Abstract
Hepatitis B virus (HBV) is a small enveloped DNA virus which replicates its tiny 3.2 kb genome by reverse transcription inside an icosahedral nucleocapsid, formed by a single ~180 amino acid capsid, or core, protein (Cp). HBV causes chronic hepatitis B (CHB), a severe liver disease responsible for nearly a million deaths each year. Most of HBV’s only seven primary gene products are multifunctional. Though less obvious than for the multi-domain polymerase, P protein, this is equally crucial for Cp with its multiple roles in the viral life-cycle. Cp provides a stable genome container during extracellular phases, allows for directed intracellular genome transport and timely release from the capsid, and subsequent assembly of new nucleocapsids around P protein and the pregenomic (pg) RNA, forming a distinct compartment for reverse transcription. These opposing features are enabled by dynamic post-transcriptional modifications of Cp which result in dynamic structural alterations. Their perturbation by capsid assembly modulators (CAMs) is a promising new antiviral concept. CAMs inappropriately accelerate assembly and/or distort the capsid shell. We summarize the functional, biochemical, and structural dynamics of Cp, and discuss the therapeutic potential of CAMs based on clinical data. Presently, CAMs appear as a valuable addition but not a substitute for existing therapies. However, as part of rational combination therapies CAMs may bring the ambitious goal of a cure for CHB closer to reality.
Highlights
Hepatitis B virus (HBV), the etiological agent of acute and chronic hepatitis B (CHB)in humans, is a hepatotropic small enveloped DNA virus that replicates through reverse transcription
As many Cp mutations affecting capsid envelopment contribute to this pocket, we proposed that occupancy of the pocket by a natural pocket factor, either cellular or viral, is involved in signaling readiness for envelopment
This cysteine (C-7) forms a specific intramolecular disulfide bond with C61 [55] which completely changes the way in which hepatitis B e antigen (HBeAg) dimerizes [54] (Figure 5B,C) compared to Cp and prevents it from assembling into particles the entire assembly domain of Cp is present
Summary
Hepatitis B virus (HBV), the etiological agent of acute and chronic hepatitis B (CHB). Most patients are instead treated with one of the six FDA approved and better tolerated nucleos(t)ide analogs (NUCs) which inhibit reverse transcription by the multidomain HBV polymerase (P protein). Approved and better tolerated nucleos(t)ide analogs (NUCs) which inhibit reverse transcription by the multidomain HBV polymerase (P protein). Is Translation of pgRNA yields Cp from the first and P protein from the second ORF; the latter initiation mechanism is still unclear. NUC therapy is necessary for most patients because, despite dampened inflammation, HBsAg seroclearance is rare This is in part due to mRNA transcription liver. RNA-containing nucleocapsids is largely blocked by NUCs, viral antigens, and immature. As cccDNA may persist for decades, HBV reactivation can even occur long after a past past self-limited acute hepatitis B [8] when immune control is lost by an unrelated disease self-limited acute hepatitis B [? We intend to provide a comprehensive and comprehensible overview on the functional dynamics of HBV Cp in the viral life-cycle, on the basics of the underlying biochemical and structural dynamics, and on up-to-date clinical data on the therapeutic use of CAMs against CHB
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