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HBcAg

The core antigen (HBcAg) is a 21-kDa multifunctional protein encoded by the (HBV) core , serving as the primary building block of the viral that encloses the partially double-stranded genome and the viral polymerase within an icosahedral nucleocapsid structure. This antigen is essential for viral assembly and , forming stable, non-enveloped particles approximately 27-34 nm in diameter that are detectable in infected hepatocytes but not in the bloodstream, distinguishing it from other HBV antigens like the surface (HBsAg) or e-antigen (HBeAg). HBcAg's presence in liver signifies active viral in both acute and chronic HBV infections, making it a critical diagnostic indicator, while its high elicits robust humoral and cellular immune responses that contribute to viral clearance or persistence. Structurally, HBcAg monomers dimerize through interactions at their C-termines, with each dimer featuring a central α-helical protruding from the surface, enabling into two polymorphic icosahedral forms: the T=3 with 180 subunits (arranged as 90 dimers) or the T=4 with 240 subunits (120 dimers). High-resolution crystallographic and cryo-electron microscopy studies have revealed an unusual predominantly α-helical fold for HBcAg, with atomic details showing four major domains per protomer that facilitate inter-dimer contacts and RNA binding during genome packaging. These structural features, resolved to 3.3 Å and 3.5 Å, underscore HBcAg's role in stabilizing the virion and its adaptability, as seen in genotype-specific variations like those in HBV genotype , which form unique core-like particles. Functionally, beyond capsid formation, HBcAg interacts with host factors to regulate viral and may influence cellular pathways, including trafficking via its arginine-rich C-terminal domain for pregenomic encapsidation. Immunologically, HBcAg acts as both a T-cell-independent and T-cell-dependent , driving strong production (anti-HBc) that persists lifelong as a marker of resolved or ongoing , and eliciting cytotoxic T-lymphocyte responses central to HBV control. Its particulate nature enhances immunogenicity compared to soluble antigens like HBeAg, positioning HBcAg as a prime target for therapeutic vaccines and monoclonal antibodies aimed at disrupting viral persistence. As of 2025, capsid assembly modulators (CAMs) that target HBcAg by disrupting capsid formation are in advanced clinical development and demonstrate potent antiviral effects.

Discovery and nomenclature

Historical discovery

The discovery of (HBV) markers began with Blumberg's identification of the Australia antigen, later recognized as the hepatitis B surface antigen (HBsAg), in 1965 during studies of serum proteins in patients. This breakthrough provided the first serological marker for HBV infection, prompting further investigations into the virus's structure through electron microscopy in the late 1960s, which revealed spherical viral particles known as Dane particles in 1970. The core antigen (HBcAg) was first described in 1971 by June Almeida and colleagues, who used electron to visualize 27-nm core particles released from particles after treatment with non-ionic detergent, distinguishing this internal component from the envelope-associated . Shortly thereafter, techniques enabled the detection of HBcAg in liver biopsies from HBV-infected patients, confirming its localization in nuclei and associating its presence with active . These early observations, supported by serological studies in the 1970s, linked HBcAg expression to ongoing , with radioimmunoassays developed around 1974 improving sensitivity for detecting anti-HBc antibodies as indicators of recent or HBV exposure. Key advancements in the included electron microscopy studies by Almeida and others that further characterized core particles, solidifying HBcAg's role as the structural protein of the viral nucleocapsid. By the late , the cloning of the HBV genome in , achieved by Pierre Charnay and colleagues in 1979, facilitated the production of recombinant HBcAg, paving the way for non-invasive research tools and assays in the that reduced reliance on invasive liver biopsies.

