Early Steps of Hepatitis B Life Cycle: From Capsid Nuclear Import to cccDNA Formation

Abstract

Hepatitis B virus (HBV) remains a major public health concern, with more than 250 million chronically infected people who are at high risk of developing liver diseases, including cirrhosis and hepatocellular carcinoma. Although antiviral treatments efficiently control virus replication and improve liver function, they cannot cure HBV infection. Viral persistence is due to the maintenance of the viral circular episomal DNA, called covalently closed circular DNA (cccDNA), in the nuclei of infected cells. cccDNA not only resists antiviral therapies, but also escapes innate antiviral surveillance. This viral DNA intermediate plays a central role in HBV replication, as cccDNA is the template for the transcription of all viral RNAs, including pregenomic RNA (pgRNA), which in turn feeds the formation of cccDNA through a step of reverse transcription. The establishment and/or expression of cccDNA is thus a prime target for the eradication of HBV. In this review, we provide an update on the current knowledge on the initial steps of HBV infection, from the nuclear import of the nucleocapsid to the formation of the cccDNA.

Ca2+/Calmodulin-Dependent Protein Kinase II Inhibits Hepatitis B Virus Replication from cccDNA via AMPK Activation and AKT/mTOR Suppression

“…Since CaMKII overexpression decreases cccDNA level ( Figure 9 C and Figure S8 A) and CaMKII α contains a nuclear localization signal (NLS) [ 73 , 74 ], further studies are needed to determine the intracellular localization of CaMKII α and its indirect association with cccDNA. We hypothesized that the decreased levels of HBV RNAs in cells overexpressing CaMKII ( Figure 9 A,B) were due to decreased levels of cccDNA ( Figure 9 C and Figure S8 A), the template for HBV RNA transcription [ 75 ]. Furthermore, CaMKII overexpression might affect the recruitment of host RNA polymerase II or transcriptional activators or repressors, suggesting the need to evaluate the transcriptional activities of cccDNA in CaMKII-overexpressing HBV replicating cells.…”

Pathogenicity and virulence of Hepatitis B virus

“…Thus, besides these five factors, additional protein factors such as ataxia telangiectasia mutated (ATM), a serine/threonine kinase that is activated by DNA double-strand breaks[ 65 ], had also been reported to be involved in the formation of HBV cccDNA. The topic on the repair of the HBV rcDNA has recently been reviewed, and readers are referred to this recent article for further details[ 66 ].…”

Mechanism of Hepatitis B Virus cccDNA Formation

“…Lastly, we will summarize the effects and therapeutic potential of small molecule inhibitors targeting these repair factors on cccDNA formation. Since the remainder of this review will focus on rcDNA repair, we refer readers to previous reviews for additional details of the HBV life cycle and other steps of cccDNA biogenesis, including the nuclear transport of nucleocapsids and the chromatinization of cccDNA [ 15 , 45 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ].…”