Review: The neurobiology of varicella zoster virus infection

Abstract

Varicella zoster virus (VZV) is a neurotropic herpesvirus that infects nearly all humans. Primary infection usually causes chickenpox (varicella), after which virus becomes latent in cranial nerve ganglia, dorsal root ganglia and autonomic ganglia along the entire neuraxis. Although VZV cannot be isolated from human ganglia, nucleic acid hybridization and, later, polymerase chain reaction proved that VZV is latent in ganglia. Declining VZV-specific host immunity decades after primary infection allows virus to reactivate spontaneously, resulting in shingles (zoster) characterized by pain and rash restricted to one to three dermatomes. Multiple other serious neurological and ocular disorders also result from VZV reactivation. This review summarizes the current state of knowledge of the clinical and pathological complications of neurological and ocular disease produced by VZV reactivation, molecular aspects of VZV latency, VZV virology and VZV-specific immunity, the role of apoptosis in VZV-induced cell death and the development of an animal model provided by simian varicella virus infection of monkeys.

Figure 1

Neurological complications of varicella zoster virus reactivation.

Figure 2

Haematoxylin and eosin-stained sections of dorsal root ganglia from patients with postherpetic neuralgia, revealing diffuse and focal infiltration by chronic inflammatory cells (A). Arrow in panel B points to a prominent collection of lymphocytes. Figure 2 previously published in Surg Neurol, 1978; 10:50-3; Smith FP; Pathological studies of spinal nerve ganglia in relation to intractable intercostal pain. Reprinted with permission of Elsevier, Copyright 1978.

Figure 3

Virological analysis of an asymptomatic left temporal artery from a patient with VZV vasculopathy. Sections of the temporal artery were deparaffinized and incubated with 10% normal sheep serum (NSS) in phosphate-buffered saline (PBS) for 1 hour at room temperature. To prevent non-specific binding, primary antibodies were adsorbed with normal human liver powder for 30 minutes and again for 20 hours at 4°C. Sections were then incubated with polyclonal antibodies raised against VZV ORF 63 protein (1:1000 dilution) or normal rabbit serum (1:1000 dilution), rinsed with PBS and incubated with a 1:300 dilution of biotinylated goat anti-rabbit IgG in PBS containing 5% NSS, washed 3 times in PBS, incubated with alkaline phosphatase-conjugated streptavidin (1:100 dilution) and washed three times with PBS. The color reaction was developed for 5-30 minutes with fresh fuchsin substrate system. Levimasole was added to the colour reaction to block endogenous phosphatase. Uninfected and VZV-infected BSC-1 cells were used as controls (not shown). The normal cerebral artery does not contain VZV antigen (A), whereas the temporal artery contains abundant VZV antigen in the arterial adventitia (B, red). Panels A, B 600X.

Figure 4

Ganglionitis and intranuclear inclusions in zoster sine herpete. Haematoxylin and eosin staining of the trigeminal ganglion (top panel) shows widespread chronic inflammation with fibrosis and loss of neurons. Cells in some foci contain Cowdry type A intranuclear inclusions (arrow, inset) indicative of virus infection; the inflammatory cells are mainly lymphocytes with some plasma cells (arrowhead, inset). Immunohistochemical staining of the same ganglion (bottom panel) with mouse monoclonal antibody directed against VZV gene 63 protein indicates VZV antigen (brown staining) in multiple cells throughout the ganglion. Adjacent sections stained with antibody directed against HSV or with normal rabbit serum were negative (not shown).

Figure 5

VZV genes transcribed during latency. The VZV genome consists of ~125,000 base pairs of double-stranded DNA arranged in two units. The unique long segment (U_L) and unique short (U_S) segments are each bounded by internal and terminal invert repeat sequences (TR_L, terminal repeat of unique long, IR_L, internal repeat of unique long; IR_S, internal repeat of unique short; TR_S, terminal repeat of short [red shaded boxes]). The VZV genome contains 71 predicted open reading frames (ORFs) consecutively numbered from the leftward end of the virus genome. The entire VZV transcriptome has been identified in productively infected cells. In latently infected ganglia, VZV genes that have been sequence-verified include ORFs 11, 21, 29, 41, 43, 57, 62, 63, 66, 68, 70 and 71 (yellow). VZV ORF 4 and 40 transcripts have been detected by two independent techniques (PCR and in situ hybridization [dark green]), while VZV ORF 18 transcripts have been detected by only one technique (in situ hybridization [light green]).

Figure 6

Detection of VZV and SVV ORF 63 proteins in the cytoplasm of neurons in ganglia of a human latently infected with VZV and a rhesus macaque latently infected with SVV. Paraformaldehyde-fixed, paraffin-embedded sections of thoracic ganglia from a VZV-seropositive 46-year-old man (A) and from a rhesus macaque latently infected with SVV (B) were analyzed by immunohistochemistry using rabbit anti-VZV ORF 63. Both VZV and SVV ORF 63 proteins (arrows) are located exclusively in the cytoplasm of neurons in the respective ganglia.