Page 124 - Read Online

Page 2 of 8 Ding et al. Hepatoma Res 2019;5:10 I http://dx.doi.org/10.20517/2394-5079.2018.115

of developing serious liver complications, such as cirrhosis, hepatic failure, and primary hepatocellular
carcinoma. Although the application of anti-HBV drugs [i.e., nucleos(t)ide analogues and pegylated
interferon (peg-IFN)] can effectively suppress HBV replication and decrease the occurrence of corresponding
[2]
complications, still more than 680,000 patients die of the fatal consequences of CHB every year . The
proportion of cirrhosis and liver cancer caused by HBV infection is about 30% and 45% worldwide. In
[3]
China, the proportion is 60% and 80%, which is much higher . Therefore, it is urgent to acquire a better
understanding of virus-host interaction to develop new therapeutics that increases the HBV cure rate.

HBV is an enveloped DNA virus which contains a 3.2 kb circular, partially double-stranded DNA genome.
HBV establishes its genome as a covalently closed circular DNA (cccDNA) in the nucleus of the infected
[4]
hepatocytes . In the life cycle of HBV, the transcription of cccDNA to generate HBV mRNA is the
beginning of HBV replication and the key factor for the continuous infection. Therefore, cccDNA is the
most direct evidence of HBV infection and replication in vivo. Since the detection of cccDNA counts on
biopsy, which is an invasive procedure, it is warrant to find some serum biomarkers that reflect the activity
of intrahepatic cccDNA. The cccDNA is transcribed to 5 mRNAs during the viral replication. One of these
transcripts, the pregenomic RNA (pgRNA) is not only the template for reversing transcription of viral
[5]
DNA but also the coding mRNA for core protein and polymerase of HBV (pol) . Recently, an increasing
number of studies suggest that the HBV RNA can also be detected in serum. Circulating HBV RNA is HBV
[6-8]
pgRNA and it may be used as a new serum biomarker for HBV infection, treatment and prognosis . Thus,
further comprehension of HBV pgRNA may provide new horizon for the better understanding the virus-
host interaction and the development of new HBV therapeutics. In this paper, we will review the current
knowledge on the clinical significance of HBV RNA and its biological impact on host liver cells.

THE ORIGIN AND NATURE OF HBV RNA
The life cycle of HBV begins with the invasion of viral particles containing a 3.2-kb long partially
double-stranded genome called relaxed circular DNA (rcDNA) into the hepatocytes through the sodium
taurocholate co-transporting polypeptide (NTCP) receptor. The rcDNA is converted into cccDNA when
[9]
coming into the nucleus . The cccDNA plays a role as the transcription template for all the viral transcripts,
involving the 3.5 kb pgRNA and precore mRNA (pre-C RNA), the 2.4 kb and 2.1 kb surface mRNAs,
[10]
and a 0.7 kb X mRNA . Among the 5 HBV mRNA, pgRNA not only serves as the template for reverse
[11]
transcription of HBV, but also is the template for translation of pol and core proteins . The 5’-ε region of
[12]
pgRNA has the ability to combine with the pol. Once combined, they are packaged into viral capsid . And
inside the capsid, with the assist of the pol, pgRNA produces rcDNA through reverse transcription. Since
newly created viral capsids can re-infect the nucleus, a small part of the newly formed rcDNAs re-enter into
the nucleus to replenish the cccDNA pool. The remaining capsids are enveloped by the viral surface protein
[13]
and released as Dane particles to infect new cells . A recent research shows that HBV RNA can be detected
in the serum of CHB patients, especially in those who have been taking antiviral drugs for a long time
with their serum HBV DNA low or even undetectable. The research also revealed that serum HBV RNA is
pgRNA which was presented in the virion-like particles, and serum pgRNA is produced by the transcription
[8]
of cccDNA inside the hepatocytes . The discovery of HBV RNA virion-like particle may complete the
traditional life cycle of HBV infection. In theory, after the encapsidated pgRNAs get into hepatocytes, the
reverse transcription to form rcDNA and cccDNA might be restarted, and this process eventually leads to
HBV re-infection. However, more and stronger evidences are needed to prove the infection potential of HBV
RNA virion-like particles.

ROLES OF HBV RNA IN HBV-ASSOCIATED DISEASES
HBV RNA not only is the template for both viral DNA reverse transcription and viral protein synthesis,
but also plays a crucial role in the pathogenesis of HBV-associated diseases. Recently, many studies reveal