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The ND10 component promyelocytic leukemia protein relocates to human papillomavirus type 1 E4 intranuclear inclusion bodies in cultured keratinocytes and in warts.

Human papillomavirus type 1 (HPV1) E4 protein is associated with cytoplasmic and nuclear inclusions in productively infected keratinocytes. Here we have used transient expression of HPV1 E4 (also known as E1E4) protein in keratinocytes to reproduce formation of E4 inclusions. Immunofluorescence analysis showed that progressive formation of inclusions correlated with diminished colocalization between E4 and keratin intermediate filaments (IFs). Our results support a model in which the HPV1 E4-keratin IF association is transient, occurring only at an early stage of inclusion formation. We also demonstrate that E4 induces relocation of the promyelocytic leukemia protein (PML) from multiple intranuclear speckles (ND10 bodies) to the periphery of nuclear E4 inclusions and that this activity is specific to full-length E4 protein. Analysis of HPV1-induced warts demonstrated that nuclear PML-E4 inclusions were present in productively infected keratinocytes, indicating that reorganization of PML occurs during the virus's replication cycle. It has been suggested that ND10 bodies are the sites for papillomavirus genome replication and virion assembly. Our finding that E4 induces reorganization of ND10 bodies in vitro and in vivo is further strong evidence that these domains play an important role in the papillomavirus life cycle. This study indicates that HPV1 is analogous to other DNA viruses that disrupt or reorganize ND10 domains, possibly to increase efficiency of virus infection. We hypothesize that HPV1 E4-induced reorganization of PML is necessary for efficient replication of the virus during the virus-producing phase.

Cells, Cultured↗

Intranuclear inclusion bodies in recurrent aphthous ulcers with a herpetiform pattern.

Spherical granular and filamentous intranuclear bodies were found in the marginal epithelial cells of recurrent aphthous ulcers with a herpetiform pattern. They ranged from 0.8 to 1.2 mu in size with one to four bodies being present in any one nucleus. Because of their size and the demonstrated lack of DNA or RNA, it was thought that they were not viral in nature, as has been previously reported. It is hypothesized that intranuclear bodies of the type found in this study represent a common manifestation of altered cellular metabolsim produced by several etiologic factors.

Cell Nucleolus↗

Brain neurotransmitter abnormalities in neuronal intranuclear inclusion body disorder.

Biochemical markers for the major neurotransmitter systems were measured in the brain of a patient who died with neuronal intranuclear inclusion disease. A severe nigrostriatal dopamine deficiency constitutes the basis for the parkinsonian features in the patient. A marked loss of brain norepinephrine and serotonin was found in the basal ganglia and hypothalamus. Brain amino acid (gamma-aminobutyric acid and glutamate) and cholinergic (choline acetyltransferase activity) systems were either normal or less severely affected.

Adolescent↗

Glial intranuclear inclusion bodies in a patient with Alzheimer's disease.

We report a case of dementia in an elderly woman with the pathological findings of Alzheimer's disease and numerous intranuclear inclusions in astrocytes and occasionally in neurons. These inclusions were seen in the cerebral cortex, limbic areas, basal ganglia, thalamus, brain stem and cerebellum. They expressed ubiquitin and were ultrastructurally composed of haphazardly arranged straight filaments. The presence of similar intranuclear inclusions in previous cases of adult-onset dementia without other neuropathological changes suggests an important link between these kind of inclusions and dementia. To our knowledge, this type of intranuclear inclusions has not been previously described in association with Alzheimer pathology.

Aged↗

Intranuclear inclusion bodies in liver of chronic hepatitis B with delta infection.

Seventy-two patients with HBsAg-positive chronic hepatitis were studied for serum antibody to delta antigen (anti-HD) by radioimmunoassay. Delta antigen (HDAg) in liver of the 72 patients was also studied immunohistochemically using peroxidase-labeled anti-HD. In one of the 72 patients, high titers of anti-HD and intrahepatic HDAg were detected. In this patient, HDAg was localized mainly in nuclei and occasionally in the cytoplasm of hepatocytes. By immunoelectron microscopy, HDAg was observed diffusely in some hepatocytic nuclei, but their nucleoli, perichromatin and heterochromatin were devoid of HDAg. Occasionally, inclusion body-like ring-shaped or irregularly shaped aggregates of HDAg were observed in nuclei. At higher magnification, these aggregates consisted of an HDAg-positive amorphous substance and microtubular structures. In their vicinity, scattered HDAg-positive granules were also present. By conventional electron microscopy, similar inclusion bodies composed of a clustered amorphous substance and microtubular structures 10-20 nm in diameter, together with 20-30 nm irregular granules were observed in hepatocyte nuclei, but no core of Dane particles were found. These novel intranuclear structures were not observed in other patients with chronic hepatitis B. It is suggested that they may represent the characteristic ultrastructure associated with delta infection.

Cell Nucleus↗

Ultrastructural investigation of lead-induced intranuclear inclusion bodies in mice.

By means of optical and electron microscopy and by atomic absorption spectrophotometry in a graphite chamber, this study evaluated the effect of temperature (22-35 degrees C) on lesions in the kidney, liver, and brain, and on concentrations of lead caused by the administration of 2 and 5 mg/kg/IP of lead acetate to Swiss mice. The most pronounced effects were observed in the kidney and in groups of animals receiving the highest doses (5 mg/kg at 22 and 35 degrees C). These effects consisted of significantly higher (p < .05) lead concentrations in the tissues, a significant decrease (p < .05) in kidney weights, and progressive kidney atrophy and fibrosis with, at the ultrastructural level, constant intranuclear inclusions, which were also observed in the cytoplasm of renal and endothelial cells.

Animal Feed↗