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J Hepatol. 2016 Oct;65(4):700-710. doi: 10.1016/j.jhep.2016.05.029. Epub 2016 May 28.

Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound.

Author information

1
State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
2
Assembly Biosciences, Inc., San Francisco, CA, USA.
3
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China.
4
Clinical Epidemiology and EBM Unit, Being Friendship Hospital, Capital Medical University, China.
5
Hepatology Unit and Key Laboratory for Organ Failure Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
6
The Pirbright Institute, Pirbright, UK.
7
Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China. Electronic address: gaozl@21cn.com.
8
Department of Infectious Diseases, Institute of Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. Electronic address: renhong0531@vip.sina.com.
9
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China. Electronic address: nsxia@xmu.edu.cn.
10
State Key Laboratory of Natural and Biomimetic Drugs, Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. Electronic address: lu.fengmin@hsc.pku.edu.cn.

Abstract

BACKGROUND & AIMS:

Hepatitis B virus (HBV) RNA in serum has recently been linked to efficacy and prognosis of chronic hepatitis B (CHB) treatment. This study explored the nature, origin, underlying mechanisms, and potential clinical significance of serum HBV RNA.

METHODS:

The levels of HBV DNA and RNA were determined in the supernatant of induced HepAD38, HBV-expressing HepG2.2.15 cells and primary human hepatocytes (PHH), and in the serum of transgenic mice and CHB patients. NP-40 and proteinase K treatment, sucrose density gradient centrifugation, electron microscopy, northern blot, multiple identification PCRs and 5' rapid-amplification of cDNA ends were performed to identify the nature of serum HBV RNA.

RESULTS:

Although significantly lower than HBV DNA levels, abundant HBV RNA was present in the serum of CHB patients. A series of experiments demonstrated that serum HBV RNA was pregenome RNA (pgRNA) and present in virus-like particles. HBV pgRNA virion levels increased after blocking the reverse transcription activity of HBV DNA polymerase, and decreased after blocking the encapsidation of pgRNA. Furthermore, the presence of HBV pgRNA virion was associated with risk of viral rebound after discontinuation of nucleot(s)ide analogues (NAs) therapy in CHB patients.

CONCLUSIONS:

Serum HBV RNA was confirmed to be pgRNA present in virus-like particles. HBV pgRNA virions were produced from encapsidated particles in which the pgRNA was non- or partially reverse transcribed. Clinically, HBV pgRNA virion might be a potential biomarker for monitoring safe discontinuation of NA-therapy.

LAY SUMMARY:

HBV may have another virion form in which the nucleic acid is composed of RNA, not DNA. The level of HBV RNA virion in serum may be associated with risk of HBV viral rebound after withdrawal of treatment, and therefore, a potential predictive biomarker to monitor the safe discontinuation of nucleot(s)ide analogues-therapy.

KEYWORDS:

HBV pgRNA virion; Hepatitis B virus; Nucleot(s)ide analogues therapy

PMID:
27245431
DOI:
10.1016/j.jhep.2016.05.029
[Indexed for MEDLINE]
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