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

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• 作者：Jie Wang¹ ; ^&dagger ; ; Tao Shen¹ ; ^&dagger ; ; Xiangbo Huang¹ ; ^&dagger ; ; G. Renuka Kumar² ; ^&dagger ; ; Xiangmei Chen¹ ; Zhenzhen Zeng¹ ; Ruiyang Zhang¹ ; Ran Chen¹ ; Tong Li¹ ; Tianying Zhang³ ; Quan Yuan³ ; Pao-Chen Li² ; Qi Huang² ; Richard Colonno² ; Jidong Jia⁴ ; Jinlin Hou⁵ ; Malcolm A. McCrae⁶ ; Zhiliang Gao⁷ ; ^{gaozl@21cn.com" class="auth_mail" title="E-mail the corresponding author} ; Hong Ren⁸ ; ^{renhong0531@vip.sina.com" class="auth_mail" title="E-mail the corresponding author} ; Ningshao Xia³ ; ^{nsxia@xmu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Hui Zhuang¹ ; Fengmin Lu¹ ; ^{lu.fengmin@hsc.pku.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HBV ; hepatitis B virus ; cccDNA ; covalently closed circular DNA ; pgRNA ; pregenome RNA ; NAs ; nucleot(s)ide analogues ; CHB ; chronic hepatitis B ; HCC ; hepatocellular carcinoma ; ETV ; entecavir ; LMV ; lamivudine ; EoT ; end of treatment ; ADV ; adefovir dipivoxil ; LdT ; telbivudine
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：65
• 期：4
• 页码：700-710
• 全文大小：1738 K

文摘

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.