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.
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.
|Paintsil, Elijah; Binka, Mawuena; Patel, Amisha et al. (2014) Hepatitis C virus maintains infectivity for weeks after drying on inanimate surfaces at room temperature: implications for risks of transmission. J Infect Dis 209:1205-11|
|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|
|Counihan, Natalie A; Rawlinson, Stephen M; Lindenbach, Brett D (2011) Trafficking of hepatitis C virus core protein during virus particle assembly. PLoS Pathog 7:e1002302|
|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|