Circulating HBV RNA: From biology to clinical applications

Abstract

Chronic HBV infection can hardly be cured due to the persistence of an intrahepatic pool of viral covalently closed circular DNA (cccDNA) transcription template, which is refractory to current antivirals. The direct analyses of cccDNA quantity and transcriptional activity require an invasive biopsy. Recently, circulating HBV RNA has been identified as a promising noninvasive surrogate marker of cccDNA and can be used for monitoring disease progression and predicting prognosis of patients with chronic HBV infection. To better understand this surrogate biomarker of cccDNA, we reviewed the current knowledge about the molecular characteristics and potential clinical applications of circulating HBV RNA. Specifically, we summarized the reported species and existing forms of circulating HBV RNA and discussed their biogenesis and the capacity of de novo infection by RNA virions. Moreover, we described the potential applications of circulating HBV RNA in different clinical scenarios, such as classifying the phases of chronic HBV infection, analyzing sustained on‐treatment and off‐treatment outcomes of treated patients, as well as predicting HCC development. Perspectives on future research of circulating HBV RNA were also proposed in this review.

Hepatitis B virus movement through the hepatocyte: An update

“…Moreover, in animal models, like immunocompromised HBV‐transgenic mice or HBV‐infected humanized chimeric mice, only very low levels of naked capsids were detectable (Hong et al., 2021). Although the physiological relevance of naked capsids must be confirmed beyond doubt, they may carry HBV‐specific DNA and RNA species (Deng et al., 2022; Liu et al., 2019) and have been shown to be competent for clathrin‐mediated endocytosis (Cooper & Shaul, 2006). Accordingly, their uptake may enhance transmission of HBV genomes.…”

Characterization of hepatitis B viral forms from patient plasma using velocity gradient: Evidence for an excess of capsids in fractions enriched in Dane particles

“…First, we confirmed the circulation of enveloped HBV-RNA containing particles in plasmas [ 15 ]. These particles were present in lower fractions together with Dane particles, both in velocity and density gradients.…”

Characterization of a Novel Capsid Assembly Modulator for the Treatment of Chronic Hepatitis B Virus Infection

“…In addition to inhibiting the production of HBV virions, we show that GS-SBA-1, but not TAF, can also prevent the production of extracellular HBV RNA-containing particles. We and others have demonstrated that circulating HBV RNA particles, which can contain various HBV RNAs, including HBx transcripts, are present in cell culture-derived virus preparations and the serum of CHB patients ( 38 , 43 , 44 ). Circulating HBV RNAs have been linked with an increased risk of HCC ( 45 , 46 ).…”

“…It has been suggested that HBV RNAs may directly promote HCC development through interactions with host oncogenes and/or increased intrahepatic inflammation and fibrosis ( 47 , 48 ). HBV DNA integration, which is considered to play a role in HCC development, may also lead to the production of circulating HBV RNAs ( 43 ). Additionally, HBV RNA transcripts potentially could directly express HBx protein upon infection in a cccDNA-independent manner to support cccDNA transcription by antagonizing host restriction factors such as the SMC5/6 complex ( 38 , 44 ).…”