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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 the hepatitis C virus (HCV) life cycle and targets for antiviral therapy. HCV interacts with the basolateral membrane of hepatocytes, resulting in viral entry into the host cell. The virus is internalized via endocytosis and translation of the HCV RNA occurs in the cytoplasm following viral fusion and uncoating. Viral replication takes place within the cytoplasm in perinuclear endoplasmic reticulum (ER)-derived membranes called the “membranous web”. Progeny virions are assembled on cytosolic lipid droplets and subsequently transported along the secretory pathway and maturated in the Golgi before their release through microtubular transport and endocytic recycling compartment. Targets for antiviral therapy are highlighted in red.
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viruses-07-02898-f001: Schematic representation of the hepatitis C virus (HCV) life cycle and targets for antiviral therapy. HCV interacts with the basolateral membrane of hepatocytes, resulting in viral entry into the host cell. The virus is internalized via endocytosis and translation of the HCV RNA occurs in the cytoplasm following viral fusion and uncoating. Viral replication takes place within the cytoplasm in perinuclear endoplasmic reticulum (ER)-derived membranes called the “membranous web”. Progeny virions are assembled on cytosolic lipid droplets and subsequently transported along the secretory pathway and maturated in the Golgi before their release through microtubular transport and endocytic recycling compartment. Targets for antiviral therapy are highlighted in red.

Mentions: The HCV life cycle can be subdivided into five different steps, including viral entry, viral translation, viral replication, viral assembly, and release of new virions. Each of these steps requires defined virus-host interactions to ultimately enable the virus to establish chronic infection. Given the amount of host factors involved in the HCV life cycle, this review solely focuses on some of these host factors that have been suggested to represent potential targets for HTAs during distinct steps of the HCV life cycle within hepatocytes (Figure 1). Other compounds exhibiting a broader mechanism of action by modulating the host’s immune responses, also termed biological response modifiers (Table 1), such as IFNs, Toll-like receptor (TLR) 7, or TLR9 agonists [14,15,16,17], are not reviewed in detail here.


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

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

Schematic representation of the hepatitis C virus (HCV) life cycle and targets for antiviral therapy. HCV interacts with the basolateral membrane of hepatocytes, resulting in viral entry into the host cell. The virus is internalized via endocytosis and translation of the HCV RNA occurs in the cytoplasm following viral fusion and uncoating. Viral replication takes place within the cytoplasm in perinuclear endoplasmic reticulum (ER)-derived membranes called the “membranous web”. Progeny virions are assembled on cytosolic lipid droplets and subsequently transported along the secretory pathway and maturated in the Golgi before their release through microtubular transport and endocytic recycling compartment. Targets for antiviral therapy are highlighted in red.
© Copyright Policy
Related In: Results  -  Collection

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

viruses-07-02898-f001: Schematic representation of the hepatitis C virus (HCV) life cycle and targets for antiviral therapy. HCV interacts with the basolateral membrane of hepatocytes, resulting in viral entry into the host cell. The virus is internalized via endocytosis and translation of the HCV RNA occurs in the cytoplasm following viral fusion and uncoating. Viral replication takes place within the cytoplasm in perinuclear endoplasmic reticulum (ER)-derived membranes called the “membranous web”. Progeny virions are assembled on cytosolic lipid droplets and subsequently transported along the secretory pathway and maturated in the Golgi before their release through microtubular transport and endocytic recycling compartment. Targets for antiviral therapy are highlighted in red.
Mentions: The HCV life cycle can be subdivided into five different steps, including viral entry, viral translation, viral replication, viral assembly, and release of new virions. Each of these steps requires defined virus-host interactions to ultimately enable the virus to establish chronic infection. Given the amount of host factors involved in the HCV life cycle, this review solely focuses on some of these host factors that have been suggested to represent potential targets for HTAs during distinct steps of the HCV life cycle within hepatocytes (Figure 1). Other compounds exhibiting a broader mechanism of action by modulating the host’s immune responses, also termed biological response modifiers (Table 1), such as IFNs, Toll-like receptor (TLR) 7, or TLR9 agonists [14,15,16,17], are not reviewed in detail here.

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