Effects of structural variations of APOBEC3A and APOBEC3B genes in chronic hepatitis B virus infection.
OBJECTIVE
Human APOBEC3 deaminases induce G to A hypermutation in nascent DNA strand of hepatitis B virus (HBV) genomes and seem to operate as part of the innate antiviral immune system. We analyzed the importance of APOBEC3A (A3A) and APOBEC3B (A3B) proteins, which are potent inhibitors of adeno-associated-virus and long terminal repeat (LTR)-retrotransposons, in chronic HBV infection.


METHODS
We focused on the common deletion polymorphism that spans from the 3' part of A3A gene to the 3' portion of A3B gene. An association study was carried out in 724 HBV carriers and 469 healthy control subjects. We also analyzed hypermutated genomes detected in deletion and insertion (non-deletion) homozygous patients to determine the effect of APOBEC3 gene deletion. Further, we performed functional analysis of A3A gene by transient transfection experiments.


RESULTS
The association study showed no significant association between deletion polymorphism and chronic HBV carrier state. Context analysis also showed a negligible effect for the deletion. Rather, mild liver fibrosis was associated with APOBEC gene deletion homozygosity, suggesting that A3B deletion is not responsible for chronic HBV infection. Functional analysis of A3A showed that overexpression of A3A induced hypermutation in HBV genome, although the levels of hypermutants were less than those introduced by A3G. However, overexpression of A3A did not decrease replicative intermediates of HBV.


CONCLUSIONS
These results suggest that A3A and A3B play little role in HBV elimination through anti-viral defense mechanisms. The significance of hypermutation induced by A3A should be investigated further.
Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Japan.
Hiromi
H
Abe
Hidenori
H
Ochi
Toshiro
T
Maekawa
Tsuyoshi
T
Hatakeyama
Masataka
M
Tsuge
Shosuke
S
Kitamura
Takashi
T
Kimura
Daiki
D
Miki
Fukiko
F
Mitsui
Nobuhiko
N
Hiraga
Michio
M
Imamura
Yoshifumi
Y
Fujimoto
Shoichi
S
Takahashi
Yusuke
Y
Nakamura
Hiromitsu
H
Kumada
Kazuaki
K
Chayama