Mechanism of Hepatitis B Virus cccDNA Formation

Wei, Lei; Ploß, Alexander

doi:10.3390/v13081463

Cited by 58 publications

(57 citation statements)

References 151 publications

(232 reference statements)

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“…A number of small molecules have been shown in vitro to interfere with HBV‐DNA repair mechanisms. [ 80 ] Zinc finger nucleases can directly cleave specific sequences within cccDNA and transcription activator‐like effector nucleases can edit HBV genes or induce epigenetic modifications, thereby silencing cccDNA. [ 81 ] The CRISPR‐associated 9 system is a targeted nuclease that can directly cleave cccDNA, but it can also result in double‐strand breaks in the host genome, leading to pathological consequences.…”

Section: Future Therapies: Viral Targetsmentioning

confidence: 99%

Getting to HBV cure: The promising paths forward

et al. 2022

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Chronic HBV infection is a global public health burden estimated to impact nearly 300 million persons worldwide. Despite the advent of potent antiviral agents that effectively suppress viral replication, HBV cure remains difficult to achieve because of the persistence of covalently closed circular DNA (cccDNA), HBV‐DNA integration into the host genome, and impaired immune response. Indefinite treatment is necessary for most patients to maintain level of viral suppression. The success of direct‐acting antivirals (DAAs) for hepatitis C treatment has rejuvenated the search for a cure for chronic hepatitis B (CHB), though an HBV cure likely requires an additional layer: immunomodulators for restoration of robust immune responses. DAAs such as entry inhibitors, capsid assembly modulators, inhibitors of subviral particle release, cccDNA silencers, and RNA interference molecules have reached clinical development. Immunomodulators, namely innate immunomodulators (Toll‐like receptor agonists), therapeutic vaccines, checkpoint inhibitors, and monoclonal antibodies, are also progressing toward clinical development. The future of the HBV cure possibly lies in triple combination therapies with concerted action on replication inhibition, antigen reduction, and immune stimulation. Many obstacles remain, such as overcoming translational failures, choosing the right endpoint using the right biomarkers, and leveraging current treatments in combination regimens to enhance response rates. This review gives an overview of the current therapies for CHB, HBV biomarkers used to evaluate treatment response, and development of DAAs and immune‐targeting drugs and discusses the limitations and unanswered questions on the journey to an HBV cure.

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Section: Future Therapies: Viral Targetsmentioning

confidence: 99%

Getting to HBV cure: The promising paths forward

et al. 2022

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“…There the capsid shell disintegrates and releases the rcDNA genome, which is covalently linked to the viral P protein, into the nucleoplasm [ 29 ]. In a multi-step process involving host DNA replication and repair factors [ 30 , 31 , 32 ] rcDNA is then converted into the plasmid-like episomal covalently closed circular (ccc) DNA form.…”

Section: Functional Dynamics Of the Hbv Core Protein And Capsid In Virus Replicationmentioning

confidence: 99%

The Hepatitis B Virus Nucleocapsid—Dynamic Compartment for Infectious Virus Production and New Antiviral Target

2021

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Hepatitis B virus (HBV) is a small enveloped DNA virus which replicates its tiny 3.2 kb genome by reverse transcription inside an icosahedral nucleocapsid, formed by a single ~180 amino acid capsid, or core, protein (Cp). HBV causes chronic hepatitis B (CHB), a severe liver disease responsible for nearly a million deaths each year. Most of HBV’s only seven primary gene products are multifunctional. Though less obvious than for the multi-domain polymerase, P protein, this is equally crucial for Cp with its multiple roles in the viral life-cycle. Cp provides a stable genome container during extracellular phases, allows for directed intracellular genome transport and timely release from the capsid, and subsequent assembly of new nucleocapsids around P protein and the pregenomic (pg) RNA, forming a distinct compartment for reverse transcription. These opposing features are enabled by dynamic post-transcriptional modifications of Cp which result in dynamic structural alterations. Their perturbation by capsid assembly modulators (CAMs) is a promising new antiviral concept. CAMs inappropriately accelerate assembly and/or distort the capsid shell. We summarize the functional, biochemical, and structural dynamics of Cp, and discuss the therapeutic potential of CAMs based on clinical data. Presently, CAMs appear as a valuable addition but not a substitute for existing therapies. However, as part of rational combination therapies CAMs may bring the ambitious goal of a cure for CHB closer to reality.

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“…Currently, however, efficient direct antiviral therapies using nucleoside inhibitors are used for treatment in patients with chronic hepatitis B, which inhibit HBV replication but fail to induce protective HBV-specific immunity. The main reason for direct antiviral therapies to fail to achieve a cure from chronic hepatitis B, is the establishment of a persistent form in HBV-infected hepatocytes, the so-called covalently closed circular DNA (cccDNA) that serves as an extrachromosomal template for viral replication [6,7]. Despite successful control of HBV replication by direct antiviral drugs, treatment interruption is accompanied by re-activating cccDNA and initiation of viral replication, leading again to chronic viral hepatitis.…”

Section: The Challenge Of Chronic Viral Hepatitismentioning

confidence: 99%

Improving Therapeutic Vaccination against Hepatitis B—Insights from Preclinical Models of Immune Therapy against Persistent Hepatitis B Virus Infection

et al. 2021

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Chronic hepatitis B affects more than 250 million individuals worldwide, putting them at risk of developing liver cirrhosis and liver cancer. While antiviral immune responses are key to eliminating hepatitis B virus (HBV) infections, insufficient antiviral immunity characterized by failure to eliminate HBV-infected hepatocytes is associated with chronic hepatitis B. Prophylactic vaccination against hepatitis B successfully established protective immunity against infection with the hepatitis B virus and has been instrumental in controlling hepatitis B. However, prophylactic vaccination schemes have not been successful in mounting protective immunity to eliminate HBV infections in patients with chronic hepatitis B. Here, we discuss the current knowledge on the development and efficacy of therapeutic vaccination strategies against chronic hepatitis B with particular emphasis on the pathogenetic understanding of dysfunctional anti-viral immunity. We explore the development of additional immune stimulation measures within tissues, in particular activation of immunogenic myeloid cell populations, and their use for combination with therapeutic vaccination strategies to improve the efficacy of therapeutic vaccination against chronic hepatitis B.

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Mechanism of Hepatitis B Virus cccDNA Formation

Cited by 58 publications

References 151 publications

Getting to HBV cure: The promising paths forward

Getting to HBV cure: The promising paths forward

The Hepatitis B Virus Nucleocapsid—Dynamic Compartment for Infectious Virus Production and New Antiviral Target

Improving Therapeutic Vaccination against Hepatitis B—Insights from Preclinical Models of Immune Therapy against Persistent Hepatitis B Virus Infection

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