Novel viral and host targets to cure hepatitis B

Ko, Chunkyu; Michler, Thomas; Protzer, Ulrike

doi:10.1016/j.coviro.2017.03.019

Cited by 24 publications

(22 citation statements)

References 70 publications

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“…A number of exciting new approaches are under development targeting different stages of the HBV lifecycle (3)(4)(5). However, it is unlikely that future antiviral drugs will be able to clear every trace of cccDNA from the large burden of infected hepatocytes.…”

Section: Rational For An Immunotherapeutic Approachmentioning

confidence: 99%

Defective T-cell immunity in hepatitis B virus infection: why therapeutic vaccination needs a helping hand

Maini

Pallett

2018

The Lancet Gastroenterology & Hepatology

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Hepatitis B virus (HBV) remains a major cause of morbidity and mortality worldwide. Treatments that can induce functional cure in patients chronically infected with this hepatotropic, non-cytopathic virus are desperately needed. Attempts to use therapeutic vaccines to expand the weak antiviral T-cell response and induce sustained immunity have been unsuccessful. However, exciting progress has been made in defining the molecular defects that must be overcome to harness T-cell immunity. A large arsenal of immunotherapeutic agents and direct-acting antivirals targeting multiple steps of the viral lifecycle is emerging. In this Review, we discuss how to translate the new insights into T-cell manipulation, combined with better understanding of patient heterogeneity, into optimisation of therapeutic vaccines against HBV. We review the opportunities and risks involved in boosting endogenous T-cell responses using combinations of next generation therapeutic vaccines and immunotherapy agents.

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Section: Rational For An Immunotherapeutic Approachmentioning

confidence: 99%

Defective T-cell immunity in hepatitis B virus infection: why therapeutic vaccination needs a helping hand

Maini

Pallett

2018

The Lancet Gastroenterology & Hepatology

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“…HBV uses cellular transcriptional machinery to support viral gene expression . In fact, efficient transcription of HBV genes requires both viral proteins and host transcription factors.…”

mentioning

confidence: 99%

“…(7,8) HBV uses cellular transcriptional machinery to support viral gene expression. (9) In fact, efficient transcription of HBV genes requires both viral proteins and host transcription factors. The expression of viral HBx protein has been shown to be essential for efficient HBV transcription by inducing degradation of the host restriction factor "structural maintenance of chromosomes" (Smc) complex Smc5/6.…”

mentioning

confidence: 99%

PAPD5/7 Are Host Factors That Are Required for Hepatitis B Virus RNA Stabilization

et al. 2019

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RG7834 is a potent, orally bioavailable small‐molecule inhibitor of hepatitis B virus (HBV) gene expression that belongs to the dihydroquinolizinone (DHQ) chemical class and uniquely blocks production of both viral DNA and antigens. In this study, we used DHQ compounds as tools in a compound‐based adaptation version of the yeast three‐hybrid screen to identify the cognate cellular protein targets, the non‐canonical poly(A) RNA polymerase associated domain containing proteins 5 and 7 (PAPD5 and PAPD7). Interaction with RG7834 was mapped to the catalytic domains of the two cellular enzymes. The role of PAPD5 and PAPD7 in HBV replication was confirmed by oligonucleotide‐mediated knockdown studies that phenocopied the result seen with RG7834‐treated HBV‐infected hepatocytes. The greatest effect on HBV gene expression was seen when PAPD5 and PAPD7 mRNAs were simultaneously knocked down, suggesting that the two cellular proteins play a redundant role in maintaining HBV mRNA levels. In addition, as seen previously with RG7834 treatment, PAPD5 and PAPD7 knockdown led to destabilization and degradation of HBV mRNA without impacting production of viral RNA transcripts. Conclusion: We identify PAPD5 and PAPD7 as cellular host factors required for HBV RNA stabilization and as therapeutic targets for the HBV cure.

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“…Recent studies growingly revealed the significance of host cellular factors in the viral life cycle [46] and also carcinopathogenesis [47,48]. Exemplarily, cyclophilin (CyP) has been demonstrated to be a critical host cellular factor [49].…”

Section: Discussionmentioning

confidence: 99%

Orchestration of Intracellular Circuits by G Protein-Coupled Receptor 39 for Hepatitis B Virus Proliferation

Goto¹,

Nishitsuji²,

Sugiyama³

et al. 2020

IJMS

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Hepatitis B virus (HBV), a highly persistent pathogen causing hepatocellular carcinoma (HCC), takes full advantage of host machinery, presenting therapeutic targets. Here we aimed to identify novel druggable host cellular factors using the reporter HBV we have recently generated. In an RNAi screen of G protein-coupled receptors (GPCRs), GPCR39 (GPR39) appeared as the top hit to facilitate HBV proliferation. Lentiviral overexpression of active GPR39 proteins and an agonist enhanced HBV replication and transcriptional activities of viral promoters, inducing the expression of CCAAT/enhancer binding protein (CEBP)-β (CEBPB). Meanwhile, GPR39 was uncovered to activate the heat shock response, upregulating the expression of proviral heat shock proteins (HSPs). In addition, glioma-associated oncogene homologue signaling, a recently reported target of GPR39, was suggested to inhibit HBV replication and eventually suppress expression of CEBPB and HSPs. Thus, GPR39 provirally governed intracellular circuits simultaneously affecting the carcinopathogenetic gene functions. GPR39 and the regulated signaling networks would serve as antiviral targets, and strategies with selective inhibitors of GPR39 functions can develop host-targeted antiviral therapies preventing HCC.

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Novel viral and host targets to cure hepatitis B

Cited by 24 publications

References 70 publications

Defective T-cell immunity in hepatitis B virus infection: why therapeutic vaccination needs a helping hand

Defective T-cell immunity in hepatitis B virus infection: why therapeutic vaccination needs a helping hand

PAPD5/7 Are Host Factors That Are Required for Hepatitis B Virus RNA Stabilization

Orchestration of Intracellular Circuits by G Protein-Coupled Receptor 39 for Hepatitis B Virus Proliferation

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