Understanding HBcrAg components improves the interpretation of clinical HBcrAg assay results

Clinical efficacy of a novel, high-sensitivity HBcrAg assay in the management chronic hepatitis B and HBV reactivationJournal HepatologyVol. 75Issue 2PreviewA fully automated, novel core-related antigen (iTACT-HBcrAg) has been developed. We demonstrate clinical utility iTACT-HBcrAg for monitoring (CHB) early detection reactivation. Full-Text PDF Reply to: “Understanding components improves interpretation results”Journal 4PreviewWe thank Hong Hu1 their interest our article2 we also Journal Hepatology opportunity to reply thoughtful discussion on nature HBcrAg. appreciate questions, but does not influence major conclusion that quantitative assay, iTACT-HBcrAg, could be useful monitor responses HBeAg-negative patients detect read with great paper by Inoue et al. development its application e (HBeAg)-negative reactivation.[1]Inoue T. Kusumoto S. Iio E. Ogawa Suzuki Yagi al.Clinical reactivation.J Hepatol. 2021; 75: 302-310Abstract Full Text PubMed Scopus (24) Google Scholar Without doubt, this sensitivity current is timely ongoing pursuit an cure. However, few important issues need clarified. Firstly, authors used HBeAg chemiluminescence enzyme immunoassay (CLEIA) select patients. CLEIA may have lower detecting than assays. Thus, “HBeAg-negative” study might truly HBeAg-negative. The should clarify limits HBeAg-specific vs. Secondly, employed OptiPrep gradient fractionation define concluded detected before reactivation represented empty virion particles containing so-called 22-kDa precore protein (p22cr).[1]Inoue characterization was incomplete entirely correct. recently characterized based biochemical biophysical properties.[2]Hong X. Luckenbaugh L. Mendenhall M. Walsh R. Cabuang Soppe al.Characterization precore/core-related antigens.J Virol. 95 (e01695-20)Crossref (25) Scholar,[3]Hong Perlman D. Revill P.A. Wieland S.F. Menne antigens animal models virus infection.Hepatology. https://doi.org/10.1002/hep.31720Crossref (15) found includes core or HBcAg (10%), p22cr predominantly (80%).[2]Hong Indeed, both p22cr, which renamed PreC owing closer relatedness protein, contain multiple species resulting from genotype-specific C-terminal processing common precursor p25. PreC/p22cr shared similar properties (e.g. buoyant density size) HBeAg, neither nor forms capsids virions.[2]Hong In contrast, main sole component virions,[2]Hong Scholar,[4]Ning Liu K. Bruss V. Sureau C. Hu J. Common distinct capsid surface requirements secretion complete genome-free virions.J 2018; 92 (e00272-18)Crossref (39) virions (i.e. enveloped devoid DNA RNA) are formed absence no PreC/p22cr).[4]Ning Scholar,[5]Ning Nguyen Mentzer Adams Lee H. Ashley al.Secretion virus--single strand blocking model morphogenesis para-retrovirus.PLoS Pathog. 2011; 7e1002255Crossref (130) Although mechanism PreC/p22cr, retains N-terminal signal peptide, remains mysterious, concentrations always proportional (ca. 10 20%) HBV-infected primary human hepatocytes chimpanzees, HBeAg-positive patients.[2]Hong glycosylated as well eAg, woodchuck virus-infected woodchucks.[3]Hong Together, these results strongly indicate like involves cellular secretory pathway where glycosylation occurs. it extremely unlikely can produced any secretion, when cannot produced. suggest fractions 11 13 (Fig. 7A) fraction 12 7B) actually particles, instead proposed,[1]Inoue assuming patient As demonstrated,[2]Hong HBcAg-specific antibodies, do cross-react either point. If kU values converted mass units picograms), would facilitate results, such those presented Table S10, terms contribution overall quantity Thirdly, repeated reference plasma 990776 previous study[1]Inoue Scholar,[6]Kimura Ohno N. Terada Rokuhara A. Matsumoto al.Hepatitis DNA-negative dane lack without arginine-rich domain.J Biol Chem. 2005; 280: 21713-21719Abstract (109) S3). difficult interpret presented. referred “peaks” analysis using sucrose fractionation.[6]Kimura It compare profiles 2 different approaches (sucrose OptiPrep) separate studies directly. supposedly peaks were separated at all figure. How HBsAg (spheres filaments), (empty complete), fractionate will more vigorously defined solid conclusions made regarding association physical entities. regard, shown CsCl reliably entities.[2]Hong Lastly, believe better understanding fundamental biology guide improved marker intrahepatic covalently closed circular levels activity, allowing us natural course infection antiviral treatments. First, Our recent helped number regard.[2]Hong Second, each component, separately, allow precise viral activity mechanisms HBcAg, follow same kinetics during following treatments.[3]Hong particular, highly sensitive cross-reactivity informative, especially cases promoter coding sequence mutations lead reduction elimination (but HBcAg) actual loss transcriptional activity. Furthermore, therapies, e.g. targeting protein,[7]Viswanathan U. Mani Z. Ban Du Y. al.Targeting multifunctional potential cure B.Antivir Res. 2020; 182: 104917Crossref (28) affect differently, require PreC/p22cr. received financial support produce manuscript. XH: Writing draft; JH: Critical revision. declare conflicts pertain work. Please refer accompanying ICMJE disclosure further details. supplementary data article: Download .pdf (.15 MB) Help pdf files Multimedia 1