Pathogenesis of experimental Hantaan virus infection in laboratory rats

Summary Weanling Fischer rats inoculated intramuscularly with Hantaan virus (strain 76–118) developed subclinical infections characterized by transient viremia and shedding of virus in saliva, persistence of virus in lung, pancreas, spleen and liver, and development of fluorescent and neutralizing antibodies in serum with immune complex deposition in lung. Viremia and virus shedding in saliva occurred 10 to 13 days after inoculation. Horizontal intracage transmission of infection occurred between 35 and 63 days post-inoculation, long after disappearance of virus in oropharyngeal secretions and blood. Multiple attempts to demonstrate infectious virus in feces and urine during this period were unsuccessful. The inability to detect virus in urine samples of experimentally infected rats may have resulted from intermittent or low-titered viruria. This contrasts sharply with the prolonged high-titered viruria reported in striped field mice(Apodemus agrarius) infected with Hantaan virus, suggesting differences in the mode(s) of virus transmission in nature.With 2 Figures     

Persistent asymptomatic infection of the laboratory mouse by simian foamy virus type 6: A new model of retrovirus latency

Summary Simian foamy virus (SFV) type 6, originally isolated from the kidney of a kuru-inoculated chimpanzee, has been adapted to produce an asymptomatic infection in Swiss-Webster white mice, with virus detected in the kidney and spleen for up to 10 months after intra-peritoneal inoculation, and the presence in some animals of complement-fixing, but not neutralizing, serum antibody. This first successful experimental infection of the laboratory mouse by a representative of the foamy virus group has special interest as a convenient model in which to study pathogenesis and viral latency, particularly in view of the isolation and recent characterization of a foamy virus from human tissue which is virtually indistinguishable from the SFV type 6 used in the present study.With 1 Figure     

Comparative ultrastructural neuropathology of naturally occurring bovine spongiform encephalopathy and experimentally induced scrapie and Creutzfeldt-Jakob disease.

We report the ultrastructural neuropathology of bovine spongiform encephalopathy (BSE), a recently described slow virus disease first recognized in Friesian/Holstein cattle, and compare it to that of experimental scrapie and Creutzfeldt-Jakob disease. The spongiform change, which was most pronounced in the central grey matter of the midbrain, consisted of membrane-bound vacuoles within neuronal processes, containing curled membrane fragments, secondary chambers and vesicles. Axons and dendrites accumulated whorls of neurofilaments and other subcellular organelles, such as mitochondria and dense bodies, which were entrapped within the filamentous masses. Other neurites accumulated electron-dense bodies, and still others electron-lucent cisterns and branching tubules. Membrane-bound neuronal inclusions, composed of tubules measuring 10 nm in diameter, were found in axonal terminals. Tubulovesicular structures were loosely packed and were occasionally surrounded by a common membrane, a finding previously described only in natural scrapie in sheep. Except for the intraneuronal inclusions, all of the ultrastructural features of BSE resembled those found in scrapie and Creutzfeldt-Jakob disease.     

Ultrastructural Pathology of Human T-Cell Lymphotropic Virus Type I Encephalomyelopathy in a White Patient with Adult T-Cell Leukemia/Lymphoma

A white patient with human T-cell lymphotropic virus type I (HTLV-I)-associated adult T-cell leukemia/lymphoma for 10 years died 4 months after the onset of spastic myelopathy. Ultrastructurally, the neuropathologic findings consisted of dystrophic neurites (spheroids) filled with neurofilaments or electron-dense bodies, intense astrocytic reaction with abundant formation of corpora amylacea, and multilamellar bodies. Demyelination and spongiform change were absent. Viruslike particles resembling HTLV-I were detected adjacent to brain endothelial cells.     

