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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 entry. The initial viral attachment on the basolateral membrane of hepatocytes is believed to involve the interaction of the viral particle—both viral (HCV envelope glycoproteins) and host-derived (apolipoproteins) factors—with HSPGs (heparan sulfate proteoglycans), LDLR (low density lipoprotein receptor) and SR-BI (scavenger receptor class B type I). Following interaction between the virus and different host factors expressed at the hepatocyte cell surface, including CD81 (cluster of differentiation 81) and CLDN1 (claudin 1), as well as rearrangement of cell surface proteins, the virus is ultimately internalized into its host cell via clathrin-mediated endocytosis. Additional host factors, including EGFR (epidermal growth factor receptor), NPC1L1 (Niemann-Pick C1-like 1) and TfR1 (transferrin receptor 1), contribute to the HCV entry process, for example by modulating intracellular signaling pathways or endocytosis. Following acidification of the endosome and subsequent fusion of viral and endosomal membranes, the viral genome is released into the cytoplasm. In addition to cell-free virus entry, HCV has also been described to transmit between hepatocytes through direct cell-to-cell transmission involving CD81, SR-BI, CLDN1, OCLN (occludin), EGFR, EphA2 (ephrin receptor A2) and NPC1L1. HTAs can interfere with different steps of the HCV entry process as highlighted in red.
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viruses-07-02898-f002: Schematic representation of HCV entry. The initial viral attachment on the basolateral membrane of hepatocytes is believed to involve the interaction of the viral particle—both viral (HCV envelope glycoproteins) and host-derived (apolipoproteins) factors—with HSPGs (heparan sulfate proteoglycans), LDLR (low density lipoprotein receptor) and SR-BI (scavenger receptor class B type I). Following interaction between the virus and different host factors expressed at the hepatocyte cell surface, including CD81 (cluster of differentiation 81) and CLDN1 (claudin 1), as well as rearrangement of cell surface proteins, the virus is ultimately internalized into its host cell via clathrin-mediated endocytosis. Additional host factors, including EGFR (epidermal growth factor receptor), NPC1L1 (Niemann-Pick C1-like 1) and TfR1 (transferrin receptor 1), contribute to the HCV entry process, for example by modulating intracellular signaling pathways or endocytosis. Following acidification of the endosome and subsequent fusion of viral and endosomal membranes, the viral genome is released into the cytoplasm. In addition to cell-free virus entry, HCV has also been described to transmit between hepatocytes through direct cell-to-cell transmission involving CD81, SR-BI, CLDN1, OCLN (occludin), EGFR, EphA2 (ephrin receptor A2) and NPC1L1. HTAs can interfere with different steps of the HCV entry process as highlighted in red.

Mentions: The HCV entry process has been particularly well characterized within the past years (for a review see [6]). The initial viral attachment on the hepatocyte cell surface is believed to involve the interaction of the viral particle with heparan sulfate proteoglycans (HSPGs) [41,42,43,44,45,46], particularly with syndecan 1 (SDC1) [47] and syndecan 4 (SDC4) [48], low density lipoprotein receptor (LDLR) [49,50,51,52,53], and scavenger receptor class B type I (SR-BI) [54,55,56,57,58,59]. Interestingly, both viral (HCV envelope glycoproteins) and host-derived (apolipoproteins) factors within the viral particle appear to mediate this process (reviewed in [6,60]). Thus, the very first steps of viral interaction with the host cell surface can be inhibited by targeting host factors expressed either on the viral particle or on the host cell membrane (Figure 2). Indeed, it has been shown that synthetic anti-lipopolysaccharide peptides that bind to heparan sulfate moieties on the cell surface as well as antibodies directed against SR-BI or LDLR inhibit HCV attachment/infection [53,59,61]. Likewise, peptides that mimic the receptor binding domain and the HSPG binding domain of apolipoprotein E (apoE) inhibit HCV infection [45,48] and antibodies directed against apoE [45,62,63] as well as preincubation of recombinant cell culture-derived HCV (HCVcc) with soluble LDLR have also been shown to neutralize HCV infection, likely at the attachment/entry level [53,64]. Recently, it has been suggested that low-molecular-weight lignin, a component of Lentinula edodes mycelia solid culture extract, that has been reported to exhibit hepatoprotective activity, might inhibit HCV attachment through binding to apoE on the viral particle [65] given the structural similarity between lignin sulfate and heparan sulfate [66]. Interestingly, lipoprotein lipase (LPL) increases HCV attachment to the target cell by bridging virus-associated lipoproteins and cell surface heparan sulfate, whereas antibodies as well as a small molecule inhibitor-targeting LDLR have been shown to decrease HCV uptake [67,68]. In addition to its bridging function, LPL has been shown to inhibit viral entry by immobilizing the virus at the cell surface [64,69]. Most recently, it has been shown that very low-density lipoprotein (VLDL) is a serum component that inhibits HCV attachment [70].


