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Chronic hepatitis B: divide and conquer?
  1. Michael Nassal
  1. Correspondence to Dr Michael Nassal, University Hospital Freiburg, Department of Internal Medicine II/Molecular Biology, Hugstetter Str. 55, D-79106 Freiburg, Germany; nassal2{at}ukl.uni-freiburg.de

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Chronic hepatitis B (CHB) puts 250 million people or more at a greatly increased risk to develop terminal liver disease.1 The causative agent, hepatitis B virus (HBV), is a small hepatotropic DNA virus that replicates via reverse transcription.2 Persistence of infection is the combined result of an inadequate host immune response3 and the stability of a special episomal form of the virus genome termed covalently closed circular (ccc) DNA.4 5 Associating with host and viral proteins into a minichromosome, cccDNA serves as template for all viral RNAs and thus progeny virions (figure 1). A true cure of CHB would thus require elimination of cccDNA from a patient’s liver; this is rarely achieved by current CHB therapies with type I interferon or nucleos(t)ide analogues (NAs) which inhibit HBV reverse transcription. Also, none of the new anti-HBV drugs in clinical development,6 including entry inhibitors such as Myrcludex-B (Myr-B)7 which block the interaction between HBV and its receptor Na+-taurocholate cotransporting polypeptide (NTCP; figure 1), directly target cccDNA. Not even recovery from acute self-limited hepatitis B appears to eradicate all cccDNA molecules although their number (corresponding to at least the ~1010 infected hepatocytes at the peak of infection) is massively reduced by the immune system within a few weeks,3 mostly with fully maintained liver function.

Figure 1

Hepatitis B virus (HBV) covalently closed circular (ccc) DNA synthesis and immune-mediated loss. (A) HBV cccDNA synthesis and amplification from relaxed circular (rc) DNA. Hepatitis B virions exploit the bile acid transporter Na+-taurocholate cotransporting polypeptide (NTCP) as entry receptor into human hepatocytes. After the envelope is stripped off, the nucleocapsids (NC) transport the rcDNA genome to the nucleus where conversion into cccDNA takes place. cccDNA associates with host and viral factors into a minichromosome (not shown) that serves as transcription template for the viral RNA; …

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