Sodium taurocholate cotransporting polypeptide inhibition efficiently blocks hepatitis B virus spread in mice with a humanized liver.
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.
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Tasuku
T
Nakabori
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Hayato
H
Hikita
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Kazuhiro
K
Murai
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Yasutoshi
Y
Nozaki
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Yugo
Y
Kai
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Yuki
Y
Makino
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Yoshinobu
Y
Saito
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Satoshi
S
Tanaka
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Hiroshi
H
Wada
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Hidetoshi
H
Eguchi
Department of Laboratory Animal Research, Central Institute for Experimental Animals, Kawasaki, Japan.
Takeshi
T
Takahashi
Department of Laboratory Animal Research, Central Institute for Experimental Animals, Kawasaki, Japan.
Hiroshi
H
Suemizu
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Ryotaro
R
Sakamori
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Naoki
N
Hiramatsu
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Tomohide
T
Tatsumi
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Tetsuo
T
Takehara
D000328:Adult; D000368:Aged; D000818:Animals; D004279:DNA, Viral / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D006509:Hepatitis B / Q000378:metabolism* / Q000821:virology; D006514:Hepatitis B Surface Antigens / Q000378:metabolism; D006515:Hepatitis B virus / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000276:immunology / Q000821:virology; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics* / Q000378:metabolism*; D027981:Symporters / Q000235:genetics* / Q000378:metabolism*; D014766:Viremia / Q000821:virology*; D053586:Virus Internalization; D014779:Virus Replication
D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C071908:sodium-bile acid cotransporter