Hepatitis B virus (HBV) infection is a global public health problem, with approximately 296 million people chronically infected with HBV worldwide and about 820,000 people dying each year from HBV-related liver disease. After the formation of chronic HBV infection, the virus covalent closed loop DNA (cccDNA) can be stable in the hepatocellular nucleus for a long time, making hepatitis B difficult to cure. The currently approved antiviral drugs - nucleoside (acid) analogues (NUCs) and interferons can effectively inhibit viral replication, but they cannot clear the cccDNA in the liver, so that the vast majority of patients have relapsed after stopping the drug. In clinical practice, direct evaluation of the intrahepatic cccDNA pool requires invasive liver puncture biopsy, which is less acceptable to patients, so effective non-invasive alternatives to monitor intrahepatic HBV activity are urgently needed. Traditional HBV serum markers, including HBV DNA, HBsAg, and HBeAg, have been reported to reflect the replication activity of intrahepatic viruses in patients in their natural state, but in the NUC antiviral therapy state, traditional viral markers have difficulty accurately reflecting the transcriptional activity of cccDNA in patients' livers. As a direct downstream product of intrahepatic cccDNA, HBV RNA has attracted much attention in recent years, effectively reflecting the amount and transcriptional activity of cccDNA in hepatic patients with hepatitis B, and has important clinical value in predicting anti-HBV treatment response and liver disease progression.
Recently, Professor Sun Jian of the Department of Infectious Medicine, Southern Hospital of Southern Medical University and Professor Guo Haitao of the University of Pittsburgh systematically introduced the molecular characteristics of serum HBV RNA and its clinical application prospects, and provided an important direction for the further study of serum HBV RNA. The review was published online on March 28, 2022 in Hepatology (IF=17.43).
HBV belongs to the hepatophiliac DNA virus family, and its genome is about 3.2 kb long partial double-stranded loose ring DNA (rcDNA). When the virus infects liver cells through the NTCP receptor, rcDNA is transported into the nucleus, forming a cccDNA microchromosome. cccDNA can be transcribed using the host's RNA polymerase II to produce five mRNAs with the same 3' end, namely 3.5 kb long preC-RNA and pgRNA, 2.4/2.1 kb long mRNA encoding surface antigens (S mRNA), and 0.7 kb long mRNA encoding X protein (X mRNA). Previous studies have reported that HBV RNA in serum is mainly pgRNA, but its length varies, including full-length pgRNA, 3' terminal truncated pgRNA and spliced pgRNA. In addition, the presence of HBV RNA in serum is also more complex. In vitro experiments have found that HBV RNA in the cellular supernatant is coated in a nucleocapsid composed of HBcAg, which can or may not cover the viral outer membrane HBsAg; however, in the serum of hepatitis B patients, HBV RNA particles without viral outer membrane are found to exist in the form of nucleocapsid-antibody complexes (CACs). The previous research of Professor Guo Haitao and Professor Sun Jian's team found that the HBV RNA particles wrapped in the viral outer membrane are secreted exocular through the multi-vesicle body (MVB) pathway, just like the HBV DNA virus particles, but the secretion route of the naked capsid HBV RNA particles has not yet been clarified. In addition, some scholars have proposed that serum HBV RNA may also be present in the form of exosomes in the patient's serum and cellular supernatant, but there is currently less evidence for this part (Figure 1).
Figure 1 Molecular characteristics and potential clinical application scenarios of serum HBV RNA
Multiple studies have shown a good correlation between serum HBV RNA levels and intrahepatic cccDNA quantification, which is expected to serve as a marker reflecting intrahepatic cccDNA levels and their transcriptional activity. At present, the exploration of clinical application scenarios of serum HBV RNA mainly includes the following four aspects: (1) the value in distinguishing the natural history of HBV infection; (2) the value of predicting the patient's treatment response; (3) the value of predicting the recurrence of patients after NUC discontinuation; (4) the value of predicting the occurrence of hepatocellular carcinoma (HCC) (Figure 1). Among them, serum HBV RNA has important application value in predicting the recurrence of patients after NUC discontinuation and predicting the occurrence of HCC, and the relevant international guidelines or consensus have gradually recommended the use of serum HBV RNA, a new viral marker, to guide clinical diagnosis and treatment activities.
There are still many problems to be solved in serum HBV RNA-related studies. In terms of basic research, the specific molecular characteristics and biological functions of serum HBV RNA in different disease states need to be further clarified, such as whether HBV RNA virus-like particles in the natural state have the ability to be de novo infected; in terms of clinical applications, the quantitative method of serum HBV RNA needs to be further standardized, and the correlation between serum HBV RNA and HCC occurrence and development still needs to be further verified by prospective, multicenter and large-sample clinical studies.
This article features Professor Sun Jian of Southern Hospital of Southern Medical University and Professor Guo Haitao of the University of Pittsburgh as the corresponding author, Deng Rui, a 2021 doctoral student in the Department of Infectious Internal Medicine of Southern Hospital of Southern Medical University, and Liu Shi, a doctoral student of 2019, as co-first authors. Director Hou Jinlin and Professor Sun Jian's team of Nanfang Hospital have long been committed to the basic and translational medicine research of chronic hepatitis B, focusing on the molecular characteristics and clinical significance of serum HBV RNA in recent years, and have been funded by a number of natural science funds. The research team's series of research results around serum HBV RNA in the past three years have been published in internationally renowned journals, including 5 Hepatology (Chinese Academy of Sciences Subclass 1, IF=17.43), 1 Clin Gastroenterol Hepatol (CAS Subclass 1, IF=11.38), 2 Aliment Pharmacol Ther (CAS Subclass 1, IF=8.17), and 1 PLoS Pathog (CAS Subclass 1, IF=6.82), 1 Clin Infect Dis (CAS Subclass 1, IF=9.08), 2 J Infect Dis (CAS Subclass 1, IF=5.23) and 1 Antiviral Res (CAS Subclass 2, IF=5.97). The high-sensitivity serum HBV RNA quantification method established by the team has been authorized by the national invention patent and is currently realizing product transformation.
文献来源：Deng R, Liu S, Shen S, Guo H, Sun J. Circulating hepatitis B virus RNA: From biology to clinical applications. Hepatology. 2022 Mar 28. doi: 10.1002/hep.32479.
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