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832
AMINO ACID POLYMORPHISM IN HEPATITIS B VIRUS
ASSOCIATED WITH NATURAL CLEARANCE OF HBV DNA AND
HBsAg
Takashi Honda1, Norie Yamada2, Asako Murayama2,
Asuka Kato1, Takanori Ito1, Yoji Ishizu1, Teiji Kuzuya1,
Masatoshi Ishigami1, Yoshiki Murakami3, Tetsuya Ishikawa1,
Mitsuhiro Fujishiro1 and Takanobu Kato2, (1)Department
of Gastroenterology and Hepatology, Nagoya University
Graduate School of Medicine, (2)Department of Virology II,
National Institute of Infectious Diseases, (3)Department of
Molecular Pathology, Tokyo Medical University
Background: Patients with chronic hepatitis B develop
liver cirrhosis and hepatocellular carcinoma along with
the progress of hepatitis However, some of these patients
naturally stabilize without treatment and eventually achieve a
favorable status with low HBV DNA and normal ALT; in some
cases, these patients also exhibit loss of HBsAg (Functional
cure: FC) The exact factors and detailed mechanisms
involved with FC are still unknown To provide an adequate
treatment strategy for the patients with chronic hepatitis B, it is
essential to know which patients are expected to have a good
prognosis and who does not require therapeutic intervention
Previously, we identified the substitution of isoleucine to
leucine at amino acid 97 (I97L) in the hepatitis B core region
as a key predictor among patients with stable hepatitis In this
study, we aimed to identify the point at which I97L affects the
HBV lifecycle and to clarify the underlying mechanisms for
the establishment of stable disease Methods: To confirm
the clinical aspect of I97L, we used a cohort of hepatitis B
e antigen (HBeAg)-negative patients with chronic hepatitis B
infected with HBV-I97 wild-type (wt) or -I97L The effects of
I97L on viral characteristics were evaluated by in vitro HBV
production and infection systems with the HBV reporter virus
and cell culture-generated HBV Results: HBeAg-negative
patients were divided into two groups according to the
amino acid, isoleucine (HBV-I97wt) or leucine (HBV-I97L),
at position 97 in the HBc region Thirty-seven patients were
included in the HBV-I97L-infected group and 40 patients
in the HBV-I97wt-infected group The annual reduction of
HBsAg in patients with HBV-I97L was significantly greater
than that in those with HBV-I97wt (-0 25 ± 0 28 vs -0 12 ±
0 22 log IU/mL, P = 0 029) The annual reduction of HBV DNA
in patients with HBV-I97L was also significantly greater than
that with those with HBV-I97wt (-0 36 ± 0 53 vs -0 12 ± 0 44
log copies/mL, P = 0 030) Undetectable rates of HBsAg and
HBV DNA in patients with HBV-I97L were significantly higher
in patients with HBV-I97wt (8 1% and 10 8% vs 27 5% and
35 0%, P=0 028 and 0 012, respectively) HBV-I97L exhibited
lower infectivity compared to HBV-I97wt in both infection
systems with reporter HBV and cell culture-generated HBV
HBV-I97L virions exhibiting low infectivity mainly contained a
single-stranded HBV genome. The lower efficiency of cccDNA
synthesis was demonstrated after infection of HBV-I97L or
transfection of the molecular clone of HBV-I97L Conclusion:
The I97L substitution reduces the efficiency of both infection
and recycling dependent cccDNA synthesis through the
generation of immature virions with single-stranded genomes
This I97L-associated low efficiency of cccDNA synthesis
seems to be involved in the establishment of stable hepatitis
Further study on this mutation would be the hint for the FC
mechanism. |
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发表于 2020-10-31 17:08