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Amphipathic DNA polymers inhibit hepatitis C virus infection by blocking viral entry.

ABSTRACT: Hepatitis C virus (HCV) gains entry into susceptible cells by interacting with cell surface receptor(s). Viral entry is an attractive target for antiviral development because of the highly conserved mechanism.HCV culture systems were used to study the effects of phosphorothioate oligonucleotides (PS-ONs), as amphipathic DNA polymers (APs), on HCV infection. The in vivo effects of APs were tested in urokinase plasminogen activator (uPA)/severe combined immunodeficient (SCID) mice engrafted with human hepatocytes.We show the sequence-independent inhibitory effects of APs on HCV infection. APs were shown to potently inhibit HCV infection at submicromolar concentrations. APs exhibited a size-dependent antiviral activity and were equally active against HCV pseudoparticles of various genotypes. Control phosphodiester oligonucleotide (PO-ON) polymer without the amphipathic structure was inactive. APs had no effect on viral replication in the HCV replicon system or binding of HCV to cells but inhibited viral internalization, indicating that the target of inhibition is at the postbinding, cell entry step. In uPA/SCID mice engrafted with human hepatocytes, APs efficiently blocked de novo HCV infection.Our results demonstrate that APs are a novel class of antiviral compounds that hold promise as a drug to inhibit HCV entry.

SUBMITTER: Matsumura T

PROVIDER: S-EPMC2803092 | biostudies-other | 2009 Aug

REPOSITORIES: biostudies-other

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Amphipathic DNA polymers inhibit hepatitis C virus infection by blocking viral entry.

Matsumura Takuya T Hu Zongyi Z Kato Takanobu T Dreux Marlene M Zhang Yong-Yuan YY Imamura Michio M Hiraga Nobuhiko N Juteau Jean-Marc JM Cosset Francois-Loic FL Chayama Kazuaki K Vaillant Andrew A Liang T Jake TJ

Gastroenterology 20090423 2

<h4>Background & aims</h4>Hepatitis C virus (HCV) gains entry into susceptible cells by interacting with cell surface receptor(s). Viral entry is an attractive target for antiviral development because of the highly conserved mechanism.<h4>Methods</h4>HCV culture systems were used to study the effects of phosphorothioate oligonucleotides (PS-ONs), as amphipathic DNA polymers (APs), on HCV infection. The in vivo effects of APs were tested in urokinase plasminogen activator (uPA)/severe combined im ...[more]

PMID: 19394333

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Project description:A distinctive feature of HCV is that its life cycle depends on lipoprotein metabolism. Viral morphogenesis and secretion follow the very low-density lipoprotein (VLDL) biogenesis pathway and, consequently, infectious HCV in the serum is associated with triglyceride-rich lipoproteins (TRL). Lipoprotein lipase (LPL) hydrolyzes TRL within chylomicrons and VLDL but, independently of its catalytic activity, it has a bridging activity, mediating the hepatic uptake of chylomicrons and VLDL remnants. We previously showed that exogenously added LPL increases HCV binding to hepatoma cells by acting as a bridge between virus-associated lipoproteins and cell surface heparan sulfate, while simultaneously decreasing infection levels. We show here that LPL efficiently inhibits cell infection with two HCV strains produced in hepatoma cells or in primary human hepatocytes transplanted into uPA-SCID mice with fully functional human ApoB-lipoprotein profiles. Viruses produced in vitro or in vivo were separated on iodixanol gradients into low and higher density populations, and the infection of Huh 7.5 cells by both virus populations was inhibited by LPL. The effect of LPL depended on its enzymatic activity. However, the lipase inhibitor tetrahydrolipstatin restored only a minor part of HCV infectivity, suggesting an important role of the LPL bridging function in the inhibition of infection. We followed HCV cell entry by immunoelectron microscopy with anti-envelope and anti-core antibodies. These analyses demonstrated the internalization of virus particles into hepatoma cells and their presence in intracellular vesicles and associated with lipid droplets. In the presence of LPL, HCV was retained at the cell surface. We conclude that LPL efficiently inhibits HCV infection by acting on TRL associated with HCV particles through mechanisms involving its lipolytic function, but mostly its bridging function. These mechanisms lead to immobilization of the virus at the cell surface. HCV-associated lipoproteins may therefore be a promising target for the development of new therapeutic approaches.

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Amphipathic DNA polymers inhibit hepatitis C virus infection by blocking viral entry.

Publications

Amphipathic DNA polymers inhibit hepatitis C virus infection by blocking viral entry.

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