Review on hepatitis B virus precore/core promoter mutations and their correlation with genotypes and liver disease severity

Of 350 million people worldwide are chronically infected with hepatitis B virus(HBV)and are at risk of developing cirrhosis and hepatocellular carcinoma(HCC)later in life.HBV is the most diverse DNA virus,and its genome is composed of four open reading frames:Presurface antigen/surface antigen gene(preS/S),precore/core gene(preC/C),polymerase gene(P),and theχgene(χ).HBV produces quasispecies naturally or in response to antiviral agents because of the absence of proofreading activity amid reverse transcription and a high replication rate.The virus has 10 genotypes(A to J)with different geographical distributions.There are various HBV mutations in the HBV genome,including preC/C mutations,preS/S mutations,P gene mutations,andχgene mutations.The core promoter region plays a vital part in the replication,morphogenesis and pathogenesis of the virus.The precore region also plays a crucial role in viral replication.Both core promoter and precore mutations rescue the virus from host immune surveillance and result in the formation of mutated strains that may have altered pathogenicity.preC/C mutations are associated with liver disease progression.Precore mutations stop hepatitis B e antigen(HBeAg)production and basal core promoter mutations downregulate HBeAg production.Mutations in the basal core promoter are also associated with increased HBV replication and an increased incidence of advanced liver diseases such as cirrhosis and HCC.The emergence of antiviral-resistant mutations is the main reason for treatment failure.This review focuses mainly on preC/C promoter mutations and their correlation with genotypes and liver disease severity.Thorough perception and knowledge of HBV genetic variety and mutants could be vital to discover techniques for the prognosis and control of HBV infection.

Systematic evaluation of HBV BCP/PC mutations on the risk of hepatocarcinogenesis

Objective:To evaluate of the effects of mutations in BCP-A1762T/G1764A and PC-G1896A genes on hepatocarcinogenesis.Methods:Computer searches for PubMed,SCI,CNKI,VIP and WanFang Data databases were conducted to collect literature on the role of mutations in the disease process associated with HBV infection from database creation to July 1,2021.Two researchers independently screened the articles,extracted information and evaluated the quality of the studies.Review Manager software version 5.4 was used for Meta-analysis.Results:A total of 40 articles were included,with a total of 12423 cases and 3710 cases of hepatocellular carcinoma.Meta-analysis showed that mutations in BCP-A1762T/G1764A gene were associated with the disease process of HBV infection and promoted hepatocellular carcinogenesis.mutations in BCP/PC gene were significant in the process of HBV infection in BCP-A1762T/G1764A in HCC vs non-HCC[OR=4.05,95%CI=2.64~6.22],CHBC[OR=3.90,95%CI=2.13~7.17],CHB[OR=2.77,95%CI=1.78~4.32],LC[OR=1.64,95%CI=0.95~2.84],which were statistically significant;in PC-G1896A mutation HCC vs non-HCC[OR=1.49,95%CI=1.02~2.17],CHBC[OR=1.56,95%CI=0.89~2.72],CHB[OR=1.80,95%CI=1.17~2.77]were statistically significant,while the difference was not statistically significant when comparing HCC with LC(P=0.4).The BCP-A1762T/G1764A mutation in the B genotypes/genotyped versus the C genotype[OR=0.36,95%CI=0.20~0.64],with a statistically significant difference,and no statistically significant difference in the PC-G1896A mutation.BCP-A1762T/G1764A mutation in the C gene in HCC versus non-HCC[OR=3.71,95%CI=1.82~7.61]and PC-G1896A mutation in HCC vs non-HCC[OR=2.81,95%CI=1.34~5.91],the differences were statistically significant.Conclusions:Current evidence suggests that mutations in the BCP-A1762T/G1764A and PC-G1896A genes have a significant effect on the increased risk of hepatocellular carcinoma and are genotype dependent.However,due to the limitation of the number and quality of included studies,these findings need to be validated by more high-quality studies.

Precore mutation enhances viral replication to facilitate persistent infection especially in HBeAg-negative patients

Naturally occurred precore(PC,G1896A)and/or basal core promoter(BCP,A1762T/G1764A)mutations are prevalent in chronic HBV-infected patients,especially those under HBeAg-negative status.However,the replicative capacity of HBV with PC/BCP mutations remains ambiguous.Herein,meta-analysis showed that,only under HBeAg-negative status,the serum HBV DNA load in patients with PC mutation was 7.41-fold higher than those without the mutation.Both PC mutation alone and BCPþPC mutations promoted HBV replication in cell and hydrodynamic injection mouse models.In human hepatocyte chimeric mouse model,BCPþPC mutations led to elevated replicative capacity and intrahepatic core protein accumulation.Mechanistically,preC RNA harboring PC mutation could serve as mRNA to express core and P proteins,and such pgRNA-like function favored the maintenance of cccDNA pool under HBeAg-negative status.Additionally,BCPþPC mutations induced more extensive and severe human hepatocyte damage as well as activated endoplasmic reticulum stress and TNF signaling pathway in livers of chimeric mice.This study indicates that HBeAg-negative patients should be monitored on HBV mutations regularly and are expected to receive early antiviral treatment to prevent disease progression.

Characterization of hepatitis B virus genotypes/subgenotypes in 1301 patients with chronic hepatitis B in North China

Background There is still a paucity of data on hepatitis B virus （HBV） subgenotype prevalence in North China based on sequencing of large-size samples. In addition, whether HBV genotypes impact drug-resistance-associated and HBV e antigen （HBeAg）-Ioss-associated mutations in patients with chronic hepatitis B （CHB） is still under investigation. This study aimed to disclose clinical prevalence of HBV genotypes/subgenotypes in North China and the clinical implications of HBV genotype classification in respect to HBeAg loss and drug-resistant occurrence. Methods Sera were collected from 1301 nucleos（t）ide analog-experienced CHB patients. Viral DNA was extracted and used as template for HBV genome amplification by nested PCR. DNA sequencing was performed for the analysis of HBV genotypes/subgenotypes, drug-resistance-associated mutations in polymerase gene and HBeAg-loss-associated mutations in precore/basal core promoter （BCP） regions. Results HBV/B, HBV/C, and HBV/D were detected in 190 （14.6%）, 1096 （84.2%）, and 15 （1.2%） patients, respectively. HBV/B2 （182/190）, HBV/C2 （1069/1096）, and HBV/D1 （12/15） were predominant subgenotypes within individual genotypes. By contrast, C2 prevalence is relatively lower in Beijing area （77.2%） than in other north areas （84.9%-87.4%）. HBV/C-infected patients had an older age and a lower serum albumin level but similar HBV DNA and alanine aminotransferase （ALT） levels compared to HBV/B-infected patients. HBV/C infection had a higher incidence of lamivudine-resistant mutations rtM2041N （44.9% vs. 30.2%, P 〈0.01） and BCP mutations A1762T＋G1764A （65.8% vs. 40.0%, P〈0.01） compared with HBV/B infection. Conclusions C2 is the most prevalent HBV subgenotype followed by B2 in CHB patients in North China; and HBV genotype prevalence is influenced by immigrant population. HBV/C infection is likely to have longer disease duration and severer liver functional impairment and might be more susceptible to develop lamivudine resistance compared to HBV/B infection.