Herpes zoster: pathogenesis and latency.
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Animals↗
Biomedical subjects
D H Gilden
Publications and source records attributed to D H Gilden.
Acute simian varicella infection. Clinical, laboratory, pathologic, and virologic features.
Five African green monkeys inoculated intratracheally with 7.5 x 10(3) to 1.4 x 10(5) plaque-forming units of simian varicella virus (SVV) were subjected to clinical, laboratory, pathologic, and virologic analyses to study the pathogenesis of acute varicella. All animals developed viremia and rash and were sacrificed 8 to 11 days post-infection. No serum was available for postmortem serologic studies. Examination of multiple organs for pathologic changes and for SVV-specific antigen and nucleic acid revealed inflammation, hemorrhagic necrosis, and intranuclear Cowdry A inclusions in liver, lung, lymph node, and spleen; mild inflammation without necrosis in adrenal gland, kidney, and bone marrow, and SVV-specific antigen and nucleic acids in all viscera examined. No pathologic changes, SVV antigen or nucleic acids were detected in the spinal cord or in the brain from any of the monkeys. Ganglia revealed mild inflammation but no necrosis, and intranuclear inclusion bodies in non-neuronal cells of one trigeminal ganglion; SVV antigen and nucleic acids were detected in both non-neuronal and neuronal cells in ganglia. The pathologic and virologic findings in viscera are consistent with those described in viscera of humans with disseminated zoster, but the mild inflammatory changes in ganglia during acute simian varicella infection contrast with the extensive hemorrhagic necrosis and intranuclear inclusion bodies seen in human ganglia after disseminated varicella or zoster. Nevertheless, these studies show that ganglia become infected with varicella virus during primary infection, although the route of primary ganglionic infection remains to be determined, and indicate the possible usefulness of the SVV model to study varicella pathogenesis in humans.
Acute Disease↗
Type-specific identification of herpes simplex and varicella-zoster virus antigen in autopsy tissues.
To identify antigens of herpes simplex virus (HSV) types 1 and 2 and varicella-zoster virus (VZV) in human tissue, polyclonal antisera and an immunoperoxidase method were used to examine formalin-fixed, paraffin-embedded tissues from autopsy cases and experimentally infected animals. These antisera readily distinguished between HSV and VZV antigen, with no evident cross-reactivity. Antiser ato HSV-1 and HSV-2 were more strongly reactive with antigen of the homologous virus than with that of heterologous virus. This difference in immunoreactivity was used to discriminate between HSV-1 and HSV-2 antigens in experimentally infected animal tissues containing HSV antigens of known type and, by extrapolation, to distinguish between these antigens in human autopsy tissues. Thus, with appropriate antisera and tissue controls, HSV-1, HSV-2, and VZV can be identified in paraffin sections.
Adult↗
Preherpetic neuralgia.
We have encountered six zoster patients whose pain preceded rash by 7 to more than 100 days. Pain was severe, burning, and radicular, and located both in dermatomes different from, as well as in, the area of eventual rash. Two patients ultimately developed disseminated zoster with neurologic complications, one of zoster paresis, and the other, a fatal zoster encephalitis; both had been taking long-term, low-dose steroids. A third case of preherpetic neuralgia developed in a patient with prior metastatic carcinoma, and another case in a patient with an earlier episode of brachial neuritis. The final two cases of preherpetic neuralgia developed in individuals with no underlying disease. An extended period of pain before the onset of zoster rash has gone largely unrecognized.
Antigens, Viral↗
Trans-activation of viral tk promoters by proteins encoded by varicella zoster virus open reading frames 61 and 62.
Plasmids containing the varicella zoster virus (VZV) open reading frames (ORFs) 61 and 62 were used in a transient co-transfection assay to test for trans-activation of the VZV and herpes simplex virus type 1 (HSV-1) thymidine kinase (tk) promoters. The trans-activating potential of the polypeptides encoded by these VZV ORFs, designated p51 and p140, was compared to that of their HSV-1 homologs ICP0 and ICP4, respectively. VZV p51 was functionally inactive in this system while p140 appeared to be a much stronger transcriptional activator than ICP4. Co-transfection of plasmids encoding VZV p140 and HSV-1 ICP0 resulted in a synergistic activation of the reporter gene as has been shown for the combination of ICP4 and ICP0.
Herpesvirus 3, Human↗
Persistence of varicella-zoster virus DNA in blood mononuclear cells of patients with varicella or zoster.