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 entry. The initial viral attachment on the basolateral membrane of hepatocytes is believed to involve the interaction of the viral particle—both viral (HCV envelope glycoproteins) and host-derived (apolipoproteins) factors—with HSPGs (heparan sulfate proteoglycans), LDLR (low density lipoprotein receptor) and SR-BI (scavenger receptor class B type I). Following interaction between the virus and different host factors expressed at the hepatocyte cell surface, including CD81 (cluster of differentiation 81) and CLDN1 (claudin 1), as well as rearrangement of cell surface proteins, the virus is ultimately internalized into its host cell via clathrin-mediated endocytosis. Additional host factors, including EGFR (epidermal growth factor receptor), NPC1L1 (Niemann-Pick C1-like 1) and TfR1 (transferrin receptor 1), contribute to the HCV entry process, for example by modulating intracellular signaling pathways or endocytosis. Following acidification of the endosome and subsequent fusion of viral and endosomal membranes, the viral genome is released into the cytoplasm. In addition to cell-free virus entry, HCV has also been described to transmit between hepatocytes through direct cell-to-cell transmission involving CD81, SR-BI, CLDN1, OCLN (occludin), EGFR, EphA2 (ephrin receptor A2) and NPC1L1. HTAs can interfere with different steps of the HCV entry process as highlighted in red.
© Copyright Policy
Related In: Results  -  Collection

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

viruses-07-02898-f002: Schematic representation of HCV entry. The initial viral attachment on the basolateral membrane of hepatocytes is believed to involve the interaction of the viral particle—both viral (HCV envelope glycoproteins) and host-derived (apolipoproteins) factors—with HSPGs (heparan sulfate proteoglycans), LDLR (low density lipoprotein receptor) and SR-BI (scavenger receptor class B type I). Following interaction between the virus and different host factors expressed at the hepatocyte cell surface, including CD81 (cluster of differentiation 81) and CLDN1 (claudin 1), as well as rearrangement of cell surface proteins, the virus is ultimately internalized into its host cell via clathrin-mediated endocytosis. Additional host factors, including EGFR (epidermal growth factor receptor), NPC1L1 (Niemann-Pick C1-like 1) and TfR1 (transferrin receptor 1), contribute to the HCV entry process, for example by modulating intracellular signaling pathways or endocytosis. Following acidification of the endosome and subsequent fusion of viral and endosomal membranes, the viral genome is released into the cytoplasm. In addition to cell-free virus entry, HCV has also been described to transmit between hepatocytes through direct cell-to-cell transmission involving CD81, SR-BI, CLDN1, OCLN (occludin), EGFR, EphA2 (ephrin receptor A2) and NPC1L1. HTAs can interfere with different steps of the HCV entry process as highlighted in red.
Mentions: The HCV entry process has been particularly well characterized within the past years (for a review see [6]). The initial viral attachment on the hepatocyte cell surface is believed to involve the interaction of the viral particle with heparan sulfate proteoglycans (HSPGs) [41,42,43,44,45,46], particularly with syndecan 1 (SDC1) [47] and syndecan 4 (SDC4) [48], low density lipoprotein receptor (LDLR) [49,50,51,52,53], and scavenger receptor class B type I (SR-BI) [54,55,56,57,58,59]. Interestingly, both viral (HCV envelope glycoproteins) and host-derived (apolipoproteins) factors within the viral particle appear to mediate this process (reviewed in [6,60]). Thus, the very first steps of viral interaction with the host cell surface can be inhibited by targeting host factors expressed either on the viral particle or on the host cell membrane (Figure 2). Indeed, it has been shown that synthetic anti-lipopolysaccharide peptides that bind to heparan sulfate moieties on the cell surface as well as antibodies directed against SR-BI or LDLR inhibit HCV attachment/infection [53,59,61]. Likewise, peptides that mimic the receptor binding domain and the HSPG binding domain of apolipoprotein E (apoE) inhibit HCV infection [45,48] and antibodies directed against apoE [45,62,63] as well as preincubation of recombinant cell culture-derived HCV (HCVcc) with soluble LDLR have also been shown to neutralize HCV infection, likely at the attachment/entry level [53,64]. Recently, it has been suggested that low-molecular-weight lignin, a component of Lentinula edodes mycelia solid culture extract, that has been reported to exhibit hepatoprotective activity, might inhibit HCV attachment through binding to apoE on the viral particle [65] given the structural similarity between lignin sulfate and heparan sulfate [66]. Interestingly, lipoprotein lipase (LPL) increases HCV attachment to the target cell by bridging virus-associated lipoproteins and cell surface heparan sulfate, whereas antibodies as well as a small molecule inhibitor-targeting LDLR have been shown to decrease HCV uptake [67,68]. In addition to its bridging function, LPL has been shown to inhibit viral entry by immobilizing the virus at the cell surface [64,69]. Most recently, it has been shown that very low-density lipoprotein (VLDL) is a serum component that inhibits HCV attachment [70].

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