scholarly journals Sodium taurocholate cotransporting polypeptide inhibition efficiently blocks hepatitis B virus spread in mice with a humanized liver

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Tasuku Nakabori ◽  
Hayato Hikita ◽  
Kazuhiro Murai ◽  
Yasutoshi Nozaki ◽  
Yugo Kai ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Sodium Taurocholate ◽  
Virus Spread ◽  
B Virus

NTCP oligomerization occurs downstream of the NTCP-EGFR interaction during hepatitis B virus internalization

2021 ◽  
Author(s):  
Kento Fukano ◽  
Mizuki Oshima ◽  
Senko Tsukuda ◽  
Hideki Aizaki ◽  
Mio Ohki ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Bile Acid ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Viral Entry ◽  
Sodium Taurocholate ◽  
Growth Factor Receptor ◽  
Host Cells ◽  
B Virus ◽  
Epidermal Growth

Sodium taurocholate cotransporting polypeptide (NTCP) is a receptor that is essential for hepatitis B virus (HBV) entry into the host cell. A number of HBV entry inhibitors targeting NTCP have been reported to date; these inhibitors have facilitated a mechanistic analysis of the viral entry process. However, the mechanism of HBV internalization into host cells after interaction of virus with NTCP remains largely unknown. Recently, we reported that troglitazone, a thiazolidinedione derivative, specifically inhibits both HBV internalization and NTCP oligomerization, resulting in inhibition of HBV infection. Here, using troglitazone as a chemical probe to investigate entry process, the contribution of NTCP oligomerization to HBV internalization was evaluated. Using surface plasmon resonance and transporter kinetics, we found that troglitazone directly interacts with NTCP and non-competitively interferes with NTCP-mediated bile acid uptake, suggesting that troglitazone allosterically binds to NTCP, rather than to the bile acid-binding pocket. Additionally, alanine scanning mutagenesis showed that a mutation at phenylalanine 274 of NTCP (F274A) caused a loss of HBV susceptibility and disrupted both the oligomerization of NTCP and HBV internalization without affecting viral attachment to the cell surface. An inhibitor of the interaction between NTCP and epidermal growth factor receptor (EGFR), another host cofactor essential for HBV internalization, impeded NTCP oligomerization. Meanwhile, co-immunoprecipitation analysis revealed that neither troglitazone nor the F274A mutation in NTCP affect the NTCP-EGFR interaction. These findings suggest that NTCP oligomerization is initiated downstream of the NTCP-EGFR interaction, and then triggers HBV internalization. This study provides significant insight into the HBV entry mechanisms. Importance Hepatitis B virus (HBV) infection is mediated by a specific interaction with sodium taurocholate cotransporting polypeptide (NTCP), a viral entry receptor. Although the virus-receptor interactions are believed to trigger viral internalization into host cells, the exact molecular mechanisms of HBV internalization are not understood. In this study, we revealed the mode of action whereby troglitazone, a specific inhibitor of HBV internalization, impedes NTCP oligomerization, and identified NTCP phenylalanine 274 as a residue essential for this oligomerization. We further analyzed the association between NTCP oligomerization and HBV internalization, a process that is mediated by epidermal growth factor receptor (EGFR), another essential host cofactor for HBV internalization. Our study provides critical information on the mechanism of HBV entry, and suggests that oligomerization of the viral receptor serves as an attractive target for drug discovery.

Role of Horizontal Transmission in Hepatitis B Virus Spread among Household Contacts in North India

Intervirology ◽  
2008 ◽  
Vol 51 (1) ◽  
pp. 7-13 ◽  
Author(s):  
Swati Gupta ◽  
Richa Gupta ◽  
Y.K. Joshi ◽  
Sarman Singh
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Horizontal Transmission ◽  
North India ◽  
Virus Spread ◽  
Household Contacts ◽  
B Virus

scholarly journals An Effective Antiviral Approach Targeting Hepatitis B Virus with NJK14047, a Novel and Selective Biphenyl Amide p38 Mitogen-Activated Protein Kinase Inhibitor

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
So-Young Kim ◽  
Hong Kim ◽  
Sang-Won Kim ◽  
Na-Rae Lee ◽  
Chae-Min Yi ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Protein Kinase ◽  
Hepatitis B ◽  
P38 Mapk ◽  
Sodium Taurocholate ◽  
Therapeutic Strategies ◽  
Host Factors ◽  
Mitogen Activated Protein Kinase ◽  
B Virus ◽  
Mitogen Activated Protein