Varicella-zoster virus (VZV) DNA was detectable by in-situ hybridization in blood mononuclear cells (MNCs) of patients with varicella or zoster for 2-56 days after the onset of a rash. VZV DNA was present in many MNCs from one acute varicella patient 2 days after the onset of the rash and was rarely found in MNCs during acute zoster, convalescent zoster, and convalescent varicella. The morphology of MNCs containing VZV was heterogenous, although most viral-DNA-containing MNCs were large monocytoid cells. Serial examination of blood MNCs from one adult with varicella revealed VZV DNA up until 8 weeks, but not 16 weeks, after the appearance of the rash; parallel studies in four zoster patients showed VZV DNA up until 3 weeks, but not later than 7 weeks after the appearance of the rash. These results indicate that MNCs become infected with VZV during the primary encounter with VZV (varicella) and during reactivation (zoster) and that infection continues for weeks after the onset of the skin rash. Furthermore, the detection of VZV DNA in blood MNCs of uncomplicated zoster patients coincides with the period during which these patients experience pain.
Adult↗
Expression of varicella-zoster virus and herpes simplex virus in normal human trigeminal ganglia.
Lysates of radiolabeled explants from four human trigeminal ganglia were immunoprecipitated with antibodies to varicella-zoster virus (VZV) and to herpes simplex virus. Both herpes simplex virus- and VZV-specific proteins were detected in lysates of all four ganglia. Absence of reactivity in ganglion explants with monoclonal antibodies suggested that herpes simplex virus and VZV were not reactivated during the culture period. In situ hybridization studies demonstrated the presence of RNA transcripts from the VZV immediate early gene 63. This approach to the detection of herpes simplex virus and VZV expression in human ganglia should facilitate analysis of viral RNA and proteins in human sensory ganglia.
Adult↗
Expression of varicella-zoster virus in blood mononuclear cells of patients with postherpetic neuralgia.
Postherpetic neuralgia (PHN), the most frequent complication of varicella-zoster virus (VZV) reactivation, is characterized by pain that persists for greater than 1 mo and often for years after zoster rash. To examine whether PHN might be related to reactivation of VZV, blood mononuclear cells of patients with PHN were tested for the presence of VZV DNA and proteins. VZV DNA was detected in the mononuclear cells of one PHN patient. VZV-specific proteins were detected in mononuclear cells of two acute-varicella patients, one acute zoster patient, and six elderly patients with PHN, but these VZV-specific proteins were not detected in three elderly zoster patients without PHN. Furthermore, pulse-chase experiments revealed further processing or degradation of VZV-specific proteins in the mononuclear cells. These findings strongly suggest that persistence, reactivation, and expression of VZV may result in PHN.
Chickenpox↗
Detection of antibodies to varicella-zoster virus proteins in sera from the elderly.
Sera from 40 elderly individuals ranging in age from 60 to 94 years were tested for the presence of antibodies to varicella-zoster virus (VZV)-specific proteins. Sodium dodecylsulfate polyacrylamide gel electrophoresis analysis of lysates of VZV-infected BSC-1 cells labeled with either [35S]methionine or [3H]mannose and immunoprecipitated with human sera revealed the variable presence of VZV-specific antibodies to four VZV glycoproteins (gpI, gpII, gpIII, and gpIV), and three nonglycosylated proteins (155, 140, 32 kilodaltons, kDa). The predominant antibody response in the sera from the elderly was to VZV gpII and the 155-kDa species. In addition, some sera from elderly individuals without an identifiable history of varicella or zoster contained antibodies to VZV proteins, suggesting a possible subclinical infection in these patients. Finally a history of zoster in the elderly was significantly correlated (p = 0.02) with the presence of antibody to gpIV.
Aged↗
Chronic progressive varicella-zoster virus encephalitis in an AIDS patient.
A patient with AIDS developed chronic, progressive encephalitis. Pathologic changes indicated that the encephalitis was produced primarily by a human herpesvirus. Hybridization of radiolabeled RNA probes transcribed from cloned DNA fragments of varicella-zoster virus (VZV), herpes simplex virus, cytomegalovirus, and the human immunodeficiency virus to DNA extracted from the patient's brain identified VZV as the causative agent. The results suggest that VZV should be considered in the differential diagnosis of chronic encephalitis of unknown etiology, particularly in immunosuppressed patients.
Acquired Immunodeficiency Syndrome↗
Detection of varicella-zoster virus nucleic acid in neurons of normal human thoracic ganglia.
Tissue sections from four normal human thoracic ganglia were hybridized in situ with a varicella-zoster virus-RNA probe. Varicella-zoster virus was detected in two of four ganglia, localized exclusively in neurons. The detection of latent varicella-zoster virus genetic material in thoracic ganglia provides further evidence of varicella-zoster virus latency at multiple levels of the human neuraxis and supports the notion that the neuron is the primary site of herpesvirus latency.
