Variations and mutations in the hepatitis B virus genome and their associations with clinical characteristics

Table 1 Position of hepatitis B virus regions and transcripts

ORF	Protein	Position	Amino acids	Protein
Pre-S/S	Pre-S1	2854-3211	119	LHBs
	Pre-S2	3211-155	55	MHBs/LHBs
	S	155-835	226	SHBs/MHBs/LHBs
P	P	2357-1623	843	Polymerase
X	X	1374-1838	154	HBxAg
Pre-C/C	Pre-C	1814-1901	29	HBeAg, HBcAg
	C	1901-2458	183

ORF: Open reading frame; S: Surface protein; LHBs: Hepatitis B large surface protein; MHBs: Hepatitis B medium surface protein; SHBs: Hepatitis B small surface protein; P: Polymerase; HBxAg: Hepatitis B X antigen; C: Core; HBeAg: Hepatitis B e antigen; HBcAg: Hepatitis B c antigen.

Table 2 Hepatitis B virus subtypes and genotypes and their geographic distributions

Genotype/subgenotype	Geographic location
A
A1	Saharan Africa, India
A2	Northern Europe
A3	Western Africa
B
B1 (Bj)	Japan
B2-5	East and Southeast Asia
B6	Alaska, Northern Canada
C
C1-3	Taiwan, China, South Korea, Southeast Asia
C4	Australia
C5	Philippines, Vietnam
D
D1-5	Africa, Europe, Mediterranean countries and India
E	West Africa
F	Central and South America
G	France, Germany, United States
H	Central America
I	Vietnam and Laos
J	Ryukyu, Japan (Kalimantan)

Table 3 Nucleotide alignment of polymerase region among different genotypes

Position	169	173	180		184		202		204			207		213						221					231		236		238		248		250
Consensus	I1	V1	L1	A1	T	-	S1	Y	M1	D	D	V	-	S	V	Q	H	L	-	F	T	A	V	-	L	-	N1	P	N	-	N	F	M1
A1_AY233288_SouthAfrica	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	Y	-	-	-	-	-	-	-	-	-	-	-	-	-
A2_AJ309370_France	-	-	-	-	-	-	-	-	-	-	-	-	-	T	-	-	-	R	-	Y	-	-	-	-	-	-	-	-	-	-	-	-	-
B1_D23679_Japan	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	Y	A	-	-	-	-	-	-	-	H	-	-	-	-
B2_AB073639_Taiwan	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	Y	A	-	-	-	-	-	-	-	H	-	-	-	-
B3_M54923_Indonesia	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	Y	A	-	-	-	-	-	-	-	Q	-	-	-	-
C1_AB112471_Thailand	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	S	I	-	-	-	-	-	-	-	-	-	-
C2_AB014376_Japan	-	-	-	-	-	-	-	-	-	-	-	-	-	T	-	-	-	-	-	-	-	S	I	-	-	-	-	-	-	-	-	-	-
D1_FJ386590_China	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	H	-	-
D2_JF754597_Turkey	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	H	-	-
D3_EU594434_Estonia	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
E_X75664_Senegal	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	R	-	-	-	Y	-	S	-	-	-	-	-	-	-	-	-	-	-
F_AF223963_Argentina	-	-	-	-	-	-	-	-	-	-	-	L	-	-	-	-	-	-	-	Y	-	-	-	-	V	-	-	T	S	-	-	-	-
G_AB064312_United States	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	Y	-	-	-	-	-	-	-	-	D	-	-	-	-
I_AB241408_Vietnam	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	Y	-	-	-	-	-	-	-	-	-	-	-	-	-

¹Indicated the known antiviral resistant against nucleos(t)ide analogue.

Table 4 Representative mutations and clinical characteristics

Region	Mutation	Clinical characteristics
Pre-S/S	P120S/E, K122R, T126A, P127T, Q129H/R, L134S, K141E, P142S, D144A/E/V, G145R/A	OBI/HBsAg decrease
	Pre-S deletion	HCC
Pre-C/C	A1896T, G1899A	HBe seroconversion HCC
X	C1653T, T1753C, A1762T, G1764A	HCC
P	L180M, A181V, T184G, S202I, M204V/I N236T, M250V	NA resistance

S: Surface; OBI: Occult hepatitis B virus infection; HCC: Hepatocellular carcinoma; HBe: Hepatitis B e; HBsAg: Hepatitis B s antigen.

Table 5 Mutations associated with resistance to nucleos(t)ide analogues

Nucleos(t)ide analogue	Resistance-conferring mutations
Lamivudine	I169T, V173L, L180M, T184G, S202G, M204V/I, M250V
Adefovir	A181V/T, N236T
Entecavir	I169T, V173L, L180M, T184G, S202G, M204V/I, M250V
Telbivudine	I169T, V173L, L180M, T184G, S202G, M204V/I, M250V
Tenofovir	N236T