ABSTRACT Despite recent advances in therapeutic strategies against hepatitis B virus (HBV) infection, chronic hepatitis B remains a major global health burden. Recent studies have shown that targeting host factors instead of viral factors can be an effective antiviral strategy with low risk of the development of resistance. Efforts to identify host factors affecting viral replication have identified p38 mitogen-activated protein kinase (MAPK) as a possible target for antiviral strategies against various viruses, including HBV. Here, a series of biphenyl amides were synthesized as novel p38 MAPK selective inhibitors and assessed for their anti-HBV activities. The suppression of HBV surface antigen (HBsAg) production by these compounds was positively correlated with p38 MAPK-inhibitory activity. The selected compound NJK14047 displayed significant anti-HBV activity, as determined by HBsAg production, HBeAg secretion, and HBV production. NJK14047 efficiently suppressed the secretion of HBV antigens and HBV particles from HBV genome-transfected cells and HBV-infected sodium taurocholate cotransporting polypeptide-expressing human hepatoma cells. Furthermore, NJK14047 treatment resulted in a significant decrease of pregenomic RNA and covalently closed circular DNA (cccDNA) of HBV in HBV-harboring cells, indicating its ability to inhibit HBV replication. Considering that suppression of HBsAg secretion and elimination of cccDNA of HBV are the major aims of anti-HBV therapeutic strategies, the results suggested the potential use of these compounds as a novel class of anti-HBV agents targeting host factors critical for viral infection.

scholarly journals Recent advances in understanding and diagnosing hepatitis B virus infection

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2243 ◽  
Author(s):  
Slim Fourati ◽  
Jean-Michel Pawlotsky
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Immune Modulation ◽  
Hepatitis B Surface Antigen ◽  
Sodium Taurocholate ◽  
Hbv Infection ◽  
New Drugs ◽  
Recent Advances ◽  
Hbsag Detection ◽  
B Virus

Hepatitis B virus (HBV) infects approximately 240 million individuals worldwide. Recent advances in the virology, immunopathogenesis, and diagnosis of HBV infection are summarized in this review article. The identification of a hepatocyte-specific cellular receptor for HBV, the sodium taurocholate co-transporting polypeptide (NTCP), made it possible to develop reliable cell culture systems and better understand the early steps of the viral lifecycle. Viral and host factors involved in covalently closed circular DNA synthesis, stability, and transcriptional regulation have also been identified and provide potential targets for new drugs. Based on recent evidence showing trained immunity in immune-tolerant patients, the immune tolerance and immune clearance phases have been renamed the non-inflammatory and inflammatory phases, respectively. New diagnostic and monitoring tools are now available, including rapid diagnostic tests for hepatitis B surface antigen (HBsAg) detection, HBsAg quantification assays, anti-HBc antibody quantification assays, an HBV core-related antigen (HBcrAg) quantification test, new HBV DNA detection and quantification assays, and an HBV RNA quantification test. Their clinical utility is under study. Finally, new antiviral and immune modulation approaches are in the preclinical or early clinical developmental stages, with the goal to achieve functional cure or ideally (if possible) eradication of HBV infection.

scholarly journals Hepatitis B Virus Entry into Cells

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1486 ◽  
Author(s):  
Charline Herrscher ◽  
Philippe Roingeard ◽  
Emmanuelle Blanchard
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
De Novo ◽  
Current Knowledge ◽  
Sodium Taurocholate ◽  
Chronic Infections ◽  
New Therapeutic Approaches ◽  
Double Stranded Dna ◽  
B Virus ◽  
Entry Receptor

Hepatitis B virus (HBV), an enveloped partially double-stranded DNA virus, is a widespread human pathogen responsible for more than 250 million chronic infections worldwide. Current therapeutic strategies cannot eradicate HBV due to the persistence of the viral genome in a special DNA structure (covalently closed circular DNA, cccDNA). The identification of sodium taurocholate co-transporting polypeptide (NTCP) as an entry receptor for both HBV and its satellite virus hepatitis delta virus (HDV) has led to great advances in our understanding of the life cycle of HBV, including the early steps of infection in particular. However, the mechanisms of HBV internalization and the host factors involved in this uptake remain unclear. Improvements in our understanding of HBV entry would facilitate the design of new therapeutic approaches targeting this stage and preventing the de novo infection of naïve hepatocytes. In this review, we provide an overview of current knowledge about the process of HBV internalization into cells.

scholarly journals Establishment of a novel hepatitis B virus culture system using immortalized human hepatocytes

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuichi Akahori ◽  
Hiroki Kato ◽  
Takashi Fujita ◽  
Kohji Moriishi ◽  
Yasuhito Tanaka ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cell Lines ◽  
Culture System ◽  
Sodium Taurocholate ◽  
Three Dimensional ◽  
Human Hepatocytes ◽  
Host Cells ◽  
B Virus ◽  
Almost All

AbstractRecent development of hepatitis B virus (HBV) culture systems has made it possible to analyze the almost all steps of the viral life cycle. However, the reproducibility of interaction between HBV and host cells seemed inaccurate in those systems because of utilization of cancer cell lines with a difference from hepatocytes in the majority of cases. In this study, in order to resolve this point, a novel HBV culture system using non-cancer-derived immortalized human hepatocytes derived cell lines, producing exogenous human sodium taurocholate cotransporting polypeptide, was developed. One of the cell clones, E/NtG8 cells, was permissive to both blood-borne HBV (HBVbb) and culture-derived recombinant HBV when cultured in the three-dimensional condition. Furthermore, the production of infectious HBV particles, which showed the similar physicochemical properties to HBVbb, was observed for about a month after HBVbb infection in this system, suggesting that it may reproduce whole steps of the HBV lifecycle under the condition analogous to human liver cells infected with HBV. This system seemed to contribute not only to find novel interactions between HBV and host cells but also to understand mechanism of HBV pathogenesis.

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