Completion of the entire hepatitis C virus life cycle in genetically humanized mice

Dorner, Marcus; Horwitz, Joshua A.; Donovan, Bridget M.; Labitt, Rachael N.; Budell, William C.; Friling, Tamar; Vogt, Alexander; Catanese, Maria Teresa; Satoh, Takashi; Kawai, Taro; Akira, Shizuo; Law, Mansun; Rice, Charles M.; Ploß, Alexander

doi:10.1038/nature12427

Cited by 204 publications

(199 citation statements)

References 42 publications

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“…Infection of the host cell by HCV is initiated by the interactions between the viral envelop protein and several previously identified HCV entry receptors, including CD81, scavenger receptor class B type I (SR-BI), claudin-1 (CLDN1), and occludin (OCLN) (19)(20)(21)(22)(23). ApoE is critical for HCV assembly (24).…”

Section: Resultsmentioning

confidence: 99%

Complete replication of hepatitis B virus and hepatitis C virus in a newly developed hepatoma cell line

Yang

Zuo

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The absence of a robust cell culture system for hepatitis B virus (HBV) and hepatitis C virus (HCV) infection has limited the analysis of the virus lifecycle and drug discovery. We have established a hepatoma cell line, HLCZ01, the first cell line, to the authors' knowledge, supporting the entire lifecycle of both HBV and HCV. HBV surface antigen (HBsAg)-positive particles can be observed in the supernatant and the lumen of the endoplasmic reticulum of the cells via electron microscopy. Interestingly, HBV and HCV clinical isolates propagate in HLCZ01 cells. Both viruses replicate in the cells without evidence of overt interference. HBV and HCV entry are blocked by antibodies against HBsAg and human CD81, respectively, and the replication of HBV and HCV is inhibited by antivirals. HLCZ01 cells mount an innate immune response to virus infection. The cell line provides a powerful tool for exploring the mechanisms of virus entry and replication and the interaction between host and virus, facilitating the development of novel antiviral agents and vaccines.cell culture model | primary human hepatocytes | cccDNA | interferon | ISGs M ore than 500 million people worldwide are persistently infected with hepatitis B virus (HBV) and/or hepatitis B virus (HCV) and are at risk of developing chronic liver diseases (1). There is no vaccine against HCV, and many patients who are persistently infected by HBV or HCV do not respond to currently available therapies (2, 3). Improved understanding of the biology and pathogenesis of these infections is required for the development of vaccine and antiviral drugs (4). The inability to grow HBV and HCV efficiently in cell culture has presented a major obstacle to understanding the virus lifecycle and pathogenesis and to developing improved therapeutics.HBV is a member of the hepadnavirus families, and its genome is a relaxed circular, partially double-stranded DNA molecule. The negative strand has an invariable length of ∼3.2 kb, and the positive strand is 50-100% of this length. Several key issues about the biology of HBV remain to be explored, including the identification of the cellular receptors, the role of the X gene, and the mechanisms by which the viral minichromosome is formed. Covalently closed circular DNA (cccDNA) is responsible for the establishment of viral infection and persistence. Understanding the mechanisms underlying cccDNA formation and regulation is critical for understanding the HBV pathogenesis and finding a cure for hepatitis B. HepG2.2.15 cells derived from the hepatoma cell line HepG2 transfected with the full genome of HBV have been used to study HBV replication (5). Primary human hepatocytes (PHH) are susceptible to HBV infection (6, 7), but the use of this model is hampered by the limited availability and unpredictable variability of human liver. Several human hepatoma cell lines support HBV replication after HBV DNA transfection, and overexpression of sodium-taurocholate cotransporting polypeptide (NTCP) in HepG2 and Huh7 cells can render these cells able t...

