Review ArticleReview

Research progress in hepatitis B virus covalently closed circular DNA

Xiaodong Zhang, Yufei Wang and Guang Yang
Cancer Biology & Medicine April 2022, 19 (4) 415-431; DOI: https://doi.org/10.20892/j.issn.2095-3941.2021.0454

Article Figures & Data

Figures

  • Figure 1
    Figure 1

    Composition of the HBV cccDNA minichromosome. In the nucleus, HBV cccDNA is converted from rcDNA, and both histones and non-histone proteins are attached. (A) Various factors directly or indirectly binding cccDNA, such as HBx, HAT1, and p300, promote the replication of HBV. (B) Some restriction factors, such as SIRT1, HDAC1, PRMT1/5, and IFI16, are loaded on cccDNA, thus inhibiting HBV replication. A3A: APOBEC3A. TF: transcription factors, such as CREB, ATF, YY1, STAT1, and STAT2.

  • Figure 2
    Figure 2

    Hypothesis schematic of the roles of HBx-mediated epigenetic regulatory factors in the HBV cccDNA minichromosome and host chromosome. On the one hand, HBx up-regulates and recruits host epigenetic regulatory factors to cccDNA, thus enhancing the transcription of cccDNA through epigenetic regulation and leading to the replication of HBV in a positive feedback loop. On the other hand, HBx up-regulates host epigenetic regulatory factors, thus enhancing the growth of liver cancer, or directly results in the development of hepatocarcinogenesis.

  • Figure 3
    Figure 3

    HBV cccDNA and HCC. (A, B) PCNAP1 enhances HBV replication through modulating miR-154/PCNA/HBV cccDNA signaling. PCNAP1/PCNA signaling drives hepatocarcinogenesis. (C) HBx-elevated MSL2 modulates HBV cccDNA in hepatoma cells, thus promoting the development of HCC, forming a positive feedback loop of HBx/MSL2/cccDNA/HBV. (D) HULC enhances HBV cccDNA minichromosome stability by down-regulating APOBEC3B in hepatoma cells, thus mediating the growth of hepatoma cells. (E, F) HBx activating Notch signaling has an important role in HBV-related HCC and facilitates cccDNA transcription via CREB. (G) Co-recruitment of the lncRNA DLEU2 and HBx to cccDNA displaces EZH2 from the viral chromatin, and boosts cccDNA transcription and HBV replication, which is associated with the development of HCC.

  • Figure 4
    Figure 4

    Therapeutic strategies against the cccDNA minichromosome. cccDNA formation: Inhibitors, such as CpAMs, hydrolyzable tannins, and MX2, inhibit cccDNA minichromosome formation through conversion from rcDNA. cccDNA degradation: IFN-α decreases the expression of UBE2L3, which is correlated with the degradation of APOBEC3A, thus decreasing HBV cccDNA. IFN-γ and TNF-α inhibit the levels of HBV cccDNA through up-regulation of APOBEC3A and APOBEC3B deaminases. TGF-β induces cccDNA degradation via activation-induced cytidine deaminase (AID) activity. IFN-β, IFN-λ1, IFN-λ2, and gene editing technologies induce the deamination and degradation of cccDNA. cccDNA transcription: epigenetic modification enzyme inhibitors such as HAT1 and p300 inhibitors inhibit the transcription of cccDNA. IFN-α restricts the acetylation levels of histone H3 lysine 9 (H3K9)/27 (H3K27) and the succinylation levels of histone H3 lysine 79 (H3K79) on the cccDNA minichromosome, thereby suppressing cccDNA transcription. Nitazoxanide (NTZ) inhibits HBx-DDB1 protein interaction, thereby accounting for the significant restoration of the SMC5/6 protein level, and suppresses cccDNA transcription and viral protein production. Dicoumarol, an NQO1 inhibitor, blocks cccDNA transcription by promoting the degradation of HBx. CDM-3008, Am80, and IL-6 prevent cccDNA transcription.

Tables

  • Table 1

    Summary of factors on HBV cccDNA and their functions

    NameFunctionReference
    HBxPrevents the recruitment of transcriptional repressors or recruits transcription factors to cccDNA, thus activating transcription of HBV genes via epigenetic regulation; degrades SMC5/6, which binds cccDNA and inhibits its transcription31
    HBcEnhances the formation of cccDNA via delivering the rcDNA to the nucleus from mature nucleocapsids41
    CBP/p300Enhances the acetylation of cccDNA-bound histones25
    PCAF/GCN5Enhances the acetylation of cccDNA-bound histones25
    ATFEnhances cccDNA transcription25
    CREBEnhances cccDNA transcription25
    YY1Enhances cccDNA transcription25,35
    STAT1/2Enhances cccDNA transcription25,35
    Par14/17Enhances cccDNA transcription activation by binding HBx29
    PRPF31Enhances cccDNA minichromosome formation or maintenance by interacting with HBx30
    HDAC1Inhibits cccDNA transcription as a transcriptional suppressor34
    SIRT1Inhibits cccDNA transcription as a chromatin modification enzyme34
    IFI16Inhibits cccDNA transcription through enhancing recruitment of transcriptional suppressors and depressing transcriptional activators34
    SMCHD1Suppresses cccDNA transcription34
    PMLInhibits cccDNA transcription34
    SMC5/6Inhibits cccDNA transcription31
    SETDB1Inhibits transcription of cccDNA by SETDB1 histone methyltransferase32
    HP1Inhibits cccDNA transcription32
    PRMT1/5Mediates epigenetic suppression of the cccDNA minichromosome36
    EZH2Inhibits cccDNA transcription34,37
    DLEU2After co-recruitment to cccDNA with HBx, displaces EZH2 from the viral chromatin and boosts cccDNA transcription37
    HAT1Modulates acetylation of histones on the cccDNA minichromosome38
    HULCServes as a scaffold in the complex of HAT1/HULC/HBc; modulates acetylation of histones on the cccDNA minichromosome38
    PCNAEnhances cccDNA formation from rcDNA39

    HBx, hepatitis B X protein; HBc, hepatitis B core protein; CBP, CREB binding protein; PCAF, P300/CBP associated factors; GCN5, general control non-derepressible 5; ATF, artificial transcription factor; CREB, cAMP-response element binding protein; YY1, Yin Yang 1; STAT1/2, signal transducer and activator of transcription 1/2; Par14/17, parvulin 14/17; PRPF31, pre-messenger RNA processing factor 31; HDAC1, histone deacetylase 1; SIRT1, sirtuin 1; IFI16, interferon-inducible protein 16; SMCHD1, structural maintenance of chromosomes flexible hinge domain containing 1; PML, promyelocytic leukemia protein; SMC5/6, structural maintenance of chromosomes complex5/6; SETDB1, SET domain bifurcated histone lysine methyltransferase 1; HP1, heterochromatin-associated protein 1; PRMT1/5, protein arginine methyltransferase 1; EZH2, enhancer of zeste homolog 2; DLEU2, deleted in lymphocytic leukemia 2; HAT1, histone acetyltransferase 1; HULC, highly upregulated in liver cancer; PCNA, proliferating cell nuclear antigen.

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