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T¹⁷⁶⁴G¹⁷⁶⁶ core promoter double mutants are restricted to Hepatitis B virus strains with an A¹⁷⁵⁷ and are common in genotype D

¹ Department of Virology, Swedish Institute for Infectious Disease Control, SE-171 82 Solna, Sweden
² Microbiology and Tumor Biology Center, Karolinska Institutet, SE-171 77 Stockholm, Sweden
³ Research Center for Gastroenterology and Liver Diseases, Shaheed Beheshti University of Medical Sciences, Taleghani Hospital, Tabnak Avenue, 19857 Tehran, Iran

Correspondence
Lars O. Magnius
Lars.Magnius{at}smi.ki.se

To investigate the role of pre-core and basal core promoter (BCP) mutants in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (e-CHB) in Iran, Hepatitis B virus strains from 30 patients and 42 anti-HBe-positive asymptomatic carriers (ASCs) were characterized. G¹⁸⁹⁶A pre-core stop mutants, detected in 77 % of e-CHB patients and 85 % of ASCs, showed no association with virus load or aminotransferase levels. Twenty per cent of e-CHB patients and 31 % of ASCs harboured T¹⁷⁶²A¹⁷⁶⁴ mutants. When this double mutation was associated with G¹⁷⁵⁷, it was linked to a higher virus load in patients than when it was associated with A¹⁷⁵⁷ (10^5·2±1·8 vs 10^3·2±0·8 copies ml^–1; P=0·004). Interestingly, the most common BCP mutations were T¹⁷⁶⁴ and G¹⁷⁶⁶, which were present in 33 % of e-CHB patients and 29 % of ASCs. These were associated with higher virus load and aminotransferase levels compared with patients lacking core promoter mutations, although this was not significant. The T¹⁷⁶⁴G¹⁷⁶⁶ double mutation was only present in strains with A¹⁷⁵⁷ (P<0·001), which is more frequent in strains of genotype D than in those belonging to other genotypes. On the other hand, the T¹⁷⁶²A¹⁷⁶⁴ double mutation was found more frequently in association with G¹⁷⁵⁷ than with A¹⁷⁵⁷. The T¹⁷⁶²A¹⁷⁶⁴ double mutation forms a binding site for hepatocyte nuclear factor 1 (HNF1), which is constrained by A¹⁷⁵⁷. However, the T¹⁷⁶⁴G¹⁷⁶⁶ double mutant may form a binding site for HNF3. Thus, position 1757 affects the emergence of promoter double mutants and would predict a relative genotypic restriction of both the T¹⁷⁶²A¹⁷⁶⁴ and the T¹⁷⁶⁴G¹⁷⁶⁶ double mutants.

The GenBank/EMBL/DDBJ accession numbers for the sequences and primer sequences reported in this study are DQ102486–DQ102557.