It is estimated that 170 million people worldwide are infected with the Hepatitis C virus (HCV) and are at risk of developing chronic hepatitis or cirrhosis, the latter often leading to hepatocellular carcinoma. There is currently no vaccine and licensed therapies are associated with modest efficacies and significant toxicities. Despite the urgency of this worldwide public health problem, our basic understanding of HCV replication and pathogenesis remains poor due to a lack of key experimental models. For example, difficulties in culturing the virus in vitro and expressing native, fusogenic envelope glycoproteins have greatly limited studies of HCV tropism and entry. These are critical aspects of viral biology because the host range and pathogenesis of enveloped virus infection is largely determined by the selective interaction of viral envelope glycoproteins with cell-surface receptors. A major goal in HCV research is to understand how HCV targets the liver and by what mechanism it enters host cells. Recently, a major breakthrough in the field has been the development of retroviruses pseudotyped with HCV envelope glycoproteins that specifically mediate infection of primary hepatocytes, as well as certain other human cells. We will use this new experimental system to study HCV entry into target cells. Alterations in naturally occurring HCV envelope glycoproteins may predicate differences in receptor usage and target cell tropism in vivo. To investigate the range of HCV cellular tropism, pseudotypes incorporating envelope glycoproteins from clinical HCV isolates will be tested for their ability to enter relevant primary cells and cell lines. A functional cDNA cloning approach will be used to identify cell-surface receptors that specifically mediate HCV entry into different target cells. However, these receptors may be ubiquitously expressed and HCV targeting to different cell types may be determined by another mechanism. We recently demonstrated that L-SIGN and DC-SIGN are specific HCV-capture receptors and we will explore whether they mediate infection of target cells in trans, thereby determining HCV tropism. The major objective of our work is to identify the basic protein interactions that mediate HCV tropism, which will serve as a foundation for detailed structure/function analyses of HCV receptors and envelope glycoproteins. ? ? ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-GMA-2 (50))
Program Officer
Koshy, Rajen
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine
Schools of Medicine
United States
Zip Code
Cukierman, Lisa; Meertens, Laurent; Bertaux, Claire et al. (2009) Residues in a highly conserved claudin-1 motif are required for hepatitis C virus entry and mediate the formation of cell-cell contacts. J Virol 83:5477-84
Meertens, Laurent; Bertaux, Claire; Cukierman, Lisa et al. (2008) The tight junction proteins claudin-1, -6, and -9 are entry cofactors for hepatitis C virus. J Virol 82:3555-60
Falkowska, Emilia; Kajumo, Francis; Garcia, Edie et al. (2007) Hepatitis C virus envelope glycoprotein E2 glycans modulate entry, CD81 binding, and neutralization. J Virol 81:8072-9
Falkowska, Emilia; Durso, Robert J; Gardner, Jason P et al. (2006) L-SIGN (CD209L) isoforms differently mediate trans-infection of hepatoma cells by hepatitis C virus pseudoparticles. J Gen Virol 87:2571-6
Bertaux, Claire; Dragic, Tatjana (2006) Different domains of CD81 mediate distinct stages of hepatitis C virus pseudoparticle entry. J Virol 80:4940-8
Cormier, Emmanuel G; Tsamis, Fay; Kajumo, Francis et al. (2004) CD81 is an entry coreceptor for hepatitis C virus. Proc Natl Acad Sci U S A 101:7270-4
Cormier, Emmanuel G; Durso, Robert J; Tsamis, Fotini et al. (2004) L-SIGN (CD209L) and DC-SIGN (CD209) mediate transinfection of liver cells by hepatitis C virus. Proc Natl Acad Sci U S A 101:14067-72