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Host-Targeting Agents to Prevent and Cure Hepatitis C Virus Infection.

Zeisel MB, Crouchet E, Baumert TF, Schuster C - Viruses (2015)

Bottom Line: In contrast to DAAs that target viral proteins, host-targeting agents (HTAs) interfere with cellular factors involved in the viral life cycle.By acting through a complementary mechanism of action and by exhibiting a generally higher barrier to resistance, HTAs offer a prospective option to prevent and treat viral resistance.Indeed, given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads.

View Article: PubMed Central - PubMed

Affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France. mirjam.zeisel@unistra.fr.

ABSTRACT
Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) which are leading indications of liver transplantation (LT). To date, there is no vaccine to prevent HCV infection and LT is invariably followed by infection of the liver graft. Within the past years, direct-acting antivirals (DAAs) have had a major impact on the management of chronic hepatitis C, which has become a curable disease in the majority of DAA-treated patients. In contrast to DAAs that target viral proteins, host-targeting agents (HTAs) interfere with cellular factors involved in the viral life cycle. By acting through a complementary mechanism of action and by exhibiting a generally higher barrier to resistance, HTAs offer a prospective option to prevent and treat viral resistance. Indeed, given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads. This review summarizes the different classes of HTAs against HCV infection that are in preclinical or clinical development and highlights their potential to prevent HCV infection, e.g., following LT, and to tailor combination treatments to cure chronic HCV infection.

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Related in: MedlinePlus

Schematic representation of HCV assembly. Virion assembly is triggered by core recruitment on cytosolic lipid droplets (cLDs) by the diacylglycerol acyltransferase-1 (DGAT-1). In turn, replication complexes are recruited through core-NS5A interactions. Nucleocapsid formation is mediated by viral budding into the ER lumen, at the site of VLDL production. The immature viral particles fuse or attach to a luminal LD (LuLD) through apoE-E1E2 and apoE-NS5A interactions. During VLDL synthesis, apolipoprotein B (apoB) is directly produced in the ER lumen and enriched in lipids by the microsomal triglyceride transfer protein (MTP) to generate VLDL precursors. Viral particles merge with these nascent VLDLs to generate mature lipoviroparticles (LVPs). LVPs enter the VLDL maturation and secretion pathway to be released from hepatocytes. HCV assembly and egress can be impaired by targeting different steps of these processes as highlighted in red.
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viruses-07-02898-f003: Schematic representation of HCV assembly. Virion assembly is triggered by core recruitment on cytosolic lipid droplets (cLDs) by the diacylglycerol acyltransferase-1 (DGAT-1). In turn, replication complexes are recruited through core-NS5A interactions. Nucleocapsid formation is mediated by viral budding into the ER lumen, at the site of VLDL production. The immature viral particles fuse or attach to a luminal LD (LuLD) through apoE-E1E2 and apoE-NS5A interactions. During VLDL synthesis, apolipoprotein B (apoB) is directly produced in the ER lumen and enriched in lipids by the microsomal triglyceride transfer protein (MTP) to generate VLDL precursors. Viral particles merge with these nascent VLDLs to generate mature lipoviroparticles (LVPs). LVPs enter the VLDL maturation and secretion pathway to be released from hepatocytes. HCV assembly and egress can be impaired by targeting different steps of these processes as highlighted in red.

Mentions: A remarkable hallmark of HCV is its association with VLDL/low density lipoprotein (LDL) to form an infectious lipoviroparticle (LVP) [199]. Intracellular assembly and egress of LVP depend on numerous factors involved in lipid metabolism (reviewed in [162,200]) and are closely linked to the VLDL production machinery [201]. Among the main factors involved in this process are lipid droplets (LDs), intracellular organelles that originate from triglyceride (TG) and cholesterol ester (CE) accumulation between the two leaflets of the ER bilayer [202]. This microenvironment represents the “platform” for HCV particle assembly. Several host factors involved in TG biosynthesis and LD biogenesis have been demonstrated to contribute to this process and thus represent targets for HTAs (Figure 3). Indeed, HCV morphogenesis is triggered by the recruitment of the viral core protein from the ER to LDs [203], a process mediated by the diacylglycerol acyltransferase-1 (DGAT-1) (Figure 3). Interestingly, a DGAT-1 chemical inhibitor, currently in clinical trials for metabolic diseases (reviewed in [204]), might serve as an antiviral against HCV infection [205]. Notably, since in hepatocytes DGAT-2 has redundant functions in LD morphogenesis, this DGAT-1-specific inhibitor did not impair LD homeostasis in vitro [205]. The safety of DGAT-1 inhibitor LCQ908 has already been evaluated in HCV-infected patients (https://clinicaltrials.gov/; Identifier: NCT01387958), but additional studies are needed to assess its antiviral efficacy in patients.