DNA, Viral↗
Varicella-zoster virus infection of human mononuclear cells.
Varicella-zoster virus (VZV) DNA was detected in mononuclear cells (MNC) of 7 humans with acute zoster 1-23 days after the onset of skin lesions. To further study the interaction of VZV with human MNC, cells obtained from seropositive normal donors were infected with VZV and analyzed for the presence of viral DNA and proteins. VZV-DNA was detected in T, B, and OKM 1 (monocyte-macrophage) positive cells, and virus-specific proteins were demonstrated by indirect immunofluorescence and immunoprecipitation. Hybridization studies revealed that VZV-DNA did not replicate in human MNC.
Adult↗
The organ tropism of mouse hepatitis virus A59 in mice is dependent on dose and route of inoculation.
The organ tropism of MHV-A59, a murine coronavirus, was studied in 4-6 week-old C57BL/6 mice inoculated by different routes and with various amounts of virus. MHV-A59 caused hepatitis after intracerebral and intraperitoneal inoculation (two clearly artificial routes) and also after intranasal and intragastric inoculation (two routes more likely to mimic naturally acquired infection). For each route, the severity of hepatitis was dependent on the amount of virus inoculated. Significantly higher doses were needed to cause hepatitis by the intranasal or intragastric routes. We have shown previously that mice inoculated intracerebrally with MHV-A59 develop mild meningoencephalitis followed by chronic central nervous system (CNS) disease, characterized by primary demyelination (1). We extend these results here to show that acute CNS disease can be produced also by intranasal and intragastric inoculation, although much larger doses are needed as compared to intracerebral inoculation. Thus induction of demyelination, not only by the intracerebral route but also by the intranasal route, provides a useful model system to study virus-induced demyelination.
Administration, Intranasal↗
Detection of MHV-A59 RNA by in situ hybridization.
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Animals↗
Persistence of mouse hepatitis virus A59 RNA in a slow virus demyelinating infection in mice as detected by in situ hybridization.
Mouse hepatitis virus strain A59 produces chronic central nervous system demyelination in rodents. As late as 6 months after intracerebral inoculation of mice 4 to 6 weeks old, when infectious virus cannot be recovered and viral antigens cannot be detected in the central nervous systems and livers of these animals, primary demyelination is still evident. Using cloned virus-specific DNAs and the highly sensitive and specific technique of in situ hybridization, we have detected low levels of mouse hepatitis virus A59 RNA in the central nervous systems and livers of mice 10 months after inoculation. We suggest that viral persistence may play a role in mouse hepatitis virus A59-induced chronic demyelination.
Animals↗
Experimental demyelination produced by the A59 strain of mouse hepatitis virus.
Intracerebral inoculation of 4- to 6-week-old C57BL/6 mice with the A59 strain of mouse hepatitis virus (MHV), a murine coronavirus, produced biphasic disease. Acute hepatitis and mild meningoencephalitis were followed by subacute spastic paralysis with demyelinating lesions in the brain and spinal cord as determined by Epon-embedded toluidine-blue-stained sections and by electronmicroscopy. MHV-A59 was cultured by plaque assay from the blood, brain, spinal cord, and liver of infected mice during the acute phase, but not in the chronic stage. MHV-A59 antigen was detected by immunofluorescence (IF) until 3 months postinfection (PI). Serum anti-MHV-A59 antibodies were detected from 7 days to 5 months PI. The induction of demyelination by MHV-A59 provides a suitable system to study virus-induced demyelination further.
Animals↗
Neurovirulence of herpes simplex virus type 1 depends on age in mice and thymidine kinase expression.
The susceptibility of mice of different ages (from four to 28 days) to infection with herpes simplex virus type 1 (HSV-1) mutants inoculated onto scarified corneas was studied. The TK+ isolate from wild type virus was pathogenic in mice of all age groups. An HSV-1 mutant (designated TK1/4) with a less active thymidine kinase (TK) gene expressing 25 per cent of the TK activity of the TK+ isolate was pathogenic for mice up to 10 days of age. In older mice, virus pathogenicity was dependent on the inoculum dose: increasing the TK1/4 virus dose tenfold raised the level of TK activity and thus the virulence of the virus. A TK- mutant with no TK activity was pathogenic for four to eight day old mice that have TK activity in the brain, but not in older mice. Thus, resistance to HSV-1 that is age-dependent in mice can be determined by the extent to which the virus strain is liable to express its TK gene and by the amount of TK activity present in the brain.
Aging↗