Terminology and distinctions

HBcAg, or hepatitis B core antigen, is the standardized nomenclature for the major structural protein forming the nucleocapsid of the (HBV), established in the early 1970s during initial characterizations of HBV proteins to denote its role in the viral core and distinguish it from other key antigens like HBsAg () and HBeAg (hepatitis B e antigen, derived from the precore region of the genome). This terminology arose during early characterizations of HBV proteins following the identification of viral markers in the mid-1970s, providing a consistent framework for scientific communication in and . The International Committee on Taxonomy of Viruses (ICTV) later classified HBV within the family and the orthohepadnavirus genus, emphasizing HBcAg's centrality to human-infecting HBV strains. A primary distinction lies in HBcAg's intracellular localization and non-secreted nature, where it assembles into symmetric icosahedral s that package the viral genome, unlike HBeAg, which is a soluble, secreted protein generated from the same precore/core (ORF) but with an additional N-terminal extension of approximately 10-29 , including a that facilitates its export from hepatocytes to promote . HBcAg, by contrast, lacks this precore , ensuring its retention in the for formation and support, while HBeAg circulates in as a non-particulate dimer without structural involvement in the virion. These differences in processing and localization—HBcAg from the core yielding a 183-185 protein, and HBeAg from an upstream ATG in the 29-amino-acid precore region—highlight their divergent roles despite sharing about 77% colinearity. Related terms include HBcrAg (hepatitis B core-related antigen), a composite serological marker introduced in the early that detects denatured forms of HBcAg, HBeAg, and the precore intermediate p22cr (a 22-kDa protein spanning the precore and partial regions), enabling sensitive quantification in for assessing intrahepatic viral covalently closed circular DNA () activity and treatment response in chronic HBV infection. The precore/ gene ORF, spanning about 540 , orchestrates this dual production: translation from the core initiation codon produces HBcAg for assembly, while precore initiation yields the pre-pro form processed into mature HBeAg via signal peptidase cleavage. Evolutionarily, HBcAg demonstrates remarkable sequence across HBV genotypes A through H, with inter-genotypic divergence typically under 8% in the core region, preserving essential motifs for dimerization, binding, and assembly despite minor variations (e.g., 1-4% differences) that can subtly alter B-cell exposure and antigenicity without disrupting core identity or function. This underscores HBcAg's critical role in viral fitness, as evidenced by its low evolutionary rate compared to more variable regions, facilitating cross-genotype immunological targeting in diagnostics and vaccines.

Molecular structure

Primary and secondary structure

The core antigen (HBcAg) is a small consisting of 183 in most HBV genotypes (e.g., B, C, D, E, F), with genotype A extending to 185 residues due to a DR insertion between 153 and 154; its molecular weight is approximately 21 . The protein is encoded by the core (ORF) of the HBV genome, spanning nucleotides approximately 1901 to 2451 in the standard ayw subtype, which overlaps with the precore region but initiates translation at the second ATG to produce the mature core protein. Structurally, HBcAg comprises an N-terminal assembly domain (residues 1-149) responsible for dimerization and formation, followed by a flexible linker (residues 150-162), and a C-terminal domain (CTD; residues 163-183) that is rich in residues organized into four motifs (SR-rich blocks) for binding. HBcAg undergoes limited post-translational modifications, primarily phosphorylation within the CTD at conserved serine and threonine residues, including Ser155, Ser162, and Ser170 (numbered according to the 183-residue isoform), which are targeted by host kinases such as and CK2; these modifications regulate protein multimerization and subcellular trafficking without affecting overall stability. The protein lacks sites, consistent with its cytoplasmic synthesis and assembly in infected hepatocytes. The secondary structure of HBcAg is dominated by alpha-helices within the assembly domain, as revealed by of dimeric and forms at resolutions up to 3.3 Å; the structure features a long α-helical consisting of residues 50–73 (α3) and 79–110 (α4) that drives dimer interfaces through a four-helix bundle, with additional helices including α1 (13–17), α2 (27–43), and α5 (112–127). Beta-sheets are minimal and primarily confined to short segments at inter-helix junctions, while random coils and unstructured loops predominate in the N-terminal region (residues 1-49) and the flexible CTD, contributing to the protein's adaptability during assembly. Sequence conservation of HBcAg is high across HBV genotypes A through H, exceeding 95% identity overall, which underscores its essential role in viral architecture; notable variability occurs in the major hydrophilic region (MHR, residues 74-89), an immunodominant loop exposed on the surface that tolerates some substitutions while maintaining functionality.

