Viral Pharmacodynamic Model for (–)-β-2′,3′-Dideoxy-5-Fluoro-3′-Thiacytidine (Emtricitabine) in Chronically Infected Woodchucks

2002 ◽  
Vol 13 (3) ◽  
pp. 165-176 ◽  
Author(s):  
Selwyn J Hurwitz ◽  
Bud C Tennant ◽  
Brent E Korba ◽  
Irina Liberman ◽  
John L. Gerin ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Half Life ◽  
Day Treatment ◽  
Dose Range ◽  
Pharmacodynamic Model ◽  
Nucleoside Triphosphate ◽  
Effect Compartment ◽  
Virus Load ◽  
B Virus

There is a need for adequate models of virus depletion in animals and humans as a function of drug dose in order to plan starting dose regimens in the clinic for new antiretroviral nucleoside agents. An indirect response pharmacodynamic model was fitted to link the plasma pharmacokinetics from a 28 day treatment with the nucleoside reverse transcription inhibitor emtricitabine [(–)-FTC], with the resulting virus depletion and recovery profiles in woodchucks chronically infected with woodchuck hepatitis B virus. In this approach it is assumed that the virus is eliminated from serum in a first order fashion and that the fraction of serum virus load produced per day is inhibited by the accumulation of nucleoside triphosphate in a manner that could be described using a Hill equation. Nadir virus load values were inversely related to pretreatment virus load levels within each dose group. A median inhibitory concentration value of 1.5 μM for (–)-FTC triphosphate, previously measured against the isolated viral polymerase of woodchuck hepatitis, was used in model fitting. The fitted value for concentration exponent η of 3.46 indicated a greater than linear sensitivity of virus inhibition with dose. Since the post-treatment virus rebound was much greater than predictions of an initial model, a dose-dependent rebound factor was incorporated in the final model. The rebound factor was maximal at the end of (–)-FTC treatment and decayed mono-exponentially with a rate constant Kreb of 0.11/day. The model inferred decay half-life of (–)-FTC triphosphate in the apparent ‘effect compartment’ of the model was similar to the half-life value previously estimated for human hepatitis B virus-infected hepatocytes. The model described adequately the virus depletion and recovery profiles for the dose range tested and could be adapted for the selection of starting doses for future animal and human studies with emtricitabine and other nucleoside analogues in development.

scholarly journals The contribution of serum hepatitis B virus load in the carcinogenesis and prognosis of hepatocellular carcinoma: evidence from two meta-analyses

Oncotarget ◽  
2016 ◽  
Vol 7 (31) ◽  
pp. 49299-49309 ◽  
Author(s):  
Xueqin Chen ◽  
Fan Wu ◽  
Yanmei Liu ◽  
Jiao Lou ◽  
Beibei Zhu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Serum Hepatitis ◽  
Virus Load ◽  
B Virus ◽  
Meta Analyses

scholarly journals Spatiotemporal Analysis of Hepatitis B Virus X Protein in Primary Human Hepatocytes

2019 ◽  
Vol 93 (16) ◽  
Author(s):  
Dmytro Kornyeyev ◽  
Dhivya Ramakrishnan ◽  
Christian Voitenleitner ◽  
Christine M. Livingston ◽  
Weimei Xing ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Half Life ◽  
Natural Infection ◽  
Spatiotemporal Analysis ◽  
Human Hepatocytes ◽  
X Protein ◽  
B Virus ◽  
Infected Cells ◽  
Structural Maintenance Of Chromosomes

ABSTRACTThe structural maintenance of chromosomes 5/6 complex (Smc5/6) is a host restriction factor that suppresses hepatitis B virus (HBV) transcription. HBV counters this restriction by expressing the X protein (HBx), which redirects the host DNA damage-binding protein 1 (DDB1) E3 ubiquitin ligase to target Smc5/6 for degradation. HBx is an attractive therapeutic target for the treatment of chronic hepatitis B (CHB), but it is challenging to study this important viral protein in the context of natural infection due to the lack of a highly specific and sensitive HBx antibody. In this study, we developed a novel monoclonal antibody that enables detection of HBx protein in HBV-infected primary human hepatocytes (PHH) by Western blotting and immunofluorescence. Confocal imaging studies with this antibody demonstrated that HBx is predominantly located in the nucleus of HBV-infected PHH, where it exhibits a diffuse staining pattern. In contrast, a DDB1-binding-deficient HBx mutant was detected in both the cytoplasm and nucleus, suggesting that the DDB1 interaction plays an important role in the nuclear localization of HBx. Our study also revealed that HBx is expressed early after infection and has a short half-life (∼3 h) in HBV-infected PHH. In addition, we found that treatment with small interfering RNAs (siRNAs) that target DDB1 or HBx mRNA decreased HBx protein levels and led to the reappearance of Smc6 in the nuclei of HBV-infected PHH. Collectively, these studies provide the first spatiotemporal analysis of HBx in a natural infection system and also suggest that HBV transcriptional silencing by Smc5/6 can be restored by therapeutic targeting of HBx.IMPORTANCEHepatitis B virus X protein (HBx) is a promising drug target since it promotes the degradation of the host structural maintenance of chromosomes 5/6 complex (Smc5/6) that inhibits HBV transcription. To date, it has not been possible to study HBx in physiologically relevant cell culture systems due to the lack of a highly specific and selective HBx antibody. In this study, we developed a novel monoclonal HBx antibody and performed a spatiotemporal analysis of HBx in a natural infection system. This revealed that HBx localizes to the nucleus of infected cells, is expressed shortly after infection, and has a short half-life. In addition, we demonstrated that inhibiting HBx expression or function promotes the reappearance of Smc6 in the nucleus of infected cells. These data provide new insights into HBx and underscore its potential as a novel target for the treatment of chronic HBV infection.

