HBx mutations emerged during antiviral therapy: a new face of a multifaceted HBV protein?
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EDITORIAL
HBx mutations emerged during antiviral therapy: a new face of a multifaceted HBV protein? Bin Zhou1,2 · Weimeng He1 · Jinlin Hou2 Received: 24 August 2020 / Accepted: 23 November 2020 © Asian Pacific Association for the Study of the Liver 2020
The hepatitis B virus (HBV) is a major human pathogen. The HBV genome encodes four overlapping open-reading frames (ORFs) including the S-ORF, C-ORF, P-ORF, and X-ORF. Among them, polymerase which encoded by P-ORF is the target of all approved nucleos(t)ide analogues (NAs) for antiviral therapy. NAs are generally efficient and well tolerated. However, resistance to non-first line antiviral agents is a major issue affecting long-term therapy [1]. HBx encoded by X-ORF is a nonstructural protein that serves multiple functions during the various stages of chronic HBV infection (CHB) through interaction with a number of host proteins. In this issue of Hepatology International, Lin et al. identified HBx mutants that emerged in patients experiencing lamivudine (LAM) resistance or entecavir (ETV) suboptimal response by sequence analysis and characterized their roles in the HBV replication cycle. Co-transfection of these HBxmutant plasmids and HBV replication-competent clone into cell lines result in increased nuclear-to-cytoplasmic ratios of core antigen and HBV-DNA, as well as the level of nuclear covalently, closed circular DNA (cccDNA). These results demonstrate that HBx mutants can emerge during LAM or ETV therapy and compensate for the replication suppression of NAs by increased cccDNA. This is an innovative study in which the researchers extend the resistant-associated mutations from polymerase to the X gene, and explore the effect of these mutations on HBV replication in vitro [2]. Mutations provide possibilities for the virus to survive a complex environment. Mutations often arise spontaneously in viral quasispecies followed by some of them were subsequently selected as predominant strains for their adaption in * Jinlin Hou [email protected] 1
Department of Infectious Diseases, Nanfang Hospital, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Southern Medical University, Guangzhou, China
Hepatology Unit of Shenzhen Hospital, Southern Medical University, Shenzhen, China
2
changing conditions. We have known that HBV resistance to NAs is achieved through polymerase mutations. Antiviral agents always target important virological mechanisms; as a result, resistance mutation often led to decreased replication fitness. There are many documented examples of the fitness costs that are associated with NA resistance in HBV antiviral therapy. In most cases, the cost can be ameliorated by the acquisition of compensatory mutations. Hughes et al. classified the common resistance-compensatory mechanisms into four categories [3]. Two of these compensating mechanisms that often appear in antiviral resistance are compensation by an intragenic mutation and compensation by an intergenic mutation. According to the above definitions, regular HBV initial primar
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