The Hepatitis B Virus Nucleocapsid—Dynamic Compartment for Infectious Virus Production and New Antiviral Target

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.

Fast Magic‐Angle‐Spinning NMR Reveals the Evasive Hepatitis B Virus Capsid C‐Terminal Domain**

“…We here aim to recover the lost resonances of the functional C-terminal domain (CTD) of the hepatitis B virus (HBV) capsid, which almost completely escaped detection by virtually all structural methods used until now, despite its central role in many important aspects of virion formation and maturation. [30] For this, we need to resolve the question whether, in the fast-spinning experiments we employ, the disappearance of resonances is due to line broadening beyond detection or to inefficient polarization transfer due to largely averaged dipolar couplings, and use this information to derive experiments able to detect the resonances. 15 N two-spin system with the parameters of an amide group in a protein and an order parameter of S = 0 (strongest broadening) at MAS frequencies between 25 and 250 kHz.…”

Multiple Regions Drive Hepatitis Delta Virus Proliferation and Are Therapeutic Targets

“…In HBV mono-infection, HBsAg is overexpressed in the endoplasmic reticulum and partially buds to the multivesicular body to bind to the HBV core particles ( Niklasch et al, 2021 ). Mature HBV particles contain an equimolar proportion of the three forms of HBsAg ( Sureau et al, 1993 ) and are secreted through the endosomal sorting complex required for transport-dependently multivesicular body (ESCRT/MVB) pathway ( Lambert et al, 2007 ; Watanabe et al, 2007 ).…”

Pharmacomodulation of a ligand targeting the HBV capsid hydrophobic pocket

“…The interdimer contacts are mediated by the last 30 residues of the assembly domain, including helix a5. The currently most advanced anti-Cp drugs are the Capsid Assembly Modulators (CAMs), 9 all targeting the interdimer interface in the capsid and interfering with the assembly of proper, genome containing nucleocapsids (as recently reviewed in 2,10,11 ). A new and unexplored option to interfere with nucleocapsid dynamics in general, and nucleocapsid envelopment in particular, is offered by the hydrophobic pocket formed in the Cp dimer at the base of the spike (Fig.…”