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Entry Inhibitors: A Perspective for Prevention of Hepatitis C Virus Infection in Organ Transplantation.

ABSTRACT: Entry inhibitors are emerging as an attractive class of therapeutics for hepatitis C virus (HCV) infection. Entry inhibitors target either virion-associated factors or cellular factors necessary for infection. By blocking entry into cells, entry inhibitors prevent both the establishment of persistent reservoirs and the emergence of resistant variants during viral replication. Furthermore, entry inhibitors protect naïve cells from virus-induced alterations. Combining entry inhibitors with direct-acting antivirals (DAAs) may therefore improve treatment outcomes, particularly in the context of organ transplantation. The role of DAAs in transplantation, while still under clinical investigation, carries the risk of recipient infection and HCV-induced disease, since DAAs act only after infection is established. Thus, entry inhibitors provide a perspective to improve patient outcomes during organ transplantation. Applying this approach for transplant of organs from HCV-positive donors to HCV-negative recipients may also contribute to alleviate the medical burden of organ shortage.

SUBMITTER: Colpitts CC

PROVIDER: S-EPMC7613425 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Entry Inhibitors: A Perspective for Prevention of Hepatitis C Virus Infection in Organ Transplantation.

Colpitts Che C CC Chung Raymond T RT Baumert Thomas F TF

ACS infectious diseases 20170816 9

Entry inhibitors are emerging as an attractive class of therapeutics for hepatitis C virus (HCV) infection. Entry inhibitors target either virion-associated factors or cellular factors necessary for infection. By blocking entry into cells, entry inhibitors prevent both the establishment of persistent reservoirs and the emergence of resistant variants during viral replication. Furthermore, entry inhibitors protect naïve cells from virus-induced alterations. Combining entry inhibitors with direct- ...[more]

PMID: 28812869

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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.

Dataset Information

Entry Inhibitors: A Perspective for Prevention of Hepatitis C Virus Infection in Organ Transplantation.

Publications

Entry Inhibitors: A Perspective for Prevention of Hepatitis C Virus Infection in Organ Transplantation.

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