A Multi-center, Open-label, Dose-ranging, Phase 1 Study to Evaluate the Safety, Tolerability, and Immunogenicity of GLS-6150, Administered ID and Followed by Cellectra® 2000 Healthy Adults and in Persons Previously Treated for Hepatitis C Virus Infection.

Hepatitis C virus (HCV) is an enveloped, single strand, positive sense RNA flavivirus. Infection by HCV is typically chronic, although an estimated
10-20% may spontaneously clear the virus. HCV affects between 1.3 - 2 billion individuals, or 2-3% of the global population. HCV has a seroprevalence of approximately 1% in developed countries such as the US and Korea. Chronic HCV infection leads to hepatic fibrosis and cirrhosis. This Phase I study will evaluate the safety, tolerability and immunogenicity of GLS-6150 administered intradermally (ID) followed by electroporation at 1.0 mg and 2.0 mg/dose assessing 3 and 4-dose regimens.

Start Date04 Sep 2018

Sponsor / Collaborator

GeneOne Life Science, Inc.

[+1]

NCT02772003

/ Active, not recruitingPhase 1IIT

Phase I Trial of a Therapeutic DNA Vaccine for Chronic Hepatitis C Virus (HCV) Infection

This phase I trial studies the side effects and best dose of deoxyribonucleic acid (DNA) vaccine therapy in treating patients with hepatitis C virus (HCV) infection that persists or progresses over a long period of time. Vaccines made from DNA may help the body build an effective immune response to kill cancer cells that express HCV infection.

Start Date06 Jun 2016

Sponsor / Collaborator

National Cancer Institute

[+1]

NCT02027116

/ CompletedPhase 1

Multi-center, Open-label, Dose Escalation, Phase I Trial to Evaluate the Safety, Tolerability and Immunogenicity of VGX-6150 for Second-line Therapy of Chronic Hepatitis C Infection

To evaluate the safety, tolerability and immunogenicity of VGX-6150 as second-line therapy in chronic hepatitis C patients

Start Date01 Jan 2014

Sponsor / Collaborator

GeneOne Life Science, Inc.

[+1]

100 Clinical Results associated with HCV NS4B

100 Translational Medicine associated with HCV NS4B

0 Patents (Medical) associated with HCV NS4B

Literatures (Medical) associated with HCV NS4B

15 Mar 2023·Archives of virology

Hepatitis C virus nonstructural protein 4B induces lipogenesis via the Hippo pathway.

Article

Author: Zhang, Zhanfeng ; Liu, Minqi ; Zheng, Yi ; Zhang, Guangping ; Zou, Chen ; Zeng, Jun ; Tan, Hongxi

Hepatitis C virus (HCV) infection causes abnormal lipid metabolism in hepatocytes, which leads to hepatic steatosis and even hepatocellular carcinoma. HCV nonstructural protein 4B (NS4B) has been reported to induce lipogenesis, but the underlying mechanism is unclear. In this study, western blots were performed to investigate the effect of NS4B protein levels on key effectors of the Hippo and AKT signaling pathways. Yes-associated protein (YAP) and moesin-ezrin-radixin-like protein (Merlin) are effectors of the Hippo pathway. NS4B downregulated Merlin and phosphorylated YAP (p-YAP) protein expression while increasing the expression of the key AKT pathway proteins p-AKT and NF-κB. By observing the levels of AKT pathway proteins when Merlin was overexpressed or silenced, it was determined that Merlin mediates the AKT pathway. We suggest that HCV NS4B may mediate the AKT signaling pathway by inhibiting the Hippo pathway. Lipid droplets were observed in Huh7.5 cells overexpressing NS4B, and they increased significantly in number when Merlin was silenced. Overexpression of NS4B and Merlin silencing enhanced the expression of sterol regulatory element binding proteins (SREBPs), which have been demonstrated to be key regulatory factors controlling fatty acid synthesis. NS4B and Merlin silencing also enhanced the in vitro proliferative capacity of hepatocellular carcinoma cells. In conclusion, NS4B induces lipogenesis via the effect of the Hippo-YAP pathway on the AKT signaling pathway and thereby plays a significant role in the pathogenesis of HCV-associated diseases.

01 Sep 2016·Tumor Biology

HCV NS4B targets Scribble for proteasome-mediated degradation to facilitate cell transformation

Article

Author: Hu, Bo ; Huang, Xianzhang ; Zhang, Zhanfeng ; Hu, Yuqian ; Xie, Shenggao ; Zheng, Yi ; Li, Shanshan

Hepatitis C virus (HCV) nonstructural protein 4B (NS4B) is a multi-transmembrane protein, but little is known about how NS4B contributes to HCV replication and tumorigenesis. Its C-terminal domain (CTD) has been shown to associate with intracellular membrane, and we have previously shown that NS4B CTD contains a class I PDZ-binding motif (PBM). Here, we demonstrated that NS4B PBM interacts with the PDZ-containing tumor suppressor protein, Scribble, using immunofluorescence and co-immunoprecipitation assays, and this interaction requires at least three contiguous PDZ domains of Scribble. In addition, NS4B PBM specifically induced Scribble degradation by activating the proteasome-ubiquitin pathway. Similar Scribble degradation was also observed in HCV-infected cells, suggesting NS4B could work in the context of HCV. Finally, NS4B PBM mutants showed reduced colony formation capacity compared with its wild-type counterpart, indicating that NS4B PBM plays important roles in NS4B-mediated cell transformation. Altogether, we provide a mechanism by which NS4B induces cell transformation through its PBM, which specifically interacts with the PDZ domains of Scribble and targets Scribble for degradation.

01 Aug 2016·Archives of VirologyQ4 · MEDICINE

Hepatitis C virus and its protein NS4B activate the cancer-related STAT3 pathway via the endoplasmic reticulum overload response

Q4 · MEDICINE

Article

Author: Guo, Yunli ; Guo, Fenglin ; Huang, Mingjie ; Xu, Ahui ; Wu, Xiaoyu ; Yu, Xilan ; Kong, Lingbao ; Li, Shanshan ; Xu, Jin ; Fang, Xiaonan

Oxidative stress induces the activation of signal transducer and activator of transcription 3 (STAT3), which plays an important role in hepatocellular carcinoma (HCC). We have previously reported that hepatitis C virus (HCV) and its protein NS4B induce the production of reactive oxygen species (ROS) via the endoplasmic reticulum overload response (EOR) in human hepatocytes. Here, we found that NS4B and HCV induce STAT3 activation and stimulate the expression of cancer-related STAT3 target genes, including VEGF, c-myc, MMP-9 and Mcl-1, by EOR in human hepatocytes. Moreover, the cancer-related STAT3 pathway activated by NS4B and HCV via EOR were found to promote human hepatocyte viability. Taken together, these findings revealed that HCV NS4B might contribute to HCC by activating the EOR-mediated cancer-related STAT3 pathway, and this could provide novel insights into HCV-induced HCC.

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