Host-Targeting Agents to Prevent and Cure Hepatitis C Virus Infection.

Zeisel MB, Crouchet E, Baumert TF, Schuster C - Viruses (2015)

Schematic representation of HCV assembly. Virion assembly is triggered by core recruitment on cytosolic lipid droplets (cLDs) by the diacylglycerol acyltransferase-1 (DGAT-1). In turn, replication complexes are recruited through core-NS5A interactions. Nucleocapsid formation is mediated by viral budding into the ER lumen, at the site of VLDL production. The immature viral particles fuse or attach to a luminal LD (LuLD) through apoE-E1E2 and apoE-NS5A interactions. During VLDL synthesis, apolipoprotein B (apoB) is directly produced in the ER lumen and enriched in lipids by the microsomal triglyceride transfer protein (MTP) to generate VLDL precursors. Viral particles merge with these nascent VLDLs to generate mature lipoviroparticles (LVPs). LVPs enter the VLDL maturation and secretion pathway to be released from hepatocytes. HCV assembly and egress can be impaired by targeting different steps of these processes as highlighted in red.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664971&req=5

viruses-07-02898-f003: Schematic representation of HCV assembly. Virion assembly is triggered by core recruitment on cytosolic lipid droplets (cLDs) by the diacylglycerol acyltransferase-1 (DGAT-1). In turn, replication complexes are recruited through core-NS5A interactions. Nucleocapsid formation is mediated by viral budding into the ER lumen, at the site of VLDL production. The immature viral particles fuse or attach to a luminal LD (LuLD) through apoE-E1E2 and apoE-NS5A interactions. During VLDL synthesis, apolipoprotein B (apoB) is directly produced in the ER lumen and enriched in lipids by the microsomal triglyceride transfer protein (MTP) to generate VLDL precursors. Viral particles merge with these nascent VLDLs to generate mature lipoviroparticles (LVPs). LVPs enter the VLDL maturation and secretion pathway to be released from hepatocytes. HCV assembly and egress can be impaired by targeting different steps of these processes as highlighted in red.
Mentions: A remarkable hallmark of HCV is its association with VLDL/low density lipoprotein (LDL) to form an infectious lipoviroparticle (LVP) [199]. Intracellular assembly and egress of LVP depend on numerous factors involved in lipid metabolism (reviewed in [162,200]) and are closely linked to the VLDL production machinery [201]. Among the main factors involved in this process are lipid droplets (LDs), intracellular organelles that originate from triglyceride (TG) and cholesterol ester (CE) accumulation between the two leaflets of the ER bilayer [202]. This microenvironment represents the “platform” for HCV particle assembly. Several host factors involved in TG biosynthesis and LD biogenesis have been demonstrated to contribute to this process and thus represent targets for HTAs (Figure 3). Indeed, HCV morphogenesis is triggered by the recruitment of the viral core protein from the ER to LDs [203], a process mediated by the diacylglycerol acyltransferase-1 (DGAT-1) (Figure 3). Interestingly, a DGAT-1 chemical inhibitor, currently in clinical trials for metabolic diseases (reviewed in [204]), might serve as an antiviral against HCV infection [205]. Notably, since in hepatocytes DGAT-2 has redundant functions in LD morphogenesis, this DGAT-1-specific inhibitor did not impair LD homeostasis in vitro [205]. The safety of DGAT-1 inhibitor LCQ908 has already been evaluated in HCV-infected patients (https://clinicaltrials.gov/; Identifier: NCT01387958), but additional studies are needed to assess its antiviral efficacy in patients.

Bottom Line: In contrast to DAAs that target viral proteins, host-targeting agents (HTAs) interfere with cellular factors involved in the viral life cycle.By acting through a complementary mechanism of action and by exhibiting a generally higher barrier to resistance, HTAs offer a prospective option to prevent and treat viral resistance.Indeed, given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads.

View Article: PubMed Central - PubMed

Affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France. mirjam.zeisel@unistra.fr.

ABSTRACT
Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) which are leading indications of liver transplantation (LT). To date, there is no vaccine to prevent HCV infection and LT is invariably followed by infection of the liver graft. Within the past years, direct-acting antivirals (DAAs) have had a major impact on the management of chronic hepatitis C, which has become a curable disease in the majority of DAA-treated patients. In contrast to DAAs that target viral proteins, host-targeting agents (HTAs) interfere with cellular factors involved in the viral life cycle. By acting through a complementary mechanism of action and by exhibiting a generally higher barrier to resistance, HTAs offer a prospective option to prevent and treat viral resistance. Indeed, given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads. This review summarizes the different classes of HTAs against HCV infection that are in preclinical or clinical development and highlights their potential to prevent HCV infection, e.g., following LT, and to tailor combination treatments to cure chronic HCV infection.

Show MeSH
Related in: MedlinePlus