Article

Efficient Hepatitis C Virus Particle Formation Requires Diacylglycerol Acyltransferase 1 (DGAT1)

Gladstone Institute of Virology and Immunology, University of California, San Francisco, USA.
Nature medicine (Impact Factor: 28.05). 10/2010; 16(11):1295-8. DOI: 10.1038/nm.2238
Source: PubMed

ABSTRACT Hepatitis C virus (HCV) infection is closely tied to the lipid metabolism of liver cells. Here we identify the triglyceride-synthesizing enzyme diacylglycerol acyltransferase-1 (DGAT1) as a key host factor for HCV infection. DGAT1 interacts with the viral nucleocapsid core and is required for the trafficking of core to lipid droplets. Inhibition of DGAT1 activity or RNAi-mediated knockdown of DGAT1 severely impairs infectious virion production, implicating DGAT1 as a new target for antiviral therapy.

Download full-text

Full-text

Available from: Katrin Kaehlcke, Mar 16, 2015
1 Follower
 · 
160 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis C virus (HCV) is a major global health burden accounting for around 170 million chronic infections worldwide. Although highly potent direct-acting antiviral drugs to treat chronic hepatitis C have been approved recently, owing to their high costs and limited availability and a large number of undiagnosed infections, the burden of disease is expected to rise in the next few years. In addition, HCV is an excellent paradigm for understanding the tight link between a pathogen and host cell pathways, most notably lipid metabolism. HCV extensively remodels intracellular membranes to establish its cytoplasmic replication factory and also usurps components of the intercellular lipid transport system for production of infectious virus particles. Here, we review the molecular mechanisms of viral replicase function, cellular pathways employed during HCV replication factory biogenesis, and viral, as well as cellular, determinants of progeny virus production.
    Cell Host & Microbe 11/2014; 16(5):569-579. DOI:10.1016/j.chom.2014.10.008 · 12.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Lipid droplets (LDs) are dynamic, cytosolic lipid-storage organelles found in nearly all cell types. Too many or too few LDs during excess or deficient fat storage lead to many different human diseases. Recent insights into LD biology and LD protein functions shed new light on mechanisms underlying those metabolic pathologies. These findings will likely provide opportunities for treatment of diseases associated with too much or too little fat.
    EMBO Molecular Medicine 07/2013; 5(7). DOI:10.1002/emmm.201100671 · 8.25 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The treatment of interferon alfa (IFN-α) and ribavirin for chronic hepatitis C virus (HCV) infection achieves limited sustained virological response (SVR). We conducted a systematic review and meta-analysis to explore the efficacy of adding statins to IFN-α and ribavirin therapy for chronic hepatitis C. Studies with data pertinent to the effect of statins on chronic hepatitis C were reviewed, and randomized controlled trials (RCTs) evaluating the efficacy of the addition of statins to IFN-α and ribavirin were included in meta-analysis. The primary outcome measure was SVR. Secondary outcome measures were rapid virological response (RVR) and early virological response (EVR). The literature was systematically searched through October 2012. After screening of the 1724 non-duplicated entries, 54 potentially relevant studies were fully reviewed. Of those, 18 studies were relevant and 5 RCTs met the inclusion criteria for meta-analysis. In comparison with IFN-α and ribavirin therapy, the addition of statins significantly increased SVR (OR = 2.02, 95% CI: 1.38 - 2.94), RVR (OR = 3.51, 95% CI: 1.08 - 11.42) and EVR (OR = 1.89, 95% CI: 1.20 - 2.94). The SVR increase remained significant for HCV genotype 1 (OR = 2.11, 95% CI: 1.40 - 3.18). There were no significant increases in adverse events and withdrawals with the addition of statins. In conclusion, the addition of statins to IFN-α and ribavirin improves SVR, RVR, and EVR without additional adverse events and thus may be considered as adjuvant to IFN-α and ribavirin for chronic hepatitis C. Statins might also be used for HCV genotypes other than genotype 1, or in patients in whom the use of protease inhibitors is contraindicated or not indicated.
    Antiviral research 04/2013; 98(3). DOI:10.1016/j.antiviral.2013.04.009 · 3.43 Impact Factor