Host factors involved in HBV cccDNA formation and transcription

Abstract

The genome of hepatitis B virus (HBV) is an incomplete double-stranded circular DNA, also known as relaxed circular (RC) DNA. RC-DNA needs to be converted to covalently closed circular (ccc) DNA during the replication process. cccDNA acts as the transcription template for viral RNAs. One of those viral RNAs, pgRNA, acts as the template in the reverse-transcription process, producing minus-DNA and plus-DNA. Subsequently, the two finally form RC-DNA and finish the viral genome replication process. The existence of cccDNA is the key obstacle for curing hepatitis type B and eliminating HBV antigen using medicines such as interferons or nucleos(t)ide analogues (NAs). Many host factors are involved in HBV cccDNA formation and transcription. We summarized some of these host factors and explained their related functions in HBV infection and replication, detailing the mechanisms of cccDNA formation and subsequent transcription. When HBV enters host cells, its surface protein L interacts with the receptor NTCP on the cell surface, allowing HBV to enter through endocytosis and leaving its envelope behind. Subsequently, the HBV genome, the RC-DNA, enters the cell nucleus, and leaves the empty nucleocapsid behind. The genome RC-DNA must convert into cccDNA to start the replication process. Many host factors participate in this process in various ways, including helping to remove special constructions, fixing the gaps and the single stand areas. These host factors include TDP1, TDP2, FEN1 and factors involved in the DNA damage response (DDR) system. This process also requires host DNA polymerase to extend DNA sequences, including POLK, POLH and POLL. cccDNA does not exist independently, but rather it exists in combination with many histones and nonhistones. The epigenetic modification of histone influences cccDNA transcription in various ways. For example, acetylization of H3 and H4 induces transcription and some acetylases such as CBP, p300, PCAF, HAT1, and KAT8 are involved. Interestingly, most of the host acetylases are recruited by two viral proteins, HBX and HBC, suggesting that these two virus proteins may help the virus to kidnap host factors for the benefit of the virus. In addition to epigenetic modification, cccDNA transcription also requires many cis-elements and host transcription factors. Many ubiquitous and liver-enriched host factors such as NF-1, sp-1, TBP, CREB, HNF3, HNF1, HNF4, C/EBP, PPARα, FXR, FTF, PGC-1αcombine with cis-elements in HBV genome, including promoter regions and enhancer regions. This combination induces or inhibits the cccDNA transcription process. In truth, HBV cccDNA formation and transcription processes require more host involvement than this article mentions. Many new factors and interactions as well as key regulators still waiting to be discovered. This article may supply suggestions for research into the detailed mechanism of the two processes of HBV cccDNA.