New therapeutic agents for chronic hepatitis B

Brahmania, Mayur; Feld, Jordan J.; Arif, Ambreen; Janssen, Harry L.A.

doi:10.1016/s1473-3099(15)00436-3

Cited by 63 publications

(49 citation statements)

References 110 publications

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“…It has been reported that more than 350 million humans were chronically infected worldwide and 600,000 people died from chronic HBV infection (1). HBV chronic infection is a crucial risk factor for cirrhosis and HBV-related hepatocellular carcinoma (HCC) (2).…”

mentioning

confidence: 99%

HDM2 Promotes NEDDylation of Hepatitis B Virus HBx To Enhance Its Stability and Function

Liu

Zhang

Yang

et al. 2017

J Virol

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Hepatitis B virus (HBV)-encoded X protein (HBx) plays a critical role in HBV-related hepatocarcinoma development. In this study, we demonstrate that HBx is specifically modified by NEDD8. We found that E3 ligase HDM2 promotes NEDDylation of HBx to enhance HBx stability by preventing its ubiquitinationmediated degradation. Consistently, analysis of 160 hepatocellular carcinoma patient specimens indicated that the amount of HDM2 protein correlates with HBx protein level. We identified that HBx K91 and K95 as the key HBx NEDDylation sites and observed that the NEDDylation-deficient HBx has shorter half-life. We generated Huh7 cell lines which ectopically express wild-type and NEDDylation-deficient HBx and found that NEDDylation-deficient HBx showed less chromatin localization and less DDB1 binding. Consistently, the expression of HBx-regulated genes (IL-8, MMP9, and YAP) and HBV transcription (the activity of HBV enhancer and the amount of pgRNA transcribed from cccDNA) were significantly higher in cells expressing wild-type (WT) HBx than that in cells expressing mutant HBx. In addition, HBx-expressing cells proliferated faster than control and mutant HBx-expressing cells. We also showed that the ability of WT HBx-expressing cells to form tumors in nude mice was significantly higher than that of mutant HBx-expressing cells. In conclusion, we revealed that E3 ligase HDM2 promotes NEDDylation of HBx to enhance HBx stability and chromatin localization, which in turn favors HBx-dependent transcriptional regulation, cell proliferation, and HBV-driven tumor growth. IMPORTANCE Hepatitis B virus (HBV) HBx protein plays a critical role in viral replication and hepatocarcinogenesis. However, the regulation of HBx stability is not well understood. We found that HBx is modified by NEDD8 and that the HDM2 E3 ligase promotes HBx NEDDylation to enhance HBx stability by inhibiting its ubiquitination. We provide a new evidence to show the positive correlation between HDM2 and HBx in clinical hepatocellular carcinoma (HCC) samples. We also identified the major NEDDylation sites on HBx. Our studies indicate that the defective NEDDylation of HBx negatively affects its ability to activate the transcription of downstream genes and promote cell proliferation and tumor growth in vivo. Taken together, our findings reveal a novel posttranslational modification of HBx by HDM2 which regulates its stability, subcellular localization, and functions. These findings indicate that HDM2 is an important regulator on HBx and a potential diagnosis/therapeutic marker for HBVassociated HCC.KEYWORDS HBx, NEDDylation, stability, chromatin localization, hepatocellular carcinoma, HDM2, hepatitis B virus

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confidence: 99%

HDM2 Promotes NEDDylation of Hepatitis B Virus HBx To Enhance Its Stability and Function

Liu

Zhang

Yang

et al. 2017

J Virol

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“…En la infección crónica por VHB se ha observado una falta de respuesta contra el virus mediada por los linfocitos T específicos debido a un fenómeno conocido como agotamiento, el cual se caracteriza por la escasez o ausencia de células T específicas contra el VHB asociado con pobre actividad citotóxica, deterioro en la producción de citoquinas y aumento en la expresión de receptores coinhibitorios, como la proteína de muerte celular programada 1 (PD-1), antígeno 4 asociado al linfocito T citotóxico (CTLA-4), proteína 3 del gen de activación de linfocitos (LAG 3), entre otros (50). Este fenómeno es mantenido por la presencia de un microambiente de citoquinas inmunosupresoras, como IL-10 y el factor de crecimiento transformante beta (TGF-β) producidas por los linfocitos T reguladores encontrados en gran cantidad en el hígado de pacientes con HBC (51,52).…”

Section: Bloqueo De Señales Inmunoinhibidoras (Pd-1)unclassified

Tratamiento actual y nuevas terapias contra la infección crónica por el virus de la Hepatitis B

Echeverri

Caraballo

Marín

et al. 2017

Rev. Colomb. Gastroenterol.

