Entrapment of viral capsids in nuclear PML cages is an intrinsic antiviral host defense against varicella-zoster virus.

The herpesviruses, like most other DNA viruses, replicate in the
host cell nucleus. Subnuclear domains known as promyelocytic
leukemia protein nuclear bodies (PML-NBs), or ND10 bodies, have
been implicated in restricting early herpesviral gene expression.
These viruses have evolved countermeasures to disperse PML-NBs, as
shown in cells infected in vitro, but information about the fate of
PML-NBs and their functions in herpesvirus infected cells in vivo
is limited. Varicella-zoster virus (VZV) is an alphaherpesvirus
with tropism for skin, lymphocytes and sensory ganglia, where it
establishes latency. Here, we identify large PML-NBs that sequester
newly assembled nucleocapsids (NC) in neurons and satellite cells
of human dorsal root ganglia (DRG) and skin cells infected with VZV
in vivo. Quantitative immuno-electron microscopy revealed that
these distinctive nuclear bodies consisted of PML fibers forming
spherical cages that enclosed mature and immature VZV NCs. Of six
PML isoforms, only PML IV promoted the sequestration of NCs. PML IV
significantly inhibited viral infection and interacted with the
ORF23 capsid surface protein, which was identified as a target for
PML-mediated NC sequestration. The unique PML IV C-terminal domain
was required for both capsid entrapment and antiviral activity.
Similar large PML-NBs, termed clastosomes, sequester aberrant
polyglutamine (polyQ) proteins, such as Huntingtin (Htt), in
several neurodegenerative disorders. We found that PML IV cages
co-sequester HttQ72 and ORF23 protein in VZV infected cells. Our
data show that PML cages contribute to the intrinsic antiviral
defense by sensing and entrapping VZV nucleocapsids, thereby
preventing their nuclear egress and inhibiting formation of
infectious virus particles. The efficient sequestration of virion
capsids in PML cages appears to be the outcome of a basic
cytoprotective function of this distinctive category of PML-NBs in
sensing and safely containing nuclear aggregates of aberrant
proteins.