Hepatitis C virus (HCV) infects more than 170 million people worldwide, causing acute and chronic hepatitis and hepatocellular carcinoma (HCC)[1]. Notably, increases in HCV cirrhosis have played a major role in the recent rise in HCC, accounting for up to 50% of cases in the United States[2]. With no vaccine available to protect against HCV infection and only a subset of chronically infected patients responding to current treatment options[3], there is an obvious and immediate need for new effective HCV antivirals as well as the HCV experimental model systems that would support advancement in this area. In particular, HCV entry represents a promising multi-faceted opportunity for drug discovery (reviewed in[4]), but a deeper understanding and coherent description of the process is needed to facilitate such endeavors. Thus, our long term goal is to understand the cellular and viral factors that mediate HCV entry in order to identify novel molecular targets amendable to therapeutic intervention and enable the development of transgenic mouse models permissive for HCV entry. Relevant to this long term goal, we recently discovered that the cellular cholesterol uptake receptor Niemann-Pick C1-like 1 (NPC1L1) is required for HCV entry. Based on the observation that exogenous expression of NPC1L1 on the surface of CHO cells results in binding of the cholesterol-enriched HCV virion and the fact that NPC1L1 exhibits restricted tissue distribution and is expressed on human but not mouse hepatocytes, we hypothesize that NPC1L1 is a cholesterol-dependent HCV entry receptor responsible for the restricted human-hepatocyte tropism of HCV entry. As such, we propose to 1) Characterize the interaction between HCV and NPC1L1 during HCV entry by identifying the determinants of the interaction and assessing how and when NPC1L1 functions during the viral entry process;and 2) Elucidate the role of NPC1L1 in HCV tropism by determining if NPC1L1 expression confers HCV permissiveness to non-hepatic and non-human cells. Importantly, these studies will lay the groundwork that will enable a more detailed and specifically focused studies aimed at thoroughly understanding how NPC1L1 participates in HCV entry so that such interactions can be potentially exploited for therapeutic intervention and the development of a mouse model that supports HCV entry.

Public Health Relevance

Hepatitis C virus (HCV) infects more than 180 million people worldwide, causing acute and chronic hepatitis and hepatocellular carcinoma, however no protective vaccine is available and only a subset of infected patients respond to current treatment options. To design more effective therapeutics it is crucial to study the HCV lifecycle and viral-host interactions that mediate disease. Hence, we propose to elucidate the role of a newly- identified, therapeutically-amenable putative HCV entry factor.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI097809-01
Application #
8226578
Study Section
Virology - B Study Section (VIRB)
Program Officer
Koshy, Rajen
Project Start
2012-02-01
Project End
2012-08-31
Budget Start
2012-02-01
Budget End
2012-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$162,041
Indirect Cost
$60,252
Name
University of Illinois at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Barretto, Naina; Sainz Jr, Bruno; Hussain, Snawar et al. (2014) Determining the involvement and therapeutic implications of host cellular factors in hepatitis C virus cell-to-cell spread. J Virol 88:5050-61
Sabahi, Ali; Uprichard, Susan L; Wimley, William C et al. (2014) Unexpected structural features of the hepatitis C virus envelope protein 2 ectodomain. J Virol 88:10280-8