Possible Reactivation of Potential Hepatitis B Virus Occult Infection by Tumor Necrosis Factor-α Blocker in the Treatment of Rheumatic Diseases

2009 ◽  
Vol 37 (2) ◽  
pp. 346-350 ◽  
Author(s):  
YUN JUNG KIM ◽  
SANG-CHEOL BAE ◽  
YOON-KYOUNG SUNG ◽  
TAE-HWAN KIM ◽  
JAE-BUM JUN ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Tumor Necrosis Factor ◽  
Hepatitis B ◽  
Rheumatic Diseases ◽  
Tumor Necrosis ◽  
Hbv Infection ◽  
Occult Infection ◽  
Tnf Α ◽  
B Virus ◽  
Necrosis Factor

Objective. To assess the safety of anti-tumor necrosis factor (TNF-α) therapy in patients with rheumatic diseases in terms of the reactivation of potential hepatitis B virus (HBV) occult infection.Methods. Patients who had taken anti-TNF-α for the treatment of rheumatic diseases from January 2002 to May 2008 were included in the study. In this patient group, we retrospectively investigated a series of serum aminotransferase levels, HBV serologic status, the type of anti-TNF-α therapy, duration of the anti-TNF-α treatment, and concurrent use of hepatotoxic drugs.Results. A total of 266 cases were documented using 3 serologic markers for HBV infection: HBV surface antigen (HBsAg), HBV surface antibody (HBsAb), and HBV core IgG Ab (HBcAb). Of these, 8 cases had chronic hepatitis B (HBsAg+), 170 cases were HBcAb-negative, and 88 cases were identified as having potential HBV occult infections represented by HBsAg-negative and HBcAb-positive, irrespective of the status of the HBsAb.The frequency of clinically significant (> 2 times normal value) and persistent increase (> 2 consecutive tests) of aminotransferase levels was significantly higher in the group with a potential HBV occult infection compared to the HBcAb-negative group. In the multiple logistic regression analysis controlling for various potential confounding factors such as prophylactic anti-tuberculosis medication, methotrexate, nonsteroidal antiinflammatory drugs, and the type of anti-TNF-α therapy, only potential HBV occult infection was a significant risk factor for abnormal liver function test (LFT).Conclusion. All rheumatic patients who plan to take anti-TNF-α treatment should undergo a test for HBV serology, including HBcAb, and have a close followup with an LFT test during therapy. Further prospective studies for hepatitis B viral load using HBV-polymerase chain reaction in patients who are HbcAb positive are needed to identify whether the abnormal LFT comes from the reactivation of occult HBV infection.

scholarly journals Tumor Necrosis Factor Alpha Inhibition of Hepatitis B Virus Replication Involves Disruption of Capsid Integrity through Activation of NF-κB

2003 ◽  
Vol 77 (7) ◽  
pp. 4033-4042 ◽  
Author(s):  
Michael Biermer ◽  
Robyn Puro ◽  
Robert J. Schneider
Keyword(s):  
Hepatitis B Virus ◽  
Tumor Necrosis Factor ◽  
Hepatitis B ◽  
Virus Replication ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
B Virus ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Chronic infection by hepatitis B virus results from an inability to clear the virus, which is associated with liver disease and liver cancer. Tumor necrosis factor alpha (TNF-α) is associated with noncytopathic clearance of hepatitis B virus in animal models. Here we demonstrate that the nuclear factor κB (NF-κB) signaling pathway is a central mediator of inhibition of hepatitis B virus by TNF-α and we describe the molecular mechanism. TNF-α is shown to suppress hepatitis B virus DNA replication without cell killing by disrupting the formation or stability of cytoplasmic viral capsids through a pathway requiring the NF-κB-activating inhibitor of κB kinase complex IKK-α/β and active transcription factor NF-κB. Hepatitis B virus replication could also be inhibited and viral capsid formation could be disrupted in the absence of TNF-α solely by overexpression of IKK-α/β or strong activation of NF-κB. In contrast, inhibition of NF-κB signaling stimulated viral replication, demonstrating that HBV replication is both positively and negatively regulated by the level of activity of the NF-κB pathway. Studies are presented that exclude the possibility that HBV inhibition by NF-κB is carried out by secondary production of gamma interferon or alpha/beta interferon. These results identify a novel mechanism for noncytopathic suppression of hepatitis B virus replication that is mediated by the NF-κB signaling pathway and activated by TNF-α.

scholarly journals Sustained Activation of p38 Mitogen-Activated Protein Kinase and c-Jun N-Terminal Kinase Pathways by Hepatitis B Virus X Protein Mediates Apoptosis via Induction of Fas/FasL and Tumor Necrosis Factor (TNF) Receptor 1/TNF-α Expression

