Hepatitis C virus (HCV) is a highly successful pathogen that causes chronic hepatitis and hepatocellular carcinoma. Current therapies for treating HCV patients are frequently ineffective, and HCV-specific antivirals and vaccines are not yet available. New opportunities for targeting this pathogen are likely to come from a thorough understanding of the viral life cycle. We have recently developed a system to efficiently grow HCV in cell culture, allowing the viral life cycle to be fully dissected at the molecular level. We will use this system to examine how infectious virus particles are assembled. One key observation is that infectious HCV particles have an unusually low buoyant density, which is likely due to interaction with serum lipoproteins. In this proposal, we examine the hypothesis that HCV particle infectivity requires interaction with serum lipoprotein components during an intracellular step in virus formation. To address this hypothesis, we will define the composition of HCV particles (Aim 1);identify early steps in HCV particle assembly by using live and fixed cells imaging methods (Aim 2);and delineate the intracellular process of HCV particle maturation by using biochemical and cell biological methods (Aim 3). These studies will provide new insights into the nature of HCV particle infectivity and virus-host interaction.

Public Health Relevance

Hepatitis C virus (HCV) is a highly successful human pathogen that causes persistent infection, chronic hepatitis, and hepatocellular carcinoma. Our studies characterize the virus particle and its interactions with the host cell, which will provide new avenues to target HCV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI076259-03
Application #
8099786
Study Section
Virology - A Study Section (VIRA)
Program Officer
Koshy, Rajen
Project Start
2009-07-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
3
Fiscal Year
2011
Total Cost
$405,516
Indirect Cost
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Lindenbach, Brett D; Rice, Charles M (2013) The ins and outs of hepatitis C virus entry and assembly. Nat Rev Microbiol 11:688-700
Lindenbach, Brett D (2013) Virion assembly and release. Curr Top Microbiol Immunol 369:199-218
Stapleford, Kenneth A; Lindenbach, Brett D (2011) Hepatitis C virus NS2 coordinates virus particle assembly through physical interactions with the E1-E2 glycoprotein and NS3-NS4A enzyme complexes. J Virol 85:1706-17
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Lindenbach, Brett D (2010) New cell culture models of hepatitis C virus entry, replication, and virus production. Gastroenterology 139:1090-3
Paintsil, Elijah; He, Huijie; Peters, Christopher et al. (2010) Survival of hepatitis C virus in syringes: implication for transmission among injection drug users. J Infect Dis 202:984-90