Hepatitis B virus DNA contains a glucocorticoid-responsive element.

Tur–Kaspa, Ran; Burk, Robert D.; Shaul, Yosef; Shafritz, David A.

doi:10.1073/pnas.83.6.1627

Cited by 371 publications

(209 citation statements)

References 44 publications

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“…This is of practical importance for these patients in view of the direct stimulatory effect of corticosteroids on HBV replication. 26,27 In the present study, we confirmed the previous observation that steroids can enhance the expression of HBsAg during a short-term culture of hepatocytes isolated from chronic HBV camers.12 Similar to cyclosporine, FK506 did not change significantly viral envelope expression in cultured hepatocytes. In the same in vitro system quantitation of intracellular HBV DNA showed no significant changes after 18 hours' culture, suggesting that the enhanced HBsAg expression in hepatocytes under these conditions may initially result from enhanced translation of viral protein, rather than immediate replication of the viral genome.…”

Section: Discussionsupporting

confidence: 89%

FK506 in liver transplantation for chronic hepatitis B: In vitro studies on lymphocyte activation and virus replication

et al. 1995

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Recurrence of hepatitis B virus (HBV) in the graft is the major problem for patients with chronic HBV infection undergoing liver transplantation, which could be potentiated by the immunosuppression. In the present study, we used lymphocytes and hepatocytes isolated from patients with chronic HBV infection to investigate in vitro the effects of FK506 with and without methylprednisolone (25 ng/mL) on mitogen-induced lymphocyte proliferation, T-cell activation marker expression, and HBV replication in human hepatocytes. Increasing concentrations of FK506 (0.1, 0.5, and 5 ng/mL) resulted in a dose-dependent inhibition of lymphocyte proliferation with a reduction of the stimulation index by 9.2%, 39.0%, and 55.1%, respectively, with no difference between 25 chronic HBV carriers and normal controls. Methylprednisolone alone had no effect but potentiated the inhibitory effect of all three FK506 concentrations, such that the stimulation index was decreased by 20%, 56.2%, and 65.7%, respectively. FK506 (0.5 ngl mL) reduced both the percentage of interleukin-2 atients with chronic Hepatitis B virus (HBV) P infection represent a considerable proportion of the candidates for liver transplantation. HBV recurrence in the graft is a major problem and is responsible for the higher morbidity and mortality in these patients, in comparison with transplantation for other indication^.'-^ The risk of graft reinfection appears to be potentiated b~y the immunosuppressive therapy, especially corticosteroids, which have been shown to enhance HBV replication and viral antigen expression in clinical s t~d i e s ,~-~ as well as in an in vitro model.8 FK506 is a potent immunosuppressive agent that is increasingly used in liver transplantation for graft receptor expressing T cells and the cell surface density of this receptor by 7.1% and 8.7% (P < .Ol), whereas it only reduced the proportion of HLA-DR expressing T cells by 6.8%. FK506 did not change significantly the intracellular HBV DNA or the hepatic expression of hepatitis B surface antigen (HBsAg) in short-term culture of human hepatocytes, whereas methylprednisolone increased the percentage of HBsAg-positive hepatocytes in all 5 patients with active viral replication. These results indicate that the effects of FK506 on T-cell activation in chronic HBV carriers are identical to normal subjects, resulting in marked suppression of T-lymphocyte function but only modest reduction in the expression of cell surface activation markers. The drug showed no direct stimulatory effect on viral replication, suggesting that FK506 can be a useful, steroidsparing immunosuppressive agent for liver graft recipients with chronic HBV infection.Copyright o 1995 by the American Association for the Study of Liver Diseases salvage in patients who develop chronic rejection, as well as a primary immunosuppression.9-11 FK506 suppresses immune reactions in rodents at doses 10-fold lower than cyclosporine, and it had been argued that steroids may not be necessary as an adjunct to FK506.1° We have previously shown th...

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Section: Discussionsupporting

confidence: 89%

FK506 in liver transplantation for chronic hepatitis B: In vitro studies on lymphocyte activation and virus replication

et al. 1995

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“…[23][24][25] The high level of HBV viremia may be, at least in part, because of a glucocorticoid response element as part of its genome that appears to enhance the replicative efficacy of HBV. 26 However, we have not found a direct relationship between viremia level and severity of hepatitis in the liver graft; this finding seems to indicate a lack of a direct cytopathic effect of HBV in this situation and suggests that disease may be mediated by immune mechanisms. In fact, the immunosuppressive agents used to avoid allograft rejection also markedly disturb host defense mechanisms directed at the HBV.…”

Section: Discussioncontrasting

confidence: 68%

Severe clinical course of de novo hepatitis B infection after liver transplantation

et al. 1999

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The aim of this study is to determine the origin, clinical outcome, allograft histological characteristics, and virological outcome of de novo hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT). We studied 136 hepatitis B surface antigen (HBsAg)-negative liver transplant recipients. HBV DNA was detected by dot-blot hybridization and polymerase chain reaction (PCR). The S gene was sequenced. Hepatitis C virus (HCV) RNA was assessed by PCR. The long-term clinical and histological outcome was determined. Six of 136 HBsAg-negative patients (4.4%) became HBsAg positive after transplantation. The source of HBV infection was reactivation of latent HBV infection in 2 patients and was not identified in 4 patients. Two donors had isolated core antibody. Two of these 6 patients developed acute liver failure related to hepatitis B. The 4 other patients had severe chronic hepatitis related to hepatitis B. All patients had high-level HBV replication. No significant mutations in the S gene were found. These data suggest that de novo hepatitis B infection is not a mild disease and might represent a significant cause of graft dysfunction. This is the first report of fulminant hepatitis caused by de novo hepatitis B infection after OLT.