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La infección crónica por el virus de la hepatitis B es un grave problema de salud pública a nivel mundial. Sus consecuencias llegan a ser mortales y el tratamiento actual no ofrece curación sino control de la enfermedad. Las principales limitantes para una cura son la dificultad para destruir el ADNccc del virus en el núcleo celular y la presencia de material genético viral integrado en el ADN de la célula hospedera. No obstante, hay múltiples frentes de investigación enfocados en encontrar una cura definitiva al potenciar la respuesta inmune del hospedero o al actuar directamente contra el virus y su ciclo de replicación. En este artículo se exponen los principales avances que se han realizado en este campo.

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“…After entry into hepatocytes, uncoated rcDNA is released into the cytoplasm and then enters the nucleus, where it is converted to cccDNA. The cccDNA remains for a long time in the nucleus, where it serves as a template for the transcription of viral mRNA [17,18] . All viral RNAs, pregenomic RNAs (pgRNA) and RNAs encoding the surface proteins, precore and HBx of HBV, are transcribed from cccDNA, with efficient transcription regulated by liver-specific transcription factors [19] and the HBx protein itself [20] .…”

Section: Hbv Replication Cyclementioning

confidence: 99%

“…Radical treatment for HBV the HBV life cycle in hepatocytes, including inhibitors of HBVDNA polymerase, virus entry, core assembly and HBsAg secretion (Table 2) [93,95,120,121] . Especially Myrcludex B, a synthetic lipopeptide that targets NTCP, has been shown to efficiently prevent viral spread and has been applied in clinical trials [15,17,122,123] . These agents, including Myrcludex, are not themselves sufficient to eliminate HBV from chronically infected hepatocytes, as shown by the remaining cccDNA in the nuclei and HBVDNAintegrated hepatocytes.…”

Section: Future Perspectives On Radical Cure Of Chronic Hbv Infectionmentioning

confidence: 99%

New horizon for radical cure of chronic hepatitis B virus infection

Tajiri¹,

Shimizu²

2016

WJH

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About 250 to 350 million people worldwide are chronically infected with hepatitis B virus (HBV), and about 700000 patients per year die of HBV-related cirrhosis or hepatocellular carcinoma (HCC). Several anti-viral agents, such as interferon and nucleos(t)ide analogues (NAs), have been used to treat this disease. NAs especially have been shown to strongly suppress HBV replication, slowing the progression to cirrhosis and the development of HCC. However, reactivation of HBV replication often occurs after cessation of treatment, because NAs alone cannot completely remove covalentlyclosed circular DNA (cccDNA), the template of HBV replication, from the nuclei of hepatocytes. Anti-HBV immune responses, in conjunction with interferon-γ and tumor necrosis factor-α, were found to eliminate cccDNA, but complete eradication of cccDNA by immune response alone is difficult, as shown in patients who recover from acute HBV infection but often show long-term persistence of small amounts of HBV-DNA in the blood. Several new drugs interfering with the life cycle of HBV in hepatocytes have been developed, with drugs targeting cccDNA theoretically the most effective for radical cure of chronic HBV infection. However, the safety of these drugs should be extensively examined before application to patients, and combinations of several approaches may be necessary for radical cure of chronic HBV infection.

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New therapeutic agents for chronic hepatitis B

Cited by 63 publications

References 110 publications

HDM2 Promotes NEDDylation of Hepatitis B Virus HBx To Enhance Its Stability and Function

HDM2 Promotes NEDDylation of Hepatitis B Virus HBx To Enhance Its Stability and Function

Tratamiento actual y nuevas terapias contra la infección crónica por el virus de la Hepatitis B

New horizon for radical cure of chronic hepatitis B virus infection

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