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Hepatitis B virus (HBV) is tightly controlled by a number of noncytotoxic mechanisms. This control occurs within the host hepatocyte at different steps of the HBV replication cycle. HBV persists by establishing a nuclear minichromosome, HBV cccDNA, serving as a transcription template for the viral pregenome and viral mRNAs. Nucleoside/nucleotide analogues widely used for antiviral therapy as well as most antiviral cytokines act at steps after transcription of HBV RNAs and thus can control virus replication but do not directly affect its gene expression. Control of HBV at the level of transcription in contrast is able to restrict both, HBV replication and gene expression. In the review, we focus on how HBV is controlled at the level of transcription. We discuss how the composition of transcription factors determines HBV gene expression and replication and how this may be influenced by antivirally active substances, e.g. the cytokine IL-6 or helioxanthin analogues, or by the differentiation state of the hepatocyte.

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Dendritic cells (DC) of hepatitis B virus (HBV) carriers have been reported to exhibit functional impairment. Possible explanations for this phenomenon are infection of HBV by DC or alteration of DC function by HBV. We therefore analyzed whether DC support the different steps of HBV infection and replication: uptake, deposition of the HBV genome in the nucleus, antigen expression, and progeny virus release. When HBV genomes were artificially introduced into monocyte-derived DC by adenoviral vectors, low-level expression of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) but no HBV replication was detected. When monocyte-derived DC were subjected to wild-type HBV or a recombinant HBV expressing Renilla luciferase under a non-liver-specific promoter, intracellular HBV DNA was detected in a low percentage of cells. However, neither nuclear cccDNA was formed nor luciferase activity was detected, indicating that either uncoating or nucleocytoplasmic transport were blocked. To verify our observation in the in vivo situation, myeloid and plasmacytoid DC were isolated from blood of high viremic HBV carriers, and analyzed by quantitative polymerase chain reaction (PCR) and electron microscopy. Although circulating DC had in vivo been exposed to more than 10 4 HBV virions per cell, HBV genomic DNA was hardly detected, and no nuclear cccDNA was detected at all. By using electron microscopy, subviral particles were found in endocytic vesicles, but virions were undetectable as were viral capsids in the cytoplasm. H epatitis B virus (HBV) infection represents a major health problem worldwide. Over 350 million individuals are chronically infected with HBV and are at high risk to develop liver cirrhosis or hepatocellular carcinoma. To eliminate the virus after infection, a strong humoral and cellular immune response is required. 1 Thus, control of HBV infection is associated with a multispecific and polyclonal cytotoxic T-cell response and a strong type 1 T helper cell response. 2,3 In contrast, chronically infected patients display oligoclonal T helper cell responses with weak or undetectable cytotoxic T-cell activity. 4 Dendritic cells (DC) are the most important professional antigen-presenting cells. They act as key players in initiating virus-specific T-cell responses. 5 This is reflected by the fact that viruses can evade immune responses by impairing DC function. [6][7][8] The role of DC during HBV infection was intensively studied during the last years, but whether total numbers of DC are reduced during chronic infection is discussed controversary. [9][10][11] In some studies, functional deficits of these cells were reported on contact of moDC with HBV, 14 whereas they remained minor in others. 12 Whether the weak or absent T-cell response described in chronic hepatitis B patients results from a defect in the DC compartment, which is caused by the virus itself, is unclear. Theoretically, numbers or functionality of DC subsets could be affected by interaction of surface receptors on DC with either vi...

SummaryHepatitis B virus (HBV) is an important human pathogen, which targets the liver extremely efficient, gaining access to hepatocytes by a so far unknown receptor and replicating in a hepatocyte-specific fashion. Cell differentiation seems to determine HBV replication. We here show that the level of hepatocyte differentiation, as indicated by hepatocyte polarization and metabolic activity, is closely correlated to the transcription of the HBV RNA pregenome. Pregenome transcription determined the level of HBV replication in various cell lines of hepatocellular origin and in primary human hepatocytes. A variety of hepatocyte-enriched nuclear factors have been described to regulate transcription of the pregenome, but it remained unknown which factors link HBV replication to hepatocyte differentiation. We determined that high expression levels of HNF4a but not its potential cofactors or other hepatocyte-enriched transcription factors were essential for efficient HBV replication, and link it to hepatocyte differentiation. HNF1a contributed to the control of HBV replication because it regulated the expression of HNF4a. Thus, a concerted action of HNF4a and HNF1a, which also determines morphological and functional differentiation of hepatocytes, links HBV replication to hepatocyte differentiation.