Sodium taurocholate cotransporting polypeptide inhibition efficiently blocks hepatitis B virus spread in mice with a humanized liver

Tasuku Nakabori, Hayato Hikita, Kazuhiro Murai, Yasutoshi Nozaki, Yugo Kai, Yuki Makino, Yoshinobu Saito, Satoshi Tanaka, Hiroshi Wada, Hidetoshi Eguchi, Takeshi Takahashi, Hiroshi Suemizu, Ryotaro Sakamori, Naoki Hiramatsu, Tomohide Tatsumi, Tetsuo Takehara

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11 Citations (Scopus)

Abstract

Sodium taurocholate cotransporting polypeptide (NTCP) is a recently discovered hepatitis B virus (HBV) receptor. In the present study, we used TK-NOG mice with a humanized liver to examine the impact of endogenous NTCP expression on HBV infection. Upon inoculation with HBV, these mice exhibited clear viremia in 2 weeks, and serum HBV DNA levels gradually increased. The frequency of HBsAg-positive hepatocytes in the liver was 5.1 ± 0.6% at 2 weeks and increased with increasing HBV DNA levels, reaching 92.9 ± 2.8% at 10 to 12 weeks. In vivo siRNA-mediated NTCP knockdown before and after HBV inoculation significantly suppressed the levels of HBV replication and the frequency of HBsAg-positive hepatocytes at 2 weeks, whereas NTCP knockdown 13 weeks after infection did not affect these parameters. Similar to the humanized mouse livers in the early phase of HBV infection, human liver samples from chronic hepatitis B patients, especially those treated with nucleos(t)ide analogues, contained a considerable number of hepatocytes that were negative for the anti-HBs antibody. In conclusion, NTCP inhibition prevents the spread of HBV-infected hepatocytes in mice with a humanized liver. NTCP-targeted therapy has potential for regulating HBV infection in patients with chronic hepatitis B.

Original languageEnglish
Article number27782
JournalScientific reports
Volume6
DOIs
Publication statusPublished - Jun 9 2016

All Science Journal Classification (ASJC) codes

  • General

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