Tertiary and quaternary structure

The tertiary structure of the HBcAg consists of a compact, predominantly α-helical fold comprising four major α-helices and two smaller ones, stabilized by a conserved hydrophobic core, with prominent spike protrusions formed by amphipathic helical hairpins at the dimer interface. Dimers, the basic building blocks of the , assemble through parallel interfaces in the N-terminal domain (residues 1–149), where hydrophobic interactions between the helical hairpins create a four-helix bundle, further reinforced by salt bridges and hydrogen bonds involving residues such as Asp78 and Arg127, forming asymmetric units essential for higher-order . At the quaternary level, HBcAg dimers self-assemble into icosahedral capsids exhibiting (180 subunits, approximately 32 in diameter) or (240 subunits, approximately 36 in diameter), with pentameric arrangements at the five-fold axes and hexameric clusters at the quasi-six-fold axes, as revealed by cryo-EM and . These structures feature a thin (about 2 thick) enclosing a central cavity, with surface pores approximately 1.5–2 in width at the five-fold axes facilitating potential import and export. The flexible C-terminal domain (CTD, residues 150–183) protrudes from the surface, contributing to multimerization and interactions with viral components, while structural studies, including the 3.3 Å of the T=4 and cryo-EM reconstructions, highlight a hydrophobic groove at dimer-dimer interfaces (involving residues near the of the assembly domain) that mediates inter-dimer contacts during formation. Variants include empty , which lack internal and exhibit similar morphology to RNA-filled ones but altered , and forms such as Y132A in the , which disrupt hydrophobic packing and prevent proper assembly, resulting in aberrant or incomplete particles.

Biological functions

Role in capsid assembly

The hepatitis B core antigen (HBcAg), also known as the core protein (), serves as the primary structural component of the viral , self-assembling into icosahedral particles that protect the viral genome. The basic unit of assembly is the Cp homodimer, formed through interactions in the N-terminal assembly domain (residues 1–149, or ARD), which creates a stable four-helix bundle stabilized by hydrophobic contacts and, under oxidizing conditions, a bond at 61. These dimers then polymerize into T=3 (90 dimers, ~32 nm diameter) or T=4 (120 dimers, ~36 nm diameter) s, with the latter being predominant under physiological conditions. Nucleation begins with the formation of a trimer of dimers, driven by inter-dimer contacts at the ARD interfaces, including A-A (fivefold symmetry) and B-C/C-D (quasi-sixfold) positions, where C-C spikes protrude at quasi-sixfold axes to facilitate . Interactions between the ARD and the flexible C-terminal (CTD, residues 150–183/185) initiate this by positioning arginine-rich motifs for transient stabilization, followed by rapid addition of further dimers to form pentamers and hexamers that close into a shell. This process exhibits sigmoidal , with as the rate-limiting step due to weak dimer-dimer binding energies (~3.5 kcal/mol), allowing error correction and favoring complete capsids over aberrant forms. In vitro assembly of recombinant Cp occurs rapidly, with a half-time of approximately 1 second for empty capsids under optimized conditions (e.g., pH 7.5, >250 mM NaCl, and protein concentrations of 0.5–2 mg/mL), reflecting the cooperative nature of . involves CTD phosphorylation at seven sites (six serines and one ), which introduces negative charges to increase domain flexibility, reduce nonspecific interactions, and prevent premature aggregation by inhibiting early oligomerization; dephosphorylated CTD mimics assemble more efficiently at low concentrations. Higher and neutral pH promote T=4 capsid formation by screening electrostatic repulsions, while deviations can shift toward incomplete structures. In vivo, assembly occurs spontaneously in the of infected hepatocytes once reaches a critical concentration (~300 ), utilizing host factors for but mirroring dynamics without requiring viral enzymes for the structural process. Recent studies indicate that assembly can also initiate in the , where HBcAg localizes early post-synthesis. Recombinant full-length or truncated expressed in heterologous systems like assembles into native-like virus-like particles (VLPs) under controlled conditions (e.g., codon-optimized vectors and mild denaturation-refolding), enabling scalable production for diagnostic and vaccine applications due to their stability and . Aberrant assembly arises from , particularly in the major hydrophilic region (MHR, residues ~–) within the ARD spikes, such as deletions (e.g., Y38-R39-E40) or insertions (e.g., EFGA after A11), which disrupt inter-dimer interfaces and yield filamentous, tubular, or irregular particles instead of closed icosahedrons; these malformed structures impair and by failing to mature properly.