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Section: Resultsmentioning

confidence: 99%

Complete replication of hepatitis B virus and hepatitis C virus in a newly developed hepatoma cell line

Yang

Zuo

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, preclinical models of HBV infection rely on transgenic mice or viral gene transfer of HBV genomes into hepatocytes. HCV also fails to infect hepatocytes in mice but transgenic expression of its receptors renders mice susceptible to HCV infection [3]. In contrast, HAV infects murine cells in vitro but fails to establish liver infection in mice.…”

Section: Infection With Hepatitis Viruses Such As Hepatitis a Virus mentioning

confidence: 99%

Hitting the right button: MAVS-mediated defense against HAV infection

Knolle

2016

Cell Res

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“…However, it is likely that other factors expressed in mouse hepatocytes can be substituted and can function cooperatively in HCV entry. Transgenic mice expressing human CD81 and OCLN also support HCV entry (25). The discovery of the involvement of mouse VLDLR in HCV entry in Huh7.5#26 cells raised the question of whether HCV entry into mouse hepatocytes occurs exclusively via the CD81-dependent pathway.…”

Section: Ectopic Expression Of Vldlr Variant 2 Showed the Greatest Enmentioning

confidence: 99%

Hepatitis C virus utilizes VLDLR as a novel entry pathway

Ujino

Nishitsuji

Hishiki

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Various host factors are involved in the cellular entry of hepatitis C virus (HCV). In addition to the factors previously reported, we discovered that the very-low-density lipoprotein receptor (VLDLR) mediates HCV entry independent of CD81. Culturing Huh7.5 cells under hypoxic conditions significantly increased HCV entry as a result of the expression of VLDLR, which was not expressed under normoxic conditions in this cell line. Ectopic VLDLR expression conferred susceptibility to HCV entry of CD81-deficient Huh7.5 cells. Additionally, VLDLR-mediated HCV entry was not affected by the knockdown of cellular factors known to act as HCV receptors or HCV entry factors. Because VLDLR is expressed in primary human hepatocytes, our results suggest that VLDLR functions in vivo as an HCV receptor independent of canonical CD81-mediated HCV entry.virus entry | VLDLR | CD81 | hypoxia | hepatitis C virus H epatitis C virus (HCV) infects more than 170 million people worldwide and is a major cause of chronic liver disease. The virus persists in 80% of infected individuals and can lead to chronic liver diseases including fibrosis, cirrhosis, steatosis, and hepatocellular carcinoma. HCV, an enveloped positive-stranded virus, enters host cells by using various host factors that function as receptors and mediate endocytosis. Several host factors, including CD81 (1), claudin-1 (CLDN1) (2), occludin (OCLN) (3), and scavenger receptor class B member I (SR-BI) (4), have been identified as receptors. Heparan sulfate glycosaminoglycan represents the first attachment site (5) before the interaction of the virus with these factors. Because all the entry factors are required for productive HCV infection, HCV entry seems to be the result of an orchestrated process involving these factors. Additionally, low-density lipoprotein receptor (LDLR) (6), Niemann-Pic C1-like 1 (NPC1L1) (7), transferrin receptor 1 (TfR1) (8), and epidermal growth factor receptor (EGFR) (9) have been shown to play a role in HCV entry. CD81 was the first factor to be identified as an HCV receptor, and it plays an important role in this process by binding with the HCV envelope glycoprotein E2 (10, 11). Indeed, CD81-deficient cell lines such as HepG2 do not permit the entry of HCV (2, 3).Recent studies have demonstrated that HCV RNA replication in Huh7.5 cells is enhanced under hypoxic conditions (12). Because the oxygen content in liver tissue in vivo is estimated to be lower (with a gradient of 9-3%) than the oxygen content under in vitro culture conditions (13), the HCV life cycle may differ significantly from that observed using in vitro culture systems. The very-low-density lipoprotein receptor (VLDLR) is induced under hypoxic conditions. In turn, this receptor enhances the uptake of low-density lipoproteins (LDLs) and very-low-density lipoproteins (VLDLs) (14), possibly through the recognition of ligands (such as apolipoprotein) that associate with the lipoproteins (15). VLDLR is a type I transmembrane lipoprotein receptor belonging to the LDLR family (16). The expre...

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Completion of the entire hepatitis C virus life cycle in genetically humanized mice

Cited by 204 publications

References 42 publications

Complete replication of hepatitis B virus and hepatitis C virus in a newly developed hepatoma cell line

Complete replication of hepatitis B virus and hepatitis C virus in a newly developed hepatoma cell line

Hitting the right button: MAVS-mediated defense against HAV infection

Hepatitis C virus utilizes VLDLR as a novel entry pathway

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