scholarly journals Kinetics of Hepatitis B Virus Load During Haemodialysis Sessions and a-Interferon: A Prospective Study

2013 ◽  
Vol 37 (4-5) ◽  
pp. 286-294 ◽  
Author(s):  
Fabrizio Fabrizi ◽  
Giovanna Lunghi ◽  
Giancarlo Alongi ◽  
Filippo Aucella ◽  
Francesco Barbisoni ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Prospective Study ◽  
Virus Load ◽  
B Virus ◽  
A Prospective Study ◽  
Kinetics Of

scholarly journals Cellular Pharmacology of the Anti-Hepatitis B Virus Agent β-l-2′,3′-Didehydro-2′,3′-Dideoxy-N4-Hydroxycytidine: Relevance for Activation in HepG2 Cells

2009 ◽  
Vol 54 (1) ◽  
pp. 341-345 ◽  
Author(s):  
E. Matthes ◽  
H. Bünger
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Half Life ◽  
Hepg2 Cells ◽  
Selective Inhibitor ◽  
Cellular Pharmacology ◽  
Hbv Replication ◽  
B Virus ◽  
Drug Free ◽  
Triphosphate Derivatives

ABSTRACT ß-l-2′,3′-Didehydro-2′,3′-dideoxy-N4-hydroxycytidine (l-Hyd4C) was demonstrated to be an effective and highly selective inhibitor of hepatitis B virus (HBV) replication in HepG2.2.15 cells (50% effective dose [ED50] = 0.03 μM; 50% cytotoxic dose [CD50] = 2,500 μM). In the present study, we investigated the intracellular pharmacology of tritiated l-Hyd4C in HepG2 cells. l-[3H]Hyd4C was shown to be phosphorylated extensively and rapidly to the 5′-mono-, 5′-di-, and 5′-triphosphate derivatives. Other metabolites deriving from a reduction or removal of the NHOH group of l-Hyd4C could not be detected, although both reactions were described as the primary catabolic pathways of the stereoisomer ß-d-N4-hydroxycytidine in HepG2 cells. Also, the formation of liponucleotide metabolites, such as the 5′-diphosphocholine derivative of l-Hyd4C, as described for some l-deoxycytidine analogues, seems to be unlikely. After incubation of HepG2 cells with 10 μM l-[3H]Hyd4C for 24 h, the 5′-triphosphate accumulated to 19.4 ± 2.7 pmol/106 cells. The predominant peak belonged to 5-diphosphate, with 43.5 ± 4.3 pmol/106 cells. The intracellular half-life of the 5′-triphosphate was estimated to be 29.7 h. This extended half-life probably reflects a generally low affinity of 5′-phosphorylated l-deoxycytidine derivatives for phosphate-degrading enzymes but may additionally be caused by an efficient rephosphorylation of the 5′-diphosphate during a drug-free incubation. The high 5′-triphosphate level and its extended half-life in HepG2 cells are consistent with the potent antiviral activity of l-Hyd4C.

scholarly journals Sensitive Enzyme Immunoassay for Hepatitis B Virus Core-Related Antigens and Their Correlation to Virus Load

2002 ◽  
Vol 40 (2) ◽  
pp. 439-445 ◽  
Author(s):  
T. Kimura ◽  
A. Rokuhara ◽  
Y. Sakamoto ◽  
S. Yagi ◽  
E. Tanaka ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Enzyme Immunoassay ◽  
Virus Load ◽  
Virus Core ◽  
B Virus

scholarly journals Detection and characterization of cytoplasmic hepatitis B virus reverse transcriptase

2004 ◽  
Vol 85 (11) ◽  
pp. 3353-3360 ◽  
Author(s):  
Feng Cao ◽  
John E. Tavis
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Reverse Transcriptase ◽  
Half Life ◽  
Core Protein ◽  
Post Translational Modifications ◽  
The Core ◽  
Duck Hepatitis ◽  
B Virus

It was recently found that the Duck hepatitis B virus (DHBV) reverse transcriptase is primarily a non-encapsidated cytoplasmic molecule that is rapidly translated and has a very short half-life. Here, a non-encapsidated reverse transcriptase from the human Hepatitis B virus (HBV) was characterized. HBV polymerase accumulated in the cytoplasm in a manner similar to non-encapsidated DHBV polymerase. However, the HBV polymerase accumulated at an apparently lower concentration and had a longer half-life than the DHBV enzyme, and it displayed no evidence of the post-translational modifications observed for DHBV. Unlike the DHBV polymerase, immunofluorescence detection of the HBV polymerase in cells was suppressed by the core protein, and this suppression occurred independently of encapsidation. This implies an interaction between the polymerase and core in addition to encapsidation, but the polymerase and core did not co-immunoprecipitate, so the interaction might not be direct. These data indicate that production of cytoplasmic, non-encapsidated polymerase is conserved among the hepadnaviral genera. Furthermore, conservation of the cytoplasmic form of the polymerase suggests that it might have function(s) in virus replication or pathology beyond copying the viral genome.

Hepatitis B Virus Load in Serum Does Not Reflect Histologic Activity in Patients With Decompensated Cirrhosis

2010 ◽  
Vol 8 (1) ◽  
pp. 60-65 ◽  
Author(s):  
Jin Dong Kim ◽  
Jong Young Choi ◽  
Si Hyun Bae ◽  
Seung Kew Yoon ◽  
Jin Mo Yang ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Decompensated Cirrhosis ◽  
Virus Load ◽  
B Virus
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