Involvement in

HBcAg plays a central role in the packaging of the pregenomic (pgRNA) into nascent s during (HBV) replication. The arginine-rich domain (ARD) at the C-terminus of HBcAg, containing multiple positively charged residues, facilitates electrostatic interactions with the negatively charged pgRNA backbone, enabling selective encapsidation of the approximately 3.2 kb molecule. This is mediated by the flexible C-terminal tails of HBcAg dimers, which extend into the interior and recruit the viral polymerase () to initiate reverse transcription within the particle. Experimental studies using truncated HBcAg mutants demonstrate that reducing the net positive charge in the ARD decreases pgRNA uptake and results in shorter packaged lengths, underscoring the charge-dependent specificity of this process. Nuclear-cytoplasmic trafficking of HBcAg is essential for coordinating pgRNA packaging and export of immature capsids to the , as well as of mature capsids for cccDNA in the HBV lifecycle. of serine residues in the C-terminal (CTD) of HBcAg, such as S155, S162, and S170, modulates its localization and capsid dynamics, with required for efficient via importin-α/β recognition of arginine-rich nuclear localization signals (NLS) in the CTD.; Recent studies (as of 2023) show that HBcAg localizes to the early, where capsid assembly and pgRNA packaging can initiate, forming capsids that are exported to the through the CRM1-dependent pathway, as evidenced by retention upon leptomycin B treatment. In the , reverse transcription produces mature rcDNA-containing capsids, some of which are back to the . HBcAg associates with in the , potentially aiding its .; ; HBcAg exerts regulatory functions that enhance replication efficiency and specificity. Through interactions of its CTD with cellular factors, HBcAg influences host , such as by binding to promoters of approximately 3,100 genes and activating CRE-mediated transcription via the CRE/CREB/CBP pathway, which may support viral persistence. Additionally, the ARD ensures pgRNA encapsidation specificity by preventing incorporation of non-viral RNAs, with states of CTD serines regulating this selectivity and avoiding off-target packaging. During virion maturation, HBcAg stabilizes the intra- reverse transcription process that converts pgRNA to relaxed circular DNA (rcDNA). In immature , the phosphorylated CTD of HBcAg positions the to prime and elongate the minus-strand DNA, while the structure confines the reaction to prevent premature release. As replication progresses, of the CTD correlates with completion of plus-strand synthesis and rcDNA formation, rendering mature competent for nuclear import or envelopment, whereas immature exhibit limited activity due to structural constraints.

Immunological properties

Antigenicity and immune recognition

The hepatitis B core antigen (HBcAg) exhibits strong antigenicity due to its exposure of multiple B-cell s, particularly within the major hydrophilic region (MHR) spanning residues 74-131, where the segment from residues 74-89 serves as a highly immunogenic linear that elicits robust responses, including anti-HBc antibodies. This region is exposed on the surface of the icosahedral , facilitating recognition by B cells and promoting . Additionally, conformational s located on the surface, such as the immunodominant c/e1 at the spike tips formed by residues around 70-90 and 130-140, further enhance binding and contribute to the potent serological response against HBcAg. These structural features make HBcAg one of the most immunogenic components of the (HBV), often inducing higher titers compared to other viral antigens. HBcAg also contains well-defined T-cell epitopes that drive cellular immune responses. For CD8+ T cells, a prominent epitope is HBcAg18-27 (sequence TPPAYRPPNAP), which is restricted by HLA-A*0201 and generated through proteasomal processing of the core protein within infected hepatocytes. This epitope is frequently targeted in acute HBV infections, contributing to viral clearance via cytotoxic activity. CD4+ T-cell epitopes, such as those located in residues 1–20 and 50–69, support helper responses by activating CD4+ T cells that amplify both humoral and cellular immunity against HBV. These T-cell epitopes are conserved, enabling broad immune recognition across diverse host MHC alleles. The immunodominance of HBcAg stems from its repetitive structure, which mimics particulate antigens and enables T-cell-independent B-cell activation through multivalent cross-linking of B-cell receptors, leading to rapid IgM production without initial T-cell help. This property, combined with the dense array of surface epitopes on the 180-subunit , results in exceptionally strong humoral responses. HBcAg epitopes also demonstrate across HBV genotypes A through J due to high sequence conservation in the core protein (typically >95% identity), allowing a single to confer protection against variant strains. Serologically, anti-HBc IgM emerges early in acute HBV as a marker of active and liver , typically peaking within weeks and declining after resolution. In contrast, anti-HBc IgG persists lifelong, indicating past or , and serves as a correlate of resolved immunity. Notably, HBcAg protein can persist in hepatocytes even after seroclearance, reflecting ongoing low-level expression from covalently closed circular DNA () or integrated viral genomes in occult HBV carriers.

