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World J Gastroenterol. Oct 14, 2016; 22(38): 8489-8496
Published online Oct 14, 2016. doi: 10.3748/wjg.v22.i38.8489
Elucidation of the early infection machinery of hepatitis B virus by using bio-nanocapsule
Qiushi Liu, Masaharu Somiya, Shun’ichi Kuroda
Qiushi Liu, Masaharu Somiya, Shun’ichi Kuroda, Department of Biomolecular Science and Reaction, The Institute of Scientific and Industrial Research, Osaka University, Ibaraki 567-0047, Japan
Author contributions: Liu Q performed the majority of the writing, and prepared the figures; Somiya M provided the input in writing the paper; Kuroda S designed the outline and coordinated the writing of the paper.
Conflict-of-interest statement: There is no conflict of interest associated with any of the senior author or other coauthors contributed their efforts in this manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Shun’ichi Kuroda, PhD, Professor, Department of Biomolecular Science and Reaction, The Institute of Scientific and Industrial Research, Osaka University, Ibaraki 567-0047, Japan. skuroda@sanken.osaka-u.ac.jp
Telephone: +81-6-68798460 Fax: +81-6-68798464
Received: May 1, 2016
Peer-review started: May 2, 2016
First decision: June 20, 2016
Revised: July 19, 2016
Accepted: August 5, 2016
Article in press: August 5, 2016
Published online: October 14, 2016
Abstract

Currently, hepatitis B virus (HBV), upon attaching to human hepatocytes, is considered to interact first with heparan sulfate proteoglycan (HSPG) via an antigenic loop of HBV envelope S protein. Then, it is promptly transferred to the sodium taurocholate cotransporting polypeptide (NTCP) via the myristoylated N-terminal sequence of pre-S1 region (from Gly-2 to Gly-48, HBV genotype D), and it finally enters the cell by endocytosis. However, it is not clear how HSPG passes HBV to NTCP and how NTCP contributes to the cellular entry of HBV. Owing to the poor availability and the difficulty of manipulations, including fluorophore encapsulation, it has been nearly impossible to perform biochemical and cytochemical analyses using a substantial amount of HBV. A bio-nanocapsule (BNC), which is a hollow nanoparticle consisting of HBV envelope L protein, was efficiently synthesized in Saccharomyces cerevisiae. Since BNC could encapsulate payloads (drugs, genes, proteins) and specifically enter human hepatic cells utilizing HBV-derived infection machinery, it could be used as a model of HBV infection to elucidate the early infection machinery. Recently, it was demonstrated that the N-terminal sequence of pre-S1 region (from Asn-9 to Gly-24) possesses low pH-dependent fusogenic activity, which might play a crucial role in the endosomal escape of BNC payloads and in the uncoating process of HBV. In this minireview, we describe a model in which each domain of the HBV L protein contributes to attachment onto human hepatic cells through HSPG, initiation of endocytosis, interaction with NTCP in endosomes, and consequent provocation of membrane fusion followed by endosomal escape.

Keywords: Bio-nanocapsule, Endosomal escape, Hepatitis B virus, Heparan sulfate proteoglycan, Sodium taurocholate cotransporting polypeptide

Core tip: Owing to the poor availability and the difficulty of manipulations of hepatitis B virus (HBV), it has been difficult to analyze its early infection events in human hepatocytes. Using a bio-nanocapsule, a unique model of HBV, we could study these events by biochemical and cytochemical methods, and finally identify a low pH-dependent fusogenic domain in HBV pre-S1 region, which might play a pivotal role in the endosomal escape of HBV. We hereby postulate a model in which each domain in HBV envelope L protein participates in cell attachment, endocytosis, membrane fusion, and consequent endosomal escape (i.e., uncoating process of HBV).