Enigmatic PreS deletions in hepatitis B virus DNA
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EDITORIAL
Enigmatic PreS deletions in hepatitis B virus DNA Wolfram H. Gerlich1 · Dieter Glebe1 Received: 15 October 2020 / Accepted: 22 October 2020 © The Author(s) 2020
In this issue of Virus Genes, Ting Wang et al. describe a defective variant of hepatitis B virus (HBV) with a very high replication capacity comprising a large deletion in the preS1 domain of the open reading frame encoding the three (large, middle, and small) HBV surface proteins (LHBs, MHBs, and SHBs) [1]. The variant was isolated and cloned from the serum of a patient suffering from chronic hepatitis B (CHB) who had experienced an HBV breakthrough under antiviral therapy with the nucleotide analog adefovir. The variant showed the typical mutations A181T and N236T in the reverse transcriptase domain of the viral polymerase protein leading to adefovir resistance after previously failed lamivudine therapy. The first lamivudine-selected mutation (A181T) happens to generate the stop mutation W172* in the overlapping S domain of the HBs proteins causing carboxyterminal truncation and intracellular retention of all three HBs proteins. While this is an additional stop mutation in the S domain (C69*) that prevented the formation and release of enveloped HBV particles encoded by the variant, HBV DNA and HBsAg of the variant could nevertheless be detected in the patient serum. This indicated that the patient’s hepatocytes replicating the variant via circular covalently closed (ccc) HBV DNA contained HBV genes encoding functional HBs proteins as well, most likely as linear-integrated HBV DNA fragments. Transcomplementation with functional HBs genes of defective ccc DNA has recently been shown in CHB patients by Peiffer et al. [2]. Surprisingly, the variant described in [1] with the 68 amino acid long preS1 deletion replicated HBV DNA much more efficiently than wildtype (WT) HBV DNA of the same HBV subgenotype C2 when transfected into the HBV permissive hepatoma cell line Huh7. The variant contained also two mutations in the core promoter (A1762T/G1764A) which are known to enhance HBV replication since long [3],
* Wolfram H. Gerlich [email protected]‑giessen.de 1
Institute for Medical Virology, Justus Liebig University Giessen, Giessen, Germany
but the authors of ref [1] could elegantly prove that the major effect on replication came from the preS1 deletion. When the deleted sequence was artificially re-introduced into the variant, the replication decreased to levels comparable to WT. In addition to enhanced replication, the deletion variant showed a profoundly changed intracellular localization of the HBV core (HBc) protein from predominantly cytoplasmic to almost exclusively nuclear although the HBc protein was unchanged. Both effects are probably linked together. The preS1 sequence (aa 42-110) deleted in the variant of [1] includes the binding site (aa 103-124) of the LHBs protein to mature HBc particles containing replicated HBV DNA. This binding initiates envelopment of HBc particles and secretion of mature HBV particles [4]. The n
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