2004 ◽  
Vol 24 (23) ◽  
pp. 10352-10365 ◽  
Author(s):  
Wen-Horng Wang ◽  
Gérald Grégori ◽  
Ronald L. Hullinger ◽  
Ourania M. Andrisani
Keyword(s):  
Hepatitis B Virus ◽  
Tumor Necrosis Factor ◽  
Hepatitis B ◽  
Map Kinase ◽  
Tumor Necrosis ◽  
P38 Map Kinase ◽  
Tnf Α ◽  
B Virus ◽  
Mitogen Activated Protein ◽  
Necrosis Factor

ABSTRACT Activation of the cellular stress pathways (c-Jun N-terminal kinase [JNK] and p38 mitogen-activated protein [MAP] kinase) is linked to apoptosis. However, whether both pathways are required for apoptosis remains unresolved. Hepatitis B virus X protein (pX) activates p38 MAP kinase and JNK pathways and, in response to weak apoptotic signals, sensitizes hepatocytes to apoptosis. Employing hepatocyte cell lines expressing pX, which was regulated by tetracycline, we investigated the mechanism of apoptosis by p38 MAP kinase and JNK pathway activation. Inhibition of the p38 MAP kinase pathway rescues by 80% the initiation of pX-mediated apoptosis, whereas subsequent apoptotic events involve both pathways. pX-mediated activation of p38 MAP kinase and JNK pathways is sustained, inducing the transcription of the death receptor family genes encoding Fas/FasL and tumor necrosis factor receptor 1 (TNFR1)/TNF-α and the p53-regulated Bax and Noxa genes. The pX-dependent expression of Fas/FasL and TNFR1/TNF-α mediates caspase 8 activation, resulting in Bid cleavage. In turn, activated Bid, acting with pX-induced Bax and Noxa, mediates the mitochondrial release of cytochrome c, resulting in the activation of caspase 9 and apoptosis. Combined antibody neutralization of FasL and TNF-α reduces by 70% the initiation of pX-mediated apoptosis. These results support the importance of the pX-dependent activation of both the p38 MAP kinase and JNK pathways in pX-mediated apoptosis and suggest that this mechanism of apoptosis occurs in vivo in response to weak apoptotic signals.

scholarly journals Tumor Necrosis Factor Activates a Conserved Innate Antiviral Response to Hepatitis B Virus That Destabilizes Nucleocapsids and Reduces Nuclear Viral DNA

2007 ◽  
Vol 81 (14) ◽  
pp. 7351-7362 ◽  
Author(s):  
Robyn Puro ◽  
Robert J. Schneider
Keyword(s):  
Hepatitis B Virus ◽  
Tumor Necrosis Factor ◽  
Hepatitis B ◽  
Tumor Necrosis ◽  
Core Protein ◽  
Model Systems ◽  
Nuclear Accumulation ◽  
Broad Host Range ◽  
B Virus ◽  
Necrosis Factor

ABSTRACT Tumor necrosis factor (TNF) is critical for the control of hepatitis B virus (HBV) in the clinical setting and in model systems. TNF induces noncytopathic suppression and clearance of HBV in animal models, possibly through reduction of viral nucleocapsids, but the mechanism is not well described. Here, we demonstrate the molecular mechanism and broad host range for TNF action against HBV. We show that TNF rapidly blocks HBV replication by promoting destabilization of preexisting cytoplasmic viral nucleocapsids containing viral RNA and DNA, as well as empty nucleocapsids. TNF destabilized human HBV nucleocapsids in a variety of human hepatocytic cell lines and in primary rat hepatocytes and also destabilized duck HBV (DHBV) nucleocapsids in chicken hepatocytic cells. Lysates from TNF-treated uninfected cells also destabilized HBV nucleocapsids in vitro. Moreover, inhibition of DHBV DNA replication by TNF blocks nuclear accumulation of the viral transcription template, maintenance of which is essential for the establishment and maintenance of chronic infection. We show that TNF destabilization of HBV nucleocapsids does not involve ubiquitination or methylation of the viral core protein and is not mediated by the nitric oxide free radical arm of the TNF pathway. These results define a novel antiviral mechanism mediated by TNF against multiple types of HBVs in different species.

Interaction of interferon-α with interleukin-1β or tumor necrosis factor-α on hepatitis B virus enhancer activity

1992 ◽  
Vol 183 (2) ◽  
pp. 904-909 ◽  
Author(s):  
Keisuke Hamasaki ◽  
Keisuke Nakata ◽  
Kazuhiko Nakao ◽  
Satoru Mitsuoka ◽  
Takuya Tsutsumi ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Tumor Necrosis Factor ◽  
Hepatitis B ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Interferon Α ◽  
Enhancer Activity ◽  
B Virus ◽  
Factor Α ◽  
Necrosis Factor
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