Isolation of a New Simian Foamy Virus from a Spider Monkey Brain Culture

A syncytium-forming (foamy) virus was isolated from a spider monkey brain cell culture. Cytopathic effect was observed both in the brain culture and in human embryonic kidney cells. Neutralizing antibody was present in the sera of the spider monkey from whom the isolation was made. The virus was inhibited by 5-bromo-2-deoxyuridine (20 mug/ml), contained a ribonucleic acid-dependent deoxyribonucleic acid polymerase, and had an infectivity peak at 1.15 g/cm(3) in a sucrose density gradient. The virus passed through a 220-nm but not a 100-nm membrane filter, was chloroform sensitive, and was inactivated at 56 C in 30 min. Hemagglutinating and hemadsorption activity was not noted with a variety of erythrocytes. The virion was spherical, formed in the cytoplasm, and was 105 to 115 nm in diameter. Ring-shaped nucleoids, 45 to 50 nm in diameter, were associated with tubular profiles. The virus was not neutralized by sera prepared against known viruses, including simian foamy virus types 1 through 7, Mason-Pfizer monkey virus, and bovine syncytial and measles viruses. Sera from a rabbit hyperimmunized with the isolate and sera from 19 spider monkeys had neutralizing antibody to the isolate; however, these sera did not cross-react with simian foamy virus types 1 through 7. Neutralizing antibody to the isolate was not detected in sera from 16 humans, 9 rhesus monkeys, and 10 chimpanzees.     

Heterogeneic Autoantibody Against Neurofilament Protein in the Sera of Animals with Experimental Kuru and Creutzfeldt-Jakob Disease and Natural Scrapie Infection

Heterogeneic autoantibodies against axonal neurofilament proteins of mature mouse neurons grown in vitro were detected by the indirect immunofluorescence technique in 12.7% (9 of 71) of the sera from nonhuman primates infected with kuru, in 14.5% (17 of 117) and 4% (1 of 25), respectively, of the sera from nonhuman primates and laboratory rodents infected with Creutzfeldt-Jakob disease, and in 35% (7 of 20) of the sera from sheep naturally infected with scrapie. Autoantibody titers ranged from 1:16 to 1:512 in Creutzfeldt-Jakob disease-infected animals, 1:32 to 1:512 in kuru-infected animals, and 1:64 to 1:1,024 in sheep with natural scrapie. The sera from 11 monkeys and 17 hamsters infected with scrapie and from 19 chimpanzees inoculated with brain tissues from humans with other neurological diseases did not contain autoantibodies. Of the 41 chimpanzees with Creutzfeldt-Jakob disease, 6 had autoantibodies against neurofilament proteins before experimental inoculation, whereas 6 others developed autoantibodies after inoculation, 4 developed autoantibodies during the asymptomatic phase, and 2 developed autoantibodies during the terminal clinical phase. Of the 48 chimpanzees with kuru, 2 had autoantibodies before inoculation, 6 developed autoantibodies after inoculation, 3 developed autoantibodies during the asymptomatic phase, and 3 developed autoantibodies during the terminal clinical phase. Among the normal nonhuman primate controls, 4.6% (9 of 195) had autoantibodies. In contrast, no autoantibodies were detected in 49 control rodents and 13 control sheep. The increased incidence of autoantibodies against neurofilament proteins in animals with kuru, Creutzfeldt-Jakob disease, and scrapie constitutes the first evidence of an immunological reaction in this group of atypical infections caused by unconventional viruses and suggests that neurofilaments may be involved in pathogenesis.     

Spread of Creutzfeldt-Jakob disease virus along visual pathways after intraocular inoculation

Summary We studied the targeting of spongiform lesions within the visual pathways after intraocular injection with the Fujisaki strain of Creutzfeldt-Jakob disease (CJD) virus. The first lesions were observed 18 weeks postinoculation in the most superficial layer of the superior colliculus and in the lateral geniculate body contralateral to the side of the inoculation. Asymmetrical lesions in the superior colliculus were found also in mice sacrificed at 19, 22, and 27 weeks postinoculation. These results demonstrate that CJD virus spreads within the CNS via central axons of the visual pathways following intraocular inoculation.     

A simple and effective method for inactivating virus infectivity in formalin-fixed tissue samples from patients with Creutzfeldt-Jakob disease.

We fixed brains from hamsters infected with scrapie virus in (1) formalin, (2) phenol-saturated formalin, (3) formalin with a 1-hour immersion in formic acid, or (4) phenol-saturated formalin with a 1-hour immersion in formic acid. In addition, we used the formalin-formic acid procedure on brains from mice infected with the virus of Creutzfeldt-Jakob disease. Formic acid proved superior to phenol in respect to both disinfection and tissue preservation, almost completely eliminating virus infectivity in sections that were histologically indistinguishable from formalin-fixed material. The inclusion of a formic acid step in routine formaldehyde tissue fixation will thus provide histologic sections of excellent quality, and virtually eliminate the risk of handling infectious material in the subsequent neuropathologic processing of tissues from patients with CJD.