After infection and a prolonged incubation period, the scrapie agent causes a degenerative disease of the central nervous system in sheep and goats. Six lines of evidence including sensitivity to proteases demonstrate that this agent contains a protein that is required for infectivity. Although the scrapie agent is irreversibly inactivated by alkali, five procedures with more specificity for modifying nucleic acids failed to cause inactivation. The agent shows heterogeneity with respect to size, apparently a result of its hydrophobicity; the smallest form may have a molecular weight of 50,000 or less. Because the novel properties of the scrapie agent distinguish it from viruses, plasmids, and viroids, a new term "prion" is proposed to denote a small proteinaceous infectious particle which is resistant to inactivation by most procedures that modify nucleic acids. Knowledge of the scrapie agent structure may have significance for understanding the causes of several degenerative diseases.

http://science.sciencemag.org/content/sci/216/4542/136.full.pdf

Novel proteinaceous infectious particles cause scrapie

Nobel Lecture: Prions

In order to define the histopathological substrate of the dementia that frequently complicates the acquired immune deficiency syndrome (AIDS), we analyzed the neuropathological findings in 70 autopsied adult AIDS patients, 46 of whom had suffered clinically overt dementia. Less than 10% of the brains were histologically normal. Abnormalities were found predominantly in the white matter and in subcortical structures, with relative sparing of the cortex. Their frequency and severity generally correlated well with the degree and duration of clinical dementia. Most commonly noted was diffuse pallor in the white matter, which in the pathologically milder cases was accompanied by scanty perivascular infiltrates of lymphocytes and brown-pigmented macrophages, and in the most advanced cases by clusters of foamy macrophages and multinucleated cells associated with multifocal rarefaction of the white matter. However, in nearly one third of the demented cases the histopathological findings were remarkably bland in relation to the severity of clinical dysfunction. In addition, similar mild changes were noted in over one half of the nondemented patients, consistent with subclinical involvement. Vacuolar myelopathy was found in 23 patients and was generally more common and severe in patients with advanced brain pathology. Evidence of cytomegalovirus (CMV) infection was noted in nearly one quarter of the brains and was associated with a relative abundance of microglial nodules, but correlated neither with the major subcortical neuropathology nor with the clinical dementia, indicating that CMV infection likely represented a second, superimposed process. This study establishes the AIDS dementia complex as a distinct clinical and pathological entity and, together with accumulating virological evidence, suggests that it is caused by direct LAV/HTLV-III brain infection.

The AIDS dementia complex: II. Neuropathology

Variations in prions, which cause different incubation times and deposition patterns of the prion protein isoform called PrP
 Sc
 , are often referred to as 'strains'. We report here a highly sensitive, conformation-dependent immunoassay that discriminates PrP
 Sc
 molecules among eight different prion strains propagated in Syrian hamsters. This immunoassay quantifies PrP isoforms by simultaneously following antibody binding to the denatured and native forms of a protein. In a plot of the ratio of antibody binding to denatured/native PrP graphed as a function of the concentration of PrP
 Sc
 , each strain occupies a unique position, indicative of a particular PrP
 Sc
 conformation. This conclusion is supported by a unique pattern of equilibrium unfolding of PrP
 Sc
 found with each strain. Our findings indicate that each of the eight prion strains has a PrP
 Sc
 molecule with a unique conformation and, in accordance with earlier results, indicate the biological properties of prion strains are 'enciphered' in the conformation of PrP
 Sc
 and that the variation in incubation times is related to the relative protease sensitivity of PrP
 Sc
 in each strain.

Eight prion strains have PrP Sc molecules with different conformations

Unexplained debilitating dementia or encephalopathy occurs frequently in adults and children with the acquired immune deficiency syndrome (AIDS). Brains from 15 individuals with AIDS and encephalopathy were examined by Southern analysis and in situ hybridization for the presence of human T-cell leukemia (lymphotropic) virus type III (HTLV-III), the virus believed to be the causative agent of AIDS. HTLV-III DNA was detected in the brains of five patients, and viral-specific RNA was detected in four of these. In view of these findings and the recent demonstration of morphologic and genetic relatedness between HTLV-III and visna virus, a lentivirus that causes a chronic degenerative neurologic disease in sheep, HTLV-III should be evaluated further as a possible cause of AIDS encephalopathy.

https://science.sciencemag.org/content/sci/227/4683/177.full.pdf

HTLV-III infection in brains of children and adults with AIDS encephalopathy

RIDA, A Chronic Encephalitis of Sheep: With General Remarks on Infections Which Develop Slowly and Some of Their Special Characteristics

Visna, a demyelinating transmissible disease of sheep.

The virus of Visna, a slow, demyelinating leucoencephalitis of sheep, has been cultivated in tissue culture. The cells employed are derived from the chorioid plexus of sheep. The virus causes characteristic cytopathic changes in the culture, so that the method may be used to detect virus activity and measure the activity of virus containing material. Virus which had undergone 3, 11, and 12 passages in TC was injected intracerebrally into sheep and found to produce typical Visna lesions. Neutralizing antibody has been detected in sera from a certain proportion of sheep affected with Visna. The rate of virus multiplication in tissue culture after inocula of varying size has been studied. Small inocula tend to give rise to a mild infection which persists in the culture for long periods of time without destroying more than a certain proportion of the cells. The possible relationship between this relatively stable balance between virus and cells and the extraordinarily slow progress of Visna in the CNS of sheep is discussed.

Cultivation of visna virus in tissue culture

Maedi, a slow progressive pneumonia of sheep: an epizoological and a pathological study

VISNA, a slow demyelinating infection of the central nervous system of sheep was described in an earlier publication (Sigurdsson, Palsson, and Grimsson, 1957). This disease begins with pleocytosis in the cerebro-spinal fluid (c.s.f.) from 1 to 3 months after intracerebral inoculation of active material and develops extremely slowly. The pleocytosis may persist for a few weeks or as long as 2 years or more. A considerable proportion of sheep so affected later develop progressive paralysis which may appear as late as 1 or 2 years after the inoculation and leads to death. In other cases pleocytosis in the c.s.f. regresses and the animal recovers without ever showing external signs of the infection. The characteristic lesion in the brain and spinal cord is in the white matter and in many cases its nature and extent is reminiscent of the lesions seen in the human demyelinating diseases. Studies on Visna have continued and the methods employed are the same as described by Sigurdsson, Pa6lsson, and Grimsson (1957) unless otherwise stated.

Visna of sheep; a slow, demyelinating infection.

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