Attacking hepatitis B virus cccDNA – The holy grail to hepatitis B cure

Abstract

HBV deposits a covalently closed circular DNA form, called cccDNA, in the nucleus of infected cells. As the central transcription template, the cccDNA minichromosome is a key intermediate in the HBV life cycle. Its location in the nucleus makes cccDNA a difficult target for antivirals and immune response, and therefore it is responsible for chronicity of HBV infection. While little is known about the mechanisms involved in cccDNA formation, current research is accumulating data on the mechanisms regulating transcription from cccDNA, and the first potential targeting approaches have been reported. This review will summarize our knowledge about cccDNA biology and the latest advances in cccDNA targeting strategies in order to finally achieve an HBV cure.

Proliferation of primary human hepatocytes and prevention of hepatitis B virus reinfection efficiently deplete nuclear cccDNA in vivo

“…In our study, treatment of mice with myrcludex-B proved that cell division led to the formation of cccDNA-free hepatocytes, efficiently prevented reinfection of quiescent cccDNA-cleared PHHs and even appeared to hinder detectable increase of intracellular cccDNA contents. Although such inefficient intracellular cccDNA amplification could be related to the model, the maintenance of a low cccDNA copy number per cell is in agreement with several studies involving human hepatocyte systems 11 12 22 41…”

EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection

“…It then serves as a transcription template for all viral transcripts that are translated into the different viral proteins. 13 Besides encoding the capsid protein and the viral polymerase, the pregenomic RNA is reverse transcribed into new rcDNA within the viral capsid. The DNA containing nucleocapsids in the cytoplasm are either recycled into the nucleus to maintain cccDNA reservoir, or enveloped and secreted via the endoplasmic reticulum.…”

“…223 Furthermore, cccDNA transcriptional activity is controlled by fine epigenetic regulation which can involve viral and host factors. 13,224 Besides the need for standardized assays, the main limitation of cccDNA studies is the requirement of liver biopsy; thus surrogate biomarkers are being evaluated (see below). It is noteworthy that not all transcripts are expressed from cccDNA, but can also be expressed from viral sequences integrated in the host genome.…”

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

“…Aunque infecta a otros primates, su principal hospedero es el ser humano y se han identificado 10 genotipos (A-J) con diferente distribución geográfica, comportamiento clínico y respuesta a los tratamientos disponibles (11 El VHB ingresa al hepatocito por endocitosis mediante la interacción del HBsAg con el receptor polipéptido cotransportador de sodio-taurocolato (NTCP), con lo que pierde su envoltura (19,20). La nucleocápside es transportada hasta el núcleo donde su ADN parcial es madurado por proteínas celulares a un ADNccc, el cual es un minicromosoma muy estable que va a servir como modelo transcripcional para la ARN polimerasa II del hospedero (13,21). Esta enzima genera 4 copias de ARN mensajero (ARNm) que son traducidas por la maquinaria celular y así producen las proteínas virales (11,18).…”