Pathogenesis of visna. IV. Spinal fluid studies.

Visna is a persistent retrovirus infection of sheep which produces a chronic progressive paralytic disease after an incubation period lasting from months to years. The cerebrospinal fluid (CSF) was repeatedly sampled in a group of Icelandic sheep which were infected intracerebrally and followed up to 42 months. Minimal levels of infectious virus were isolated from the cerebrospinal fluid (CSF) up to 4 months after infection after which CSF neutralizing antibodies appeared in many sheep. These antibodies varied in titer and in some animals exceeded serum antibody levels which were moderate to high. CSF antibody is apparently produced within the CNS by local proliferation of B cell clones, and is accompanied by the appearance of considerable numbers of plasma cells in the neural parenchyma. Some sheep raised serum antibody to a second serotype of visna virus and in a number of these animals heterotypic antibody was also found in the CSF. An increase in CSF leukocytes often occurs within 1 to 3 months following infection and may then persist or wane. A persistent high level of CSF cells is an indicator of progressive CNS disease and such animals are more likely to yield virus, have higher CSF antibody levels, more severe CNS lesions, and an enhanced risk of clinical illness (progressive paralysis). CSF cells are predominantly macrophages and lymphocytes, with a consistent minority of plasma cells.

Pathogenesis of central nervous system lesions in visna: cell-mediated immunity and lymphocyte subsets in blood, brain and cerebrospinal fluid.

There are several indications that central nervous system (CNS) lesions in visna are immune-mediated and that cell-mediated immunity (CMI) may be of importance in the initiation of the lesions. To study the role of CMI in the pathogenesis of CNS lesions, five sheep were infected by intracerebral inoculation with visna virus and observed for 1 year. The following parameters were monitored at regular intervals: (1) neutralizing and ELISA antibodies; (2) visna virus-specific stimulation of lymphocytes from peripheral blood; (3) lymphocyte subpopulations in peripheral blood, cerebrospinal fluid (CSF) and brain at sacrifice. The CNS lesions were graded and compared with other parameters. The time course and titers of antibodies did not correlate with the severity of CNS lesions whereas the CMI did, indicating that CMI may play an important role in lesion development. The correlation of the number of CD8-positive cells in the CSF with the severity of lesions and the reversed ratio of CD4/CD8-positive cells in the diffusely infiltrated neuroparenchyma indicates that the CD8-positive T lymphocyte may be an important effector cell in the induction of CNS lesions.

Cerebrospinal fluid immunoglobulins in sheep with visna, a slow virus infection of the central nervous system.

Icelandic sheep were injected intracerebrally with visna virus, which produces a persistent infection of the CNS accompanied by encephalomyelitis and focal demyelinating lesions. Studies were conducted on two groups of sheep, with short-term infections (25 sheep sampled 1-3 months after infection) and long-term infections (14 sheep sampled 5-6 years after infection). Quantitative determination of CSF immunoglobulin levels 5 years after infection indicated that IgM concentration was usually elevated, IgG2 was occasionally elevated and IgG1 was rarely elevated. CSF oligoclonal bands were seen in about half the sheep examined 5 years after infection. There was a correlation between high titers of CSF antiviral antibody and both elevated CSF IgM concentration and CSF oligoclonal bands. Serum/CSF IgG1 ratios indicated that the blood-brain barrier was apparently intact in long-term visna infection, consistent with intrathecal synthesis of IgM and of antiviral antibody. The alterations in CSF immunoglobulins in visna resemble those found in other persistent CNS virus infections and in multiple sclerosis.

Pathogenesis of central nervous system lesions in visna cell-mediated immunity and lymphocyte subsets in blood, brain, and cerebrospinal fluid.

The time course and titers of antibodies did not correlate with the severity of CNS lesions whereas the CMI did, indicating that CMI may play an important role in lesion development. The correlation of the number of CD8 positive cells in the CSF with the severity of lesions and the reversed ratio of CD4/CD8 positive cells in the diffusely infiltrated neuroparenchyma indicates that the CD8 positive T cells may be an important effector cell in the induction of CNS lesions.

Human and ovine lentiviral infections compared.

