HBV RNA virion-like particles produced under nucleos(t)ide analogues treatment are mainly replication-deficient

Wang, Jie; Sheng, Qiuju; Ding, Yang; Chen, Ran; X, Sun; Chen, Xiangmei; Dou, Xiaoguang; Lu, Fengmin

doi:10.1016/j.jhep.2017.10.030

Cited by 28 publications

(44 citation statements)

References 11 publications

(12 reference statements)

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“…As a result, the progeny HBV virions produced under NA treatment may contain only incomplete, dead‐end HBV genomic DNA and are thus mainly noninfectious. In addition, previous studies also revealed the lack of preS1 NTCP‐binding domain in the RNA virion‐like particles produced under the NA treatment . In this study, we demonstrated that NAs inhibit HBV replication in cultured hepatocytes, PHH, as well as in vivo in patients with the anticipated mode of action.…”

Section: Discussionsupporting

confidence: 62%

“…HBV DNA and RNA in sera specimens collected from a cohort of 10 pregnant women were quantified by the four PCR assays in parallel. As previously described, all these individuals had high levels of HBV DNA and received LdT therapy to prevent the mother‐to‐child transmission . Briefly, the serum specimens were collected at four time points: pretreatment (baseline), 4‐8 weeks of treatment and 12 weeks of treatment at perinatal period, as well as 5‐6 weeks after delivery with LdT withdraw.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, as expected, but different from a recent report, the levels of serum HBV RNA are highest in the PreC/C region and declined from the S region to X region. Notably, HBV‐RNA level may also be affected by the RNA splicing‐variants given that some of them lack the S region, particularly after NA treatment . Therefore, in order to more accurately monitor viral level and determine the residual activity of HBV replication under NA therapies, we strongly recommend to measure viral load and serum HBV RNA by qPCR assays that detect the X gene region and PreC/C region, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Such prematurely terminated viral DNA would result in the generation of incomplete dead‐end HBV DNA in intracellular nucleocapsids and secreted virion‐like particles. We noticed, in a recent work that, in spite of approximately 10 4 copies/mL of HBV‐DNA–containing virions detected in serum specimens of pregnant women at the time of delivery, NA treatment could successfully eradicated the mother‐to‐infant vertical transmission . This phenomenon impelled us to investigate whether HBV virions produced under NA therapy are infectious.…”

mentioning

confidence: 99%

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Hepatitis B Virus Virions Produced Under Nucleos(t)ide Analogue Treatment Are Mainly Not Infectious Because of Irreversible DNA Chain Termination

Liu

et al. 2019

Hepatology

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Nucleos(t)ide analogues (NAs) have been widely used for the treatment of chronic hepatitis B (CHB). Because viral DNA polymerase lacks proofreading function (3′ exonuclease activity), theoretically, the incorporated NAs would irreversibly terminate viral DNA synthesis. This study explored the natures of nascent hepatitis B virus (HBV) DNA and infectivity of progeny virions produced under NA treatment. HBV infectivity was determined by infection of HepG2‐NTCP cells and primary human hepatocytes (PHHs). Biochemical properties of HBV DNA in the progeny virions were investigated by qPCR, northern blotting, or Southern blotting hybridization, sucrose gradient centrifugation, and in vitro endogenous DNA polymerase assay. Progeny HBV virions produced under NA treatment were mainly not infectious to HepG2‐NTCP cells or PHHs. Biochemical analysis revealed that under NA treatment, HBV DNA in nucleaocapsids or virions were predominantly short minus‐strand DNA with irreversible termination. This finding was supported by the observation of first disappearance of relaxed circular DNA and then the proportional decline of HBV‐DNA levels corresponding to the regions of PreC/C, S, and X genes in serial sera of patients receiving NA treatment. Conclusion: HBV virions produced under NA treatment are predominantly replication deficient because the viral genomes are truncated and elongation of DNA chains is irreversibly terminated. Clinically, our results suggest that the viral loads of CHB patients under NA therapy vary with the different regions of genome being detected by qPCR assays. Our findings also imply that NA prevention of perinatal and sexual HBV transmission as well as infection of transplanted livers works not only by reducing viral loads, but also by producing noninfectious virions.

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Section: Discussionsupporting

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Hepatitis B Virus Virions Produced Under Nucleos(t)ide Analogue Treatment Are Mainly Not Infectious Because of Irreversible DNA Chain Termination

Liu

et al. 2019

Hepatology

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“…If the pgRNA‐containing virions do exist, it would be interesting to know whether they are infectious and could establish a new round of infection. Wang et al reported that HBV RNA virion‐like particles produced by NA treatment are infection‐deficient . However, because NA‐treated pgRNA virion is a dead‐end due to the irreversible chain termination effect of NA, the above study does not rule out the potential infectivity of untreated pgRNA virion.…”

Section: Serum Hbv Rna In the Viral Life Cyclementioning

confidence: 91%

Serum Hepatitis B Virus RNA: A New Potential Biomarker for Chronic Hepatitis B Virus Infection

et al. 2019

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Chronic hepatitis B infection is one of the major etiological causes of liver failure, cirrhosis, and hepatocellular carcinoma (HCC) worldwide. This condition cannot be completely cured by currently available drugs due to the persistent existence of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), the bona fide transcription template for HBV RNAs, in infected hepatocytes. Because quantifying cccDNA per se requires an invasive procedure, serum biomarkers reflecting intrahepatic cccDNA activity are warranted. Recently, a growing body of research suggests that the circulating HBV RNA may serve as a serum biomarker for HBV infection, treatment, and prognosis. In order to delineate the molecular and clinical characteristics of serum HBV RNA, we systematically reviewed the available literature on serum HBV RNA dating back to the early 1990s. In this review, we summarize the reported serum HBV RNA quantification methods and discuss the potential HBV RNA species in patient serum. We also compare the reported correlations of serum HBV RNA with other serological markers, including HBV DNA, hepatitis B surface antigen, e antigen, and core‐related antigen, as well as their correlations with intrahepatic cccDNA, to assess their potential in clinical applications. Future directions for serum HBV RNA research are also discussed.

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Serum Hepatitis B Virus RNA as a Potential Diagnostic Biomarker During Chronic Hepatitis B Virus Infection

Cloherty

Butler

Kuhns

2019

Clinical Liver Disease

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HBV RNA virion-like particles produced under nucleos(t)ide analogues treatment are mainly replication-deficient

Cited by 28 publications

References 11 publications

Hepatitis B Virus Virions Produced Under Nucleos(t)ide Analogue Treatment Are Mainly Not Infectious Because of Irreversible DNA Chain Termination

Hepatitis B Virus Virions Produced Under Nucleos(t)ide Analogue Treatment Are Mainly Not Infectious Because of Irreversible DNA Chain Termination

Serum Hepatitis B Virus RNA: A New Potential Biomarker for Chronic Hepatitis B Virus Infection

Serum Hepatitis B Virus RNA as a Potential Diagnostic Biomarker During Chronic Hepatitis B Virus Infection

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