From the AGA Journals

Human liver cells can induce antiviral reaction against hepatitis C

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Human liver cells can induce antiviral reaction

Liver sinusoidal endothelial cells (LSECs) are a large component of the liver immune system but are not very well characterized for their role in diseases like chronic hepatitis C virus (HCV) infection. Dr. Giugliano and her associates tested the antiviral activity of primary human LSECs and an immortalized LSEC cell line (TMNK-1), following exposure to several viral variants. These included naturally

Dr. Arash Grakoui

occurring founder genotype 1a virus, a JFH-1 infectious clone (cloned originally from a patient with fulminant hepatitis), a modified cell culture of adaptive JFH-1 virus expressing luciferase reporter, and HCV-specific pathogen-associated molecular pattern poly UC RNA that is a substrate for RIG-I. They found LSECs were able to acquire HCV in an LSEC-to-hepatocyte–contact independent manner but that these cells were not permissive for productive infection (replication). Importantly, viral RNA through HCV uptake induced robust transcription of type I and III interferon (IFN) by LSECs via TLR7 and RIG-I pathways. LSEC-derived IFN had antiviral effects on HCV-infected human hepatoma cell line, Huh7.5 cells in vitro, and this effect was mediated through the production of exosomes. The authors concluded that LSECs likely have an important antiviral role in HCV infection through bystander induction of an antiviral state. This study highlights the idea that these cells can function similarly to other innate/phagocytic cells like monocytes/macrophages and furthers the idea that innate activation of LSECs may have protective effects on the antiviral state of hepatocytes. Mechanisms of antiviral immunity by LSECs, whether it occurs through exosomes or IFN, will have a significant impact in the field as the answers will have relevance to numerous facets of liver immunology, including gene transfer, organ transplant, and response to other hepatotropic infections.

Dr. Arash Grakoui is an associate professor jointly appointed in the departments of medicine, division of infectious diseases and Yerkes National Primate Research Center, department of microbiology and immunology at Emory University, Atlanta. He has no conflicts of interest.




Immunity against the hepatitis C virus can be induced by cultured primary human liver sinusoidal endothelial cells, according to a study published in the February issue of Gastroenterology (doi:10.1053/j.gastro.2014.10.040).

“We found HLSECs [primary human LSECs] express many of the receptors implicated in HCV [hepatitis C virus] attachment and entry and HLSEC-to-hepatocyte contact was dispensable for uptake,” wrote lead author Dr. Silvia M. Giugliano of the University of Colorado, Denver, and her associates.

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In a cohort study, investigators exposed HLSECs and immortalized liver endothelial cells (TMNK-1) to several variants of HCV: full-length transmitted/founder virus, sucrose-purified Japanese fulminant hepatitis–1 (JFH-1), a virus encoding a luciferase reporter, and the HCV-specific pathogen-associated molecular pattern molecules (PAMP, substrate for RIG-I). Cells were analyzed by using polymerase chain reaction (PCR), immunofluorescence, and immunohistochemical assays.

Results showed that HLSECs, regardless of contact between cells, were able to internalize HCV when exposed to it and replicate, though not translate HCV RNA. The HCV RNA “induced consistent and broad transcription of multiple interferons (IFNs) [via] pattern recognition receptors (TLR7 and retinoic acid-inducible gene 1).” Furthermore, supernatants from primary HLSECs transfected with HCV-specific PAMP molecules had larger inductions of IFNs and IFN-stimulated genes in HLSECs.

“Conditioned media from IFN-stimulated HLSECs induced expression of antiviral genes by uninfected primary human hepatocytes,” wrote Dr. Giugliano and her coauthors. “Exosomes, derived from HLSECs following stimulation with either type I or type III IFNs, controlled HCV replication in a dose-dependent manner.”

However, the investigators say that more study is required to understand why HCV is able to present so persistently if the means to combat the virus are so apparent in the immune system.

“These results raise a number of intriguing questions, for example, how the use of exogenous IFN to treat viral hepatitis could be expected to induce additional, previously unrecognized antiviral mechanisms involving HLSECs,” says the study. “Further work is warranted to understand why despite these innate immune responses, HCV is able to establish persistence and fail eradication with IFN-based antiviral therapy.”

The study supported by grants R21-AI103361 and U19 AI 1066328; Dr. Rosen received a Merit Review grant and Dr. Shaw received grant R21-AI 106000. The authors reported no financial conflicts of interest.

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