Varicella Zoster Virus Structure: Key Insights on the A-Capsid

Varicella-zoster virus (VZV), a member of the Herpesviridae family, causes both chickenpox and shingles. Its structure is essential for infection and replication, with the capsid playing a key role in housing the viral genome. The A-capsid is one of three intermediate forms in viral maturation, alongside the B- and C-capsids. Unlike the C-capsid, which contains the viral genome, the A-capsid is empty, making it a byproduct of abortive assembly rather than a direct precursor to infectious virions.

Understanding the A-capsid’s composition and function provides insight into VZV assembly and potential antiviral targets.

Basic Architectural Features Of The A-Capsid

The A-capsid of VZV is an icosahedral shell primarily composed of the major capsid protein (VP5), which forms hexons and pentons that create the geometric framework. This lattice is reinforced by triplexes, heterotrimeric complexes of VP19C and VP23, which stabilize interactions between adjacent capsomers. Unlike the C-capsid, which encapsidates the viral genome, the A-capsid lacks DNA.

Cryo-electron microscopy (cryo-EM) studies reveal that A-capsids exhibit a slightly expanded conformation compared to C-capsids due to the absence of internal pressure from the densely packed genome. This expansion makes them more flexible but less resistant to external forces. Internal scaffold proteins, which guide capsid assembly, are often retained within A-capsids, distinguishing them from mature forms.

A-capsid formation results from errors in the packaging process, where the viral terminase complex fails to insert DNA into the preformed shell. This failure may stem from defects in recognizing packaging signals or inefficiencies in ATP-driven translocation. As a result, A-capsids accumulate in infected cell nuclei but do not progress to later maturation stages. Their presence indicates the fidelity of the encapsidation process, with an overabundance suggesting replication disruptions.

Distinct Protein Subunits And Their Roles

The A-capsid’s structural integrity relies on a coordinated assembly of protein subunits. The major capsid protein (VP5), homologous to herpes simplex virus (HSV) UL19, forms hexameric and pentameric capsomers that establish the capsid’s geometric framework. VP5 undergoes precise self-assembly, ensuring proper formation.

Triplexes, composed of VP19C and VP23, bridge adjacent VP5 capsomers, preventing structural collapse and maintaining rigidity. These heterotrimeric complexes, analogous to HSV’s UL18 and UL38, act as molecular fasteners at the threefold symmetry axes. Cryo-EM studies show that triplexes influence the capsid’s elasticity and resistance to external forces.

Scaffold proteins, including the preVP22a precursor, guide capsid formation before being cleaved during maturation. Their presence in A-capsids indicates incomplete maturation, reinforcing the idea that these structures arise from aborted assembly. The viral protease encoded by UL26 mediates scaffold protein cleavage, a critical step in transitioning from immature to mature capsids. Disruptions in this process can lead to aberrant capsid accumulation, affecting viral replication.

Relationship Between Capsid And Viral Envelope

The transition from the A-capsid to a fully infectious VZV particle involves a complex interaction between the capsid and the viral envelope. While the A-capsid does not contribute to viral egress, understanding how mature capsids acquire their lipid bilayer provides insight into the broader assembly pathway.

Herpesviruses like VZV undergo a two-step envelopment process. Once a capsid successfully packages the viral genome, it must exit the nucleus. This occurs through nuclear egress, where capsids bud into the inner nuclear membrane, acquiring a temporary envelope. The nuclear egress complex (NEC), composed of viral proteins homologous to HSV’s UL31 and UL34, facilitates this process by deforming the nuclear lamina. However, this initial envelope is transient, as it fuses with the outer nuclear membrane, releasing the capsid into the cytoplasm through “de-envelopment.”

In the cytoplasm, capsids encounter the trans-Golgi network (TGN) or endosomal compartments, where they undergo secondary envelopment. This step is essential for producing infectious virions, as it provides a lipid bilayer embedded with glycoproteins necessary for host cell entry. Viral tegument proteins bridge the capsid and membrane structures, while glycoproteins such as gE and gI facilitate membrane curvature and fusion. The mature virion is then transported to the cell surface and released through exocytosis.

Characteristics Compared To Other Herpesviruses

VZV shares structural similarities with other herpesviruses but has notable differences in capsid architecture and maturation. Like all Herpesviridae members, VZV has an icosahedral capsid composed of VP5, triplex proteins, and scaffold components. However, its capsid is slightly smaller, measuring approximately 125 nm in diameter compared to the 130–135 nm range of HSV-1 and HSV-2. This size difference may influence genome packaging efficiency and stability.

VZV also exhibits lower structural robustness than cytomegalovirus (CMV) and Epstein-Barr virus (EBV), which have thicker tegument layers for additional reinforcement. Cryo-EM studies indicate that VZV capsids are more fragile, contributing to the virus’s strict dependence on cell-associated spread rather than free virion transmission. This structural limitation likely affects environmental stability, making VZV more sensitive to desiccation and temperature fluctuations than HSV.

Structural Insights From Cryo-EM

Cryo-electron microscopy has provided unprecedented detail on the VZV capsid, particularly the A-capsid. This imaging technique allows researchers to visualize protein subunit arrangements at near-atomic resolution, offering insight into capsid assembly. Unlike traditional crystallography, cryo-EM preserves the native state of VZV capsids, maintaining structural integrity.

Studies confirm that A-capsids exhibit a slightly expanded conformation compared to DNA-filled counterparts due to the absence of internal pressure. This expansion affects mechanical properties, making them more susceptible to deformation. Cryo-EM has also mapped the spatial arrangement of triplexes, revealing their role in stabilizing the lattice structure. These findings highlight potential antiviral drug targets, as disrupting these stabilizing elements could hinder capsid formation and reduce viral replication.

Additionally, cryo-EM has visualized scaffold protein remnants within A-capsids, providing further evidence of their abortive nature. These structural insights enhance understanding of VZV pathogenesis and may inform the development of therapeutic interventions aimed at disrupting capsid integrity before the virus reaches its infectious state.