the polarized nature of an hepatocyte may influence how HCV enter a cell. This proposal describes experiments to;1) study HCV entry into polarized cells, 2) define how the virion interacts with and utilizes the known HCV entry factors, and 3) perform additional screens for HCV entry factors able to render both human and murine cells infectable with HCV. Such investigations will provide greater, much needed insight in HCV replication, as well as lay the foundation for future studies of replication of HCV and other related viruses.
Liver failure from HCV is the leading cause of liver transplantation, which is often unsuccessful due to universal reinfection after transplantation, frequently resulting in rapid fibrosis and subsequent graft failure. The proposed experiments are directly related to the development of novel antiviral therapies to inhibit HCV cell entry, which could prevent graft reinfection and thus greatly improve liver transplantation effectiveness. In addition, this work is directly related to the development of much needed HCV small animal models.
|Hopcraft, Sharon E; Evans, Matthew J (2015) Selection of a hepatitis C virus with altered entry factor requirements reveals a genetic interaction between the E1 glycoprotein and claudins. Hepatology 62:1059-69|
|Israelow, Benjamin; Narbus, Christopher M; Sourisseau, Marion et al. (2014) HepG2 cells mount an effective antiviral interferon-lambda based innate immune response to hepatitis C virus infection. Hepatology 60:1170-9|
|Israelow, Benjamin; Mullokandov, Gavriel; Agudo, Judith et al. (2014) Hepatitis C virus genetics affects miR-122 requirements and response to miR-122 inhibitors. Nat Commun 5:5408|
|Sourisseau, Marion; Goldman, Orit; He, Wenqian et al. (2013) Hepatic cells derived from induced pluripotent stem cells of pigtail macaques support hepatitis C virus infection. Gastroenterology 145:966-969.e7|
|Sourisseau, Marion; Michta, Maria L; Zony, Chati et al. (2013) Temporal analysis of hepatitis C virus cell entry with occludin directed blocking antibodies. PLoS Pathog 9:e1003244|
|Ploss, Alexander; Evans, Matthew J (2012) Hepatitis C virus host cell entry. Curr Opin Virol 2:14-9|
|Narbus, Christopher M; Israelow, Benjamin; Sourisseau, Marion et al. (2011) HepG2 cells expressing microRNA miR-122 support the entire hepatitis C virus life cycle. J Virol 85:12087-92|
|Sabo, Michelle C; Luca, Vincent C; Prentoe, Jannick et al. (2011) Neutralizing monoclonal antibodies against hepatitis C virus E2 protein bind discontinuous epitopes and inhibit infection at a postattachment step. J Virol 85:7005-19|
|Michta, Maria L; Hopcraft, Sharon E; Narbus, Christopher M et al. (2010) Species-specific regions of occludin required by hepatitis C virus for cell entry. J Virol 84:11696-708|
|Witteveldt, Jeroen; Evans, Matthew J; Bitzegeio, Julia et al. (2009) CD81 is dispensable for hepatitis C virus cell-to-cell transmission in hepatoma cells. J Gen Virol 90:48-58|