Clinical and molecular aspects of varicella zoster virus infection

Abstract

A declining cell-mediated immunity to varicella zoster virus (VZV) with advancing age or immunosuppression results in virus reactivation from latently infected human ganglia anywhere along the neuraxis. Virus reactivation produces zoster, often followed by chronic pain (postherpetic neuralgia or PHN) as well as vasculopathy, myelopathy, retinal necrosis and cerebellitis. VZV reactivation also produces pain without rash (zoster sine herpete). Vaccination after age 60 reduces the incidence of shingles by 51%, PHN by 66% and the burden of illness by 61%. However, even if every healthy adult over age 60 years is vaccinated, there would still be about 500,000 zoster cases annually in the United States alone, about 200,000 of whom will experience PHN. Analyses of viral nucleic acid and gene expression in latently infected human ganglia and in an animal model of varicella latency in primates are serving to determine the mechanism(s) of VZV reactivation with the aim of preventing reactivation and the clinical sequelae.

Figure 1

Neurologic disease produced by reactivation of varicella zoster virus.

Figure 2. Characteristic angiographic, imaging and pathologic abnormalities in varicella zoster virus (VZV) vasculopathy

(A) Three-dimensional time-of-flight magnetic resonance angiography of the Circle of Willis shows marked narrowing of the left anterior cerebral artery (short arrow) and occlusion of the right anterior cerebral artery (long arrow). (B) Brain magnetic resonance imaging (MRI) scan shows multiple areas of infarction in both hemispheres, primarily involving white matter and grey-white matter junctions (arrows). (C) Diffusion-weighted MRI in a patient with small vessel VZV vasculopathy. Top scan reveals two ischemic lesions in the posterior thalamus, one in the hypothalamus, and a small ischemic lesion (arrow) in the posterior limb of the internal capsule; one week later, the patient became hemiplegic. A new MRI (bottom) showed a discrete infarct in the area of the posterior limb of the internal capsule, although the ischemic thalamic and hypothalamic lesions had resolved. (D) Macroscopic changes in brain from a patient who died of chronic VZV vasculopathy; arrows indicate ovoid areas of ischemia/demyelination of varying size, primarily at grey-white matter junctions. Reproduced with permission from [58].

Figure 3. Immunohistochemical analysis of cerebral artery from a patient with varicella zoster virus (VZV) vasculopathy

VZV antigen (red staining) is detected after incubation of artery with rabbit antiserum against the VZV open reading frame 63 protein. Reproduced with permission from [54].

Figure 4. Intrinsic pathway of apoptosis in SVV-infected cells

Uninfected (−) and SVV-infected (+) Vero cells were harvested at multiple times. Cell lysates were analyzed by Western blot analysis for the active forms of caspase-3 and caspase-9 and Bcl-2. Blots were reprobed for β-actin. Representative blots from four experiments are shown. Note the increased levels of caspases-3 and -9 and the decreased Bcl-2 expression in infected cells at 64 hr post-infection (hpi).