Human Liver Cells Can Induce Antiviral Reaction Against Hepatitis C

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.

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.

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.

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.

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.

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.