Interactions with host immune system

HBcAg engages the host by binding to naive B cells through their membrane immunoglobulin receptors, functioning as a T-cell-independent that cross-links B-cell receptors on the surface, thereby inducing polyclonal B-cell activation and subsequent production. This interaction leads to the of immunoglobulins, particularly IgM, without requiring T-cell help, as demonstrated in human peripheral blood lymphocyte-reconstituted /SCID mice where HBcAg triggered robust anti-HBc IgM responses in naive B cells from both adults and . Furthermore, HBcAg stimulation promotes the release of pro-inflammatory such as IL-6 from hepatocytes, enhancing local and contributing to the virus's immunomodulatory effects during . In terms of T-cell modulation, engineered fusion constructs of HBcAg-derived peptides with tapasin have been shown to stabilize the peptide-receptive conformation of MHC-I, leading to increased + T-cell activation and higher frequencies of IFN-γ-producing cells, as observed in HLA-A2 transgenic models. However, in chronic HBV infection, persistent high levels of HBcAg contribute to T-cell exhaustion, characterized by upregulated inhibitory receptors like PD-1 on HBcAg-specific + T cells, reduced production, and impaired proliferative capacity, which correlates with ongoing and liver inflammation. HBcAg-specific + T cells in chronic patients exhibit significantly higher PD-1 expression compared to those specific for other antigens, underscoring the antigen's role in driving functional T-cell impairment. Regarding innate immunity, the HBcAg can bind to Toll-like receptors (TLRs) on antigen-presenting cells, including s, where the encapsidated single-stranded serves as a , triggering type I production such as IFN-α to initiate antiviral responses. This activation promotes maturation and enhances of viral antigens, although HBV often dampens this pathway in chronic settings. Additionally, HBcAg's nuclear localization signal allows translocation to the host . HBcAg contributes to mechanisms, particularly in neonates exposed perinatally, by promoting the expansion of regulatory T cells (Tregs) that suppress antiviral responses and facilitate viral persistence leading to ity. HBcAg-specific +CD25+ Tregs, expressing and inhibitory molecules like CTLA-4 and PD-1, inhibit proliferation of effector T cells in response to HBcAg, maintaining during the immune-tolerant phase of HBV . Studies in transgenic models show that precore-HBcAg fusion proteins, such as the immature p22 precursor, alter function by inducing T-cell anergy or deletion, further skewing the toward non-responsiveness and supporting long-term viral carriage in early life exposures. This Treg-mediated suppression is reversible upon reduction of antigen load, highlighting HBcAg's dynamic role in balancing and flares in disease progression.

Clinical significance

Diagnostic applications

Direct detection of hepatitis B core antigen (HBcAg) in liver tissue via on biopsies serves as a marker for active within hepatocytes. This method identifies intrahepatic HBcAg expression, which is predominantly nuclear in early replication phases and may shift to cytoplasmic patterns with disease progression. In HBeAg-positive patients, HBcAg detection exhibits high sensitivity, often approaching 100% in studies evaluating chronic cases, though overall sensitivity across phases is reported around 45% for confirming active . Serological detection of antibodies to HBcAg (anti-HBc) remains a for assessing HBV exposure. Total anti-HBc (IgM and IgG) is considered the gold standard marker for lifetime , persisting indefinitely after resolution and appearing in nearly all exposed individuals. Anti-HBc IgM specifically indicates acute or recent , while total anti-HBc positivity without suggests past exposure. Additionally, serum hepatitis B core-related antigen (HBcrAg), which includes HBcAg, HBeAg, and precore protein, correlates strongly with intrahepatic covalently closed circular DNA () levels and serves as a predictor of reactivation in treated patients. HBcrAg quantification via the Lumipulse chemiluminescent enables monitoring of viral persistence. Common assay technologies for HBcAg-related diagnostics include enzyme-linked immunosorbent assay () and () for anti-HBc detection, with positivity typically defined by optical density (OD) ratios exceeding 1.0 (equivalent to cutoff OD >0.1 in calibrated systems). These assays offer high throughput and sensitivity for screening large populations. For HBcrAg, quantitative assays like Lumipulse provide a of approximately 1 kU/mL, allowing precise measurement of low-level and assessment of response to nucleos(t)ide analog , where declining HBcrAg levels indicate reduced activity. In clinical algorithms, intrahepatic HBcAg negativity alongside anti-HBc positivity generally indicates resolved infection, particularly when combined with undetectable and HBV DNA. For diagnosing HBV infection—defined as HBsAg-negative with detectable HBV DNA—anti-HBc positivity prompts HBV DNA testing, while HBcrAg assessment helps stratify reactivation risk in immunosuppressed patients. These markers integrate with HBV DNA quantification to guide management, such as antiviral prophylaxis.

