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 (105·2±1·8 vs 103·2±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.
Arauz-RuizP.,
NorderH.,
VisonáK. A.,
MagniusL. O.1997; Genotype F prevails in HBV infected patients of hispanic origin in Central America and may carry the precore stop mutant. J Med Virol 51:305–312[CrossRef]
BaptistaM.,
KramvisA.,
KewM. C.1999; High prevalence of 1762T 1764A mutations in the basic core promoter of hepatitis B virus isolated from black Africans with hepatocellular carcinoma compared with asymptomatic carriers. Hepatology 29:946–953[CrossRef]
BaumertT. F.,
RogersS. A.,
HasegawaK.,
LiangT. J.1996; Two core promoter mutations in a hepatitis B virus strain associated with fulminant hepatitis result in enhanced viral replication. J Clin Invest 98:2268–2276[CrossRef]
BozdayiA. M.,
BozkayaH.,
TürkyilmazA.,
AslanN.,
VerdiH.,
KenceA.,
UzunalimogluÖ.1999; Polymorphism of precore region of hepatitis B virus DNA among patients with chronic HBV infection in Turkey. Infection 27:357–360[CrossRef]
BrunettoM. R.,
GiarinM. M.,
OliveriF.8 other authors1991; Wild-type and e antigen-minus hepatitis B viruses and course of chronic hepatitis. Proc Natl Acad Sci U S A 88:4186–4190[CrossRef]
BuckwoldV. E.,
XuZ.,
ChenM.,
YenT. S. B.,
OuJ.-H.1996; Effects of a naturally occurring mutation in the hepatitis B virus basal core promoter on precore gene expression and viral replication. J Virol 70:5845–5851
CarmanW. F.,
JacynaM. R.,
HadziyannisS.,
KarayiannisP.,
McGarveyM. J.,
MakrisA.,
ThomasH. C.1989; Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet ii588–591
ChanH. L. Y.,
HussainM.,
LokA. S. F.1999; Different hepatitis B virus genotypes are associated with different mutations in the core promoter and precore regions during hepatitis B e antigen seroconversion. Hepatology 29:976–984[CrossRef]
ChanH. L. Y.,
LeungN. W. Y.,
HussainM.,
WongM. L.,
LokA. S. F.2000; Hepatitis B e antigen-negative chronic hepatitis B in Hong Kong. Hepatology 31:763–768[CrossRef]
ChangM. H.,
HsuH. Y.,
NiY. H.,
TsaiK. S.,
LeeP. I.,
ChenP. J.,
HsuY. L.,
ChenD. S.1998; Precore stop codon mutant in chronic hepatitis B virus infection in children: its relation to hepatitis B e seroconversion and maternal hepatitis B surface antigen. J Hepatol 28:915–922[CrossRef]
ErhardtA.,
ReinekeU.,
BlondinD.,
GerlichW. H.,
AdamsO.,
HeintgesT.,
NiederauC.,
HäussingerD.2000; Mutations of the core promoter and response to interferon treatment in chronic replicative hepatitis B. Hepatology 31:716–725[CrossRef]
FattovichG.,
RuggeM.,
BrolloL.,
PontissoP.,
NoventaF.,
GuidoM.,
AlbertiA.,
RealdiG.1986; Clinical, virologic and histologic outcome following seroconversion from HBeAg to anti-HBe in chronic hepatitis type B. Hepatology 6:167–172[CrossRef]
FunkM. L.,
RosenbergD. M.,
LokA. S. F.2002; World-wide epidemiology of HBeAg-negative chronic hepatitis B and associated precore and core promoter variants. J Viral Hepat 9:52–61[CrossRef]
GandheS. S.,
ChadhaM. S.,
WalimbeA. M.,
ArankalleV. A.2003; Hepatitis B virus: prevalence of precore/core promoter mutants in different clinical categories of Indian patients. J Viral Hepat 10:367–382[CrossRef]
GernerP.,
LauschE.,
FriedtM.,
TratzmüllerR.,
SpangenbergC.,
WirthS.1999; Hepatitis B virus core promoter mutations in children with multiple anti-HBe/HBeAg reactivations result in enhanced promoter activity. J Med Virol 59:415–423[CrossRef]
GüntherS.,
PiwonN.,
WillH.1998; Wild-type levels of pregenomic RNA and replication but reduced pre-C RNA and e-antigen synthesis of hepatitis B virus with C(1653)→T, A(1762)→T and G(1764)→A mutations in the core promoter. J Gen Virol 79:375–380
HadziyannisS. J.1995; Hepatitis B e antigen negative chronic hepatitis B: from clinical recognition to pathogenesis and treatment. Viral Hepatitis Rev 1:7–36
HadziyannisS. J.,
LiebermanH. M.,
KarvountzisG. G.,
ShafritzD. A.1983; Analysis of liver disease, nuclear HBcAg, viral replication, and hepatitis B virus DNA in liver and serum of HBeAg vs. anti-HBe positive carriers of hepatitis B virus. Hepatology 3:656–662
