Quantification of hepatitis B virus (HBV) surface antigen (HBsAg) is important in the management of chronic HBV infection. HBsAg levels for example, are useful for predicting response to pegylated interferon alfa, or differentiating phases of chronic HBV infection.1 HBsAg levels may become even more important with new emerging therapies aimed at functional HBV cure.2
However, several factors such as the virus genome, virus host interactions or co‐infections influence HBsAg concentrations (Figure 1). Figure 1Open in figure viewerPowerPoint
Virus and host factors determining HBsAg production and secretion. (A) HBV‐infected hepatocytes produce HBsAg via specific HBV mRNAs from episomal cccDNA and/or from linear HBV genomes integrated into the host genome. The three HBV surface proteins (LHBs, MHBs, SHBs) are translated and further modified at the endoplasmic reticulum (ER) and the Golgi apparatus and secreted as subviral particles (filaments and 20 nm spheres) via the secretory pathway. Only the circular cccDNA form can serve as a template for generation of HBV overlength pregenomic RNA (pgRNA) that is translated into core proteins, polymerase and is packaged into immature core particles that undergo reverse transcription within the cytosol. Budding of virions and subsequent secretion involves multivesicular bodies (MVB). Integrated monomeric HBV genomes are not capable of producing pgRNA and hence virion progeny, but they can be a source of (i) HBsAg even in the absence of HBV ccccDNA, (ii) transcomplementation of subviral particle production and (iii) envelopment of virions generated via cccDNA. (B) Major viral and host factors contributing to detection of different levels of HBsAg via quantitative HBsAg test assays (qHBsAg). Factors mainly associated with HBsAg serum levels according to the study of Cavallone et al. are highlighted in dark orange
HBsAg is produced both from episomal covalently closed circular DNA (cccDNA) and from integrated linear HBV DNA.3 The preS/S gene encodes three HBV surface proteins: Large (LHBs), middle (MHBs) and small (SHBs). The expression of these proteins is controlled by virus‐specific promoters and enhancers in defined protein ratios to form either the envelope of budding virions or the surplus of secreted, non‐infectious subviral particles that constitute serum HBsAg.4 Differences in the expression/secretion pattern of preS/S gene products should therefore impact serum HBsAg levels, and different HBV genotypes and/or mutations could be selected as a consequence of the host immune response.5, 6 Previous studies have suggested that preS/S mutations are associated with lower or higher HBsAg levels.5, 7
In this issue of AP&T , Brunetto et al8 investigated the effect of genetic variability of the preS/S gene on HBsAg levels in 260 HBeAg‐negative Italian patients.
In this homogeneous cohort of genotype D‐infected patients, HBsAg levels were unaffected by preS/S sequence. In contrast, age and HBV DNA, however, influenced HBsAg concentrations. The prevalence of preS mutations was lower than in other cohorts showing an effect of preS mutations on HBsAg levels. The authors concluded that long‐lasting HBV DNA control in their cohort of inactive carriers contributes to low transcriptional activity of the cccDNA. The Italian patients may also have had a shorter immune clearance phase, during which mutations are selected by immune pressure. Accordingly, patients with progressive chronic hepatitis B disease (CHB) showed higher preS/S variability, which correlated with increasing age, reflecting duration of infection. Of note, patients with CHB had higher HBsAg levels than inactive carriers but similarly in this group, age and HBV DNA were the only factors associated with HBsAg by multivariate analysis. Interestingly, patients with cirrhosis had higher preS/S variability but lower HBsAg compared to CHB patients without cirrhosis. The influence of HBV integrations, as the major source of HBsAg, might also be higher in long‐term infected HBeAg negative patients than in HBeAg positive patients. Thus, the data suggest that HBsAg levels depend on a complex biological network of circulating viral variants, and can usually not be only attributable to an isolated preS mutation affecting HBsAg production/secretion pattern in cell culture.
Overall, interpreting the determination of serum HBsAg levels is complex, and may depend on an interplay of viral genetic variants, the host immune response, the duration of infection and the stage of liver cirrhosis. Thus, HBsAg levels should always be interpreted in the context of multiple different factors as illustrated in Figure 1.
ACKNOWLEDGEMENT Declaration of personal interests: Markus Cornberg has received personal fees for lectures and/or consulting from Abbvie, Bristol‐Myers Squibb, Gilead Sciences, Janssen‐Cilag, Roche, Merck/MSD, Biogen, Falk Foundation, Siemens, Spring Bank, GlaxoSmithKline, SOBI. Dieter Glebe has received research funding from Fresenius Medical Care. 作者: StephenW 时间: 2020-8-3 19:02
PDF