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“…In the transplant setting, steroids, azathioprine, cyclosporine, and tacrolimus (FK 506) are commonly used to prevent graft rejection. In vitro, corticosteroid increases HBV DNA and RNA production by stimulating HBV transcription [70,71], by binding to the glucocorticoid responsive element (GRE), and augmenting the HBV enhancer I. In addition, the use of rituximab can effectively remove or suppress anti-HBs producing B cells and cause reactivation of HBV even in HBV immune patients.…”

Section: Chemotherapy or Immunosuppressive Therapy Related To Hbv Reamentioning

confidence: 99%

“…Among the chemotherapeutic agents used, corticosteroids and anthracyclines [1][2][3][4][5][6][7] are most frequently associated with HBV reactivation. The HBV DNA contains a glucocorticoid-responsive element that facilitates replication [70,71], while anthracyclines have been shown in vitro to stimulate HBV DNA secretion [99]. Hence, ''steroid free'' chemotherapy has been proposed to minimize the risk of HBV reactivation.…”

Section: Risk Factors Involved In Hbv Reactivationmentioning

confidence: 99%

Hepatitis B reactivation after chemotherapy: two decades of clinical research

Lau

2008

Hepatol Int

102

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Hepatitis due to hepatitis B virus reactivation after cytotoxic or immunosuppressive therapy is a serious cause of liver-related morbidity and mortality. With the characterization of the underlying pathogenesis, much progress in the management of this important clinical problem has been made in the past 2 decades. By year 2008, it is mandatory to screen for hepatitis B surface antigen status before initiating intensive chemotherapy or immunosuppressive therapy. All those who are hepatitis B surface antigen positive should be started on preemptive nucleos(t)ide analogues. However, there remains important issues, such as the type and duration of nucleos(t)ide analogue therapy, which need to be understood. As not all hepatitis B surface antigen-positive patients will suffer from HBV reactivation, it is therefore useful to identify risk factors related to HBV reactivation so that patients will not be treated unnecessarily with nucleos(t)ide analogues. To date, a high baseline level of viral replication, as reflected by high serum HBV DNA level, positive serum hepatitis B e antigen, and a high intrahepatic covalently closed circular DNA level, is the most important predictor for HBV reactivation. Recently, there has been an increased awareness of reactivation of occult hepatitis B virus, especially in hepatitis B virus endemic area, such as the Asia-Pacific region. Careful epidemiological study will be needed to clarify the impact of occult hepatitis B infection in patients treated with cytotoxic or immunosuppressive therapy. How important is the problem?Over the past 20 years of clinical practice at Queen Mary Hospital, we have seen a lot of progress in the management of hepatitis due to HBV reactivation in hepatitis B surface antigen carriers [1][2][3][4][5]. In the past, we saw patients who died of fulminant hepatic failure after being administered a few courses of cytotoxic therapy to treat their life-threatening lymphoma [6][7][8][9] and breast cancer [10][11][12] if they were also hepatitis B surface antigen positive. At that time, the literature report of this important clinical issue was scanty. The first report in the field was published by Wand et al. [13] who studied the effects of antitumor chemotherapeutic agents on hepatitis antigen (HBAg) and antibody (HBAb) in 25 patients with myeloproliferative and in 60 patients with lymphoproliferative disorders. This elegant study was performed at the time when only antigen and antibody associated with viral hepatitis could be semiquantified [14]. In those patients who had HBAg at the time of initiation of chemotherapy, bone marrow suppression by chemotherapeutic agents was associated with a marked increase in HBAg titer, which was then followed by hepatocellular damage, as manifested by an elevation in serum transaminase enzymes [13]. Since then, this important observation was further confirmed in other studies [8,15,16], with the rate of HBV reactivation ranging from 19% to 48%. Among them, one-quarter to half would be complicated, with severe hepatitis...

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Hepatitis B virus DNA contains a glucocorticoid-responsive element.

Abstract: It has recently been shown that hepatitis B virus (HBV) contains a transcriptional enhancer element. In order to determine whether this enhancer responds to

Cited by 371 publications

References 44 publications

FK506 in liver transplantation for chronic hepatitis B: In vitro studies on lymphocyte activation and virus replication

FK506 in liver transplantation for chronic hepatitis B: In vitro studies on lymphocyte activation and virus replication

Severe clinical course of de novo hepatitis B infection after liver transplantation

Hepatitis B reactivation after chemotherapy: two decades of clinical research

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