Dataset Information

Transbody against virus core protein potently inhibits hepadnavirus replication in vivo: evidence from a duck model of hepatitis B virus.

ABSTRACT:

Background and purpose

The therapeutic management of hepatitis B virus (HBV) infections remains challenging, and novel antiviral strategies are urgently required. The HBV transbody, a monoclonal antibody (MAb) against human HBcAg coupled with the trans-activator of transcription protein transduction domain (TAT PTD), was previously shown to possess cell-penetrating ability and potent antiviral activity in vitro. The purpose of the present study was to evaluate the antiviral activity of the HBcMAb-TAT PTD conjugate in vivo in a duck model of HBV.

Experimental approach

Female Peking ducks were injected i.p. with 0.03-0.3 mg·kg^-1 ·day^-1 of the DHBV transbody (DHBcMAb-TAT PTD conjugate) for 30 days. Serum DHBV DNA levels and liver DHBV DNA and covalently closed circular DNA (cccDNA) loads were determined at scheduled time points. Immunohistological examination of DHBcAg in the duck liver was also performed.

Key results

The DHBV transbody significantly reduced the serum and liver DHBV DNA levels at doses of 0.1 and 0.3 mg·kg^-1 ·day^-1 and liver cccDNA levels at a dose of 0.3 mg·kg^-1 ·day^-1 after 30 days of treatment. The suppressive effects of the DHBV transbody at 0.3 mg·kg^-1 ·day^-1 on the serum and liver DHBV DNA and liver cccDNA levels remained significant, even at 15 days after treatment cessation. Similarly, immunohistochemistry of liver sections revealed decreased DHBcAg levels within hepatocytes 15 days after treatment termination.

Conclusions and implications

The DHBV transbody inhibits DHBV replication and possesses potent anti-DHBV activities in vivo. The cell-permeable antibody against the virus core antigen may be developed as a novel treatment for patients with hepadnavirus infections.

SUBMITTER: Li Y

PROVIDER: S-EPMC5481659 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Publications

Transbody against virus core protein potently inhibits hepadnavirus replication in vivo: evidence from a duck model of hepatitis B virus.

Li Yiping Y Liu Zhengwen Z Hui Lingyun L Liu Xi X Feng Ai A Wang Wei W Zhang Lin L Li Na N Zhou Guoqing G Wang Quanli Q Han Qunying Q Lv Yi Y Wang Quanying Q Yang Guangxiao G Wang Yawen Y

British journal of pharmacology 20170607 14

<h4>Background and purpose</h4>The therapeutic management of hepatitis B virus (HBV) infections remains challenging, and novel antiviral strategies are urgently required. The HBV transbody, a monoclonal antibody (MAb) against human HBcAg coupled with the trans-activator of transcription protein transduction domain (TAT PTD), was previously shown to possess cell-penetrating ability and potent antiviral activity in vitro. The purpose of the present study was to evaluate the antiviral activity of t ...[more]

PMID: 28383135

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Project description:Hepatitis B virus (HBV) core protein (HBc) contains an N-terminal domain (NTD, assembly domain) and a C-terminal domain (CTD), which are linked by a flexible linker region. HBc plays multiple essential roles in viral replication, including capsid assembly, packaging of the viral pregenomic RNA (pgRNA) into nucleocapsids, viral reverse transcription that converts pgRNA to the genomic DNA, and secretion of DNA-containing (complete) virions or genome-free (empty) virions. The HBc linker is generally assumed to act merely as a spacer between NTD and CTD but some results suggest that the linker may affect NTD assembly. To determine its role in viral replication, we have made a number of deletion and substitution mutants in the linker region, in either the presence or absence of CTD, and tested their abilities to support capsid assembly and viral replication in human cells. Our results indicate that the linker could indeed impede NTD assembly in the absence of CTD, which could be partially relieved by partial linker deletion. In contrast, when CTD was present, the linker deletions or substitutions did not affect capsid assembly. Deletion of the entire linker or its C-terminal part resulted in a partial defect in pgRNA packaging and severely impaired viral DNA synthesis. In contrast, deletion of the N-terminal part of the linker, or substitutions of the linker sequence, had little to no effect on RNA packaging or first-strand DNA synthesis. However, the N-terminal linker deletion and two linker substitution mutants were defective in the production of mature double-stranded viral DNA. Secretion of empty virions was blocked by all the linker deletions and substitutions tested. In particular, a conservative linker substitution that allowed mature viral DNA synthesis and secretion of complete virions severely impaired the secretion of empty virions, thus increasing the ratio of complete to empty virions that were secreted. Together, these results demonstrate that the HBc linker region plays critical and complex roles at multiple stages of HBV replication.

Dataset Information

Transbody against virus core protein potently inhibits hepadnavirus replication in vivo: evidence from a duck model of hepatitis B virus.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Transbody against virus core protein potently inhibits hepadnavirus replication in vivo: evidence from a duck model of hepatitis B virus.

Similar Datasets

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