Therapeutic implications

Capsid assembly modulators (CAMs) represent a promising class of antiviral agents targeting HBcAg to disrupt (HBV) replication. These small molecules, such as heteroarylpyrimidines exemplified by JNJ-6379 (also known as JNJ-56136379), bind to HBcAg dimers and accelerate or misdirect assembly, leading to the formation of non-functional, empty that prevent the packaging of pregenomic (pgRNA). By inhibiting pgRNA encapsidation, CAMs block viral genome maturation and subsequent replication without directly affecting host cell processes. In phase II clinical trials, such as the JADE study, JNJ-6379 combined with nucleos(t)ide analogs (NAs) achieved pronounced reductions in HBV DNA levels exceeding 2 log IU/mL in HBeAg-positive patients with chronic (CHB) over 24 weeks, alongside significant decreases in HBV . HBcAg-based virus-like particles (VLPs) have emerged as versatile platforms for vaccine development, leveraging the self-assembling properties of HBcAg to display foreign epitopes and elicit robust immune responses. These VLPs serve as carriers for antigens from pathogens like malaria, where insertions of Plasmodium falciparum circumsporozoite protein epitopes (e.g., Pfs25-CP) into HBcAg structures have demonstrated immunogenicity in preclinical models and advanced to phase I trials, inducing persistent antibody responses in mice. For therapeutic applications in chronic HBV, HBcAg VLPs modified to target HBcAg and HBeAg epitopes enhance antigen presentation to restore exhausted T-cell responses, promoting HBV-specific CD8+ cytotoxic T lymphocytes (CTLs) and CD4+ helper T cells. Preclinical studies in mouse models show that such VLPs, often fused with PreS domains and delivered via permeable routes, induce epitope-specific cellular immunity capable of clearing HBV-infected hepatocytes and neutralizing viral particles. Immune-based therapies exploiting HBcAg as a target offer novel strategies to eliminate infected cells and interrupt viral persistence. Monoclonal antibodies directed against HBcAg, such as the bispecific Anti-preS1 × Anti-HBcAg-R9TAT fused with a , penetrate HBV-infected hepatocytes, bind intracellular HBcAg, and suppress viral replication by disrupting nucleocapsid assembly and reducing levels of HBcAg, , and HBeAg both intracellularly and extracellularly. This approach facilitates the clearance of infected cells by enhancing immune recognition and inhibiting pgRNA packaging . Entry inhibitors, like , indirectly impact HBcAg core trafficking by blocking HBV attachment to the sodium taurocholate cotransporting polypeptide (NTCP) receptor, preventing the retrograde transport of intact capsids through the trans-Golgi network to the and thereby averting establishment. Despite these advances, therapeutic targeting of HBcAg faces challenges, including the emergence of at interfaces that compromise efficacy. For instance, such as T33N in the HBcAg protein confer broad to multiple CAMs by altering dimer interactions and nucleocapsid formation, potentially requiring at least 50% wild-type protein for sustained drug sensitivity in chimeric systems. Combination regimens pairing CAMs or HBcAg-targeted therapies with mitigate viral breakthrough and enhance suppression of HBV DNA and , as evidenced in clinical evaluations. As of 2025, ongoing phase II trials explore HBcAg-specific small interfering RNAs (siRNAs), such as imdusiran (AB-729), which degrade core mRNA transcripts to reduce HBcAg expression and synergize with vaccines or antibodies for functional cure, showing potent HBsAg declines and improved T-cell function in CHB patients. As of November 2025, phase 2a trials of imdusiran combined with have achieved functional cures in approximately 50% of chronic HBV patients, with ongoing studies exploring combinations for broader efficacy. These prospects underscore the potential of multi-modal HBcAg-directed interventions to achieve sustained viral control.

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