HoofnagleJ. H.,
DusheikoG. M.,
SeeffL. B.,
JonesE. A.,
WaggonerJ. G.,
BalesZ. B.1981; Seroconversion from hepatitis B e antigen to antibody in chronic type B hepatitis. Ann Intern Med 94:744–748[CrossRef]
JardiR.,
RodriguezF.,
ButiM.7 other authors2004; Mutations in the basic core promoter region of hepatitis B virus. Relationship with precore variants and HBV genotypes in a Spanish population of HBV carriers. J Hepatol 40:507–514[CrossRef]
KaoJ.-H.,
ChenP.-J.,
LaiM.-Y.,
ChenD.-S.2003; Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers. Gastroenterology 124:327–334[CrossRef]
Kidd-LjunggrenK.,
ÖbergM.,
KiddA. H.1997; Hepatitis B virus X gene 1751 to 1764 mutations: implications for HBeAg status and disease. J Gen Virol 78:1469–1478
KondiliL. A.,
BrunettoM. R.,
MainaA. M.,
ArgentiniC.,
ChionneP.,
La SorsaV.,
ResuliB.,
MeleA.,
RapicettaM.2005; Clinical and molecular characterization of chronic hepatitis B in Albania: a country that is still highly endemic for HBV infection. J Med Virol 75:20–26[CrossRef]
KurosakiM.,
EnomotoN.,
AsahinaY.,
SakumaI.,
IkedaT.,
TozukaS.,
IzumiN.,
MarumoF.,
SatoC.1996; Mutations in the core promoter region of hepatitis B virus in patients with chronic hepatitis B. J Med Virol 49:115–123[CrossRef]
LarasA.,
KoskinasJ.,
HadziyannisS. J.2002; In vivo suppression of precore mRNA synthesis is associated with mutations in the hepatitis B virus core promoter. Virology 295:86–96[CrossRef]
LiJ.-S.,
TongS.-P.,
WenY.-M.,
VitvitskiL.,
ZhangQ.,
TrépoC.1993; Hepatitis B virus genotype A rarely circulates as an HBe-minus mutant: possible contribution of a single nucleotide in the precore region. J Virol 67:5402–5410
LiJ.,
BuckwoldV. E.,
HonM.,
OuJ.1999; Mechanism of suppression of hepatitis B virus precore RNA transcription by a frequent double mutation. J Virol 73:1239–1244
NorderH.,
HammasB.,
LöfdahlS.,
CouroucéA.-M.,
MagniusL. O.1992; Comparison of the amino acid sequences of nine different serotypes of hepatitis B surface antigen and genomic classification of the corresponding hepatitis B virus strains. J Gen Virol 73:1201–1208[CrossRef]
NorderH.,
HammasB.,
LeeS.-D.,
BileK.,
CouroucéA.-M.,
MushahwarI. K.,
MagniusL. O.1993; Genetic relatedness of hepatitis B viral strains of diverse geographical origin and natural variations in the primary structure of the surface antigen. J Gen Virol 74:1341–1348[CrossRef]
OkamotoH.,
YotsumotoS.,
AkahaneY.7 other authors1990; Hepatitis B viruses with precore region defects prevail in persistently infected hosts along with seroconversion to the antibody against e antigen. J Virol 64:1298–1303
OkamotoH.,
TsudaF.,
AkahaneY.,
SugaiY.,
YoshibaM.,
MoriyamaK.,
TanakaT.,
MiyakawaY.,
MayumiM.1994; Hepatitis B virus with mutations in the core promoter for an e antigen-negative phenotype in carriers with antibody to e antigen. J Virol 68:8102–8110
RealdiG.,
AlbertiA.,
RuggeM.,
BortolottiF.,
RigoliA. M.,
TremoladaF.,
RuolA.1980; Seroconversion from hepatitis B e antigen to anti-HBe in chronic hepatitis B virus infection. Gastroenterology 79:195–199
SatoS.,
SuzukiK.,
AkahaneY.8 other authors1995; Hepatitis B virus strains with mutations in the core promoter in patients with fulminant hepatitis. Ann Intern Med 122:241–248[CrossRef]
ScaglioniP. P.,
MelegariM.,
WandsJ. R.1997; Biologic properties of hepatitis B viral genomes with mutations in the precore promoter and precore open reading frame. Virology 233:374–381[CrossRef]
TakedaK.,
AkahaneY.,
SuzukiH.,
OkamotoH.,
TsudaF.,
MiyakawaY.,
MayumiM.1990; Defects in the precore region of the HBV genome in patients with chronic hepatitis B after sustained seroconversion from HBeAg to anti-HBe induced spontaneously or with interferon therapy. Hepatology 12:1284–1289[CrossRef]
TillmannH.,
TrautweinC.,
WalkerD.,
MichitakaK.,
KubickaS.,
BokerK.,
MannsM.1995; Clinical relevance of mutations in the precore genome of the hepatitis B virus. Gut 37:568–573[CrossRef]