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EBioMedicine. 2017 Sep;23:68-78. doi: 10.1016/j.ebiom.2017.08.020. Epub 2017 Aug 24.

Treatment-Induced Viral Cure of Hepatitis C Virus-Infected Patients Involves a Dynamic Interplay among three Important Molecular Players in Lipid Homeostasis: Circulating microRNA (miR)-24, miR-223, and Proprotein Convertase Subtilisin/Kexin Type 9.

Author information

1
Dept. of Microbiology and Immunology, University of British Columbia, Canada. Electronic address: ahyrina@mail.ubc.ca.
2
Dept. of Microbiology and Immunology, University of British Columbia, Canada. Electronic address: Andrea.Olmstead@bccdc.ca.
3
QIAGEN, United Kingdom. Electronic address: paul.steven@qiagen.com.
4
BCCDC Public Health Microbiology and Reference Laboratory, Canada. Electronic address: Mel.Krajden@bccdc.ca.
5
LAIR Centre, Canada. Electronic address: etam@laircentre.com.
6
Dept. of Microbiology and Immunology, University of British Columbia, Canada. Electronic address: fjean@mail.ubc.ca.

Abstract

In patients with chronic hepatitis C virus (HCV) infection, viral hijacking of the host-cell biosynthetic pathways is associated with altered lipid metabolism, which contributes to disease progression and may influence antiviral response. We investigated the molecular interplay among four key regulators of lipid homeostasis [microRNA (miR)-122, miR-24, miR-223, and proprotein convertase subtilisin/kexin type 9 (PCSK9)] in HCV-infected patients (n=72) who achieved a treatment-based viral cure after interferon-based therapy with first-generation direct-acting antivirals. Real-time PCR was used to quantify microRNA plasma levels, and ELISA assays were used to determine plasma concentrations of PCSK9. We report that levels of miR-24 and miR-223 significantly increased in patients achieving sustained virologic response (SVR), whereas the levels of miR-122, a liver-specific cofactor for HCV infection, decreased in these patients. PCSK9 concentrations were significantly increased in SVRs, suggesting that PCSK9 may help impede viral infection. The modulatory effect of PCSK9 on HCV infection was also demonstrated in the context of HCV-infected Huh-7.5.1 cells employing recombinant human PCSK9 mutants. Together, these results provide insights into a novel coordinated interplay among three important molecular players in lipid homeostasis - circulating miR-24, miR-223 and PCSK9 - whose regulation is affected by HCV infection and treatment-based viral cure.

KEYWORDS:

Antiviral therapy; Hepatitis C virus; Proprotein convertase subtilisin/kexin type 9; miR-122; miR-223; miR-24

PMID:
28864162
PMCID:
PMC5605363
DOI:
10.1016/j.ebiom.2017.08.020
[Indexed for MEDLINE]
Free PMC Article

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