Maedi-visna virus (MVV) of sheep was the first lentivirus to be isolated. The genomic organization of MVV is very similar to that of human immunodeficiency virus (HIV) with several genes regulating the expression of the viral genome. Viral replication is severely restricted in the host and some cells apparently contain the genetic information in a DNA provirus form with little or no expression of viral antigens. This seems to be a major factor in causing the "slowness" of lentiviral infections and the persistence of the virus in the host since the immune system may not recognize the provirus-containing cells. The target cells for HIV and MVV are similar although T4 lymphocytes are not specifically destroyed in maedi-visna. There are also certain similarities in the pathological changes in both diseases, both in the central nervous system, the lungs and the lymphatic system. Although the severe final immunodeficiency state characteristic of AIDS has not been observed in maedi-visna, the basic biological features of the MVV and its interaction with host cells are so similar to HIV infection, that we consider ovine maedi-visna useful animal model for the human lentivirus infections.

Precipitating antibodies in experimental visna and natural progressive pneumonia of sheep.

Serological responses of Icelandic sheep experimentally infected with visna virus (vv) were contrasted with responses in American Targhee sheep naturally infected with progressive pneumonia virus (PPV). Precipitating antibodies assayed by immunodiffusion were compared with the neutralising and complementing fixing antibody response. In experimental infections with vv, complement fixing and neutralising antibodies appeared early after infection and rose to high levels in all sheep, while precipitating antibodies were detected only at minimal titre. In natural infections with PPV, immune responses were less consistent and precipitating antibodies were detected more frequently than complement fixing or neutralising antibodies against PPV. These results may suggest important biological differences between the lytic fibroblast-tropic virus strains used for experimental infection of Icelandic sheep and the nonlytic macrophage-tropic strains of PPV circulating in nature. Lytic strains evoke a brisk response against the viral glycoprotein with high titre neutralising antibody while nonlytic strains induce a less consistent response to the glycoprotein.

Maedi-visna in sheep: host-virus interactions and utilization as a model.

Controlled animal experiments with the ovine maedi-visna virus, the prototype lentivirus, have been carried out for almost 40 years. This non-oncogenic virus leads to a life-long, persistent infection with slow development of lesions in the lungs and in the central nervous system. The virus is present in many cells in a DNA provirus state and its replication and expression is highly restricted in vivo. The basic biological features of maedi-visna virus are quite similar to those of HIV and this ovine lentiviral disease may be useful as a model for infection with human lentiviruses.

Multiple sclerosis and canine distemper in Iceland.

Iceland offers a favourable opportunity to examine the suggested relationship between canine distemper and multiple sclerosis. Distemper is not enzootic in Iceland and distemper immunisation is not practised. However, importations result in occasional epizootics, three of which have occurred since 1909. Careful enumeration of multiple sclerosis indicates that there were 129 cases during the period 1946--65. When these cases are subdivided into six regions, by place of birth, regional period-prevalence rates were highest in two regions partially involved by distemper only once in the past 70 years. Also, there was substantial prevalence in a third region, encompassing Reykjavik, where the dog population has been kept very low for over 50 years. The Icelandic experience indicates that multiple sclerosis can occur at high incidence in the virtual absence of canine distemper or in the presence of a very small dog population.

[Visna and AIDS--various comparative aspects]. / Visna og AIDS--nogle komparative aspekter.

Visna, a lingering meningo-encephalitis in sheep, was one of the diseases on which B. Sigurdsson based his theory of a special group of disorders called slow infections. The cause of the disease, a retrovirus, was isolated in 1957. Visna is now classified in a subgroup of retroviridae, lentivirinae, together with virus types in animals and the human immune deficiency virus HIV. Notwithstanding that Visna has been eradicated among Icelandic sheep for 25 years research into this virus continues since it bears many similarities to HIV and also MS.

Expression of viral antigens in the central nervous system of visna-infected sheep: an immunohistochemical study on experimental visna induced by virus strains of increased neurovirulence.

Icelandic sheep were infected by intracerebral inoculation with visna virus strains of increased neurovirulence. The character and severity of pathological lesions were studied in brains from four sheep that developed clinical signs 5 to 12 weeks after infection. Viral antigens were identified by immunostaining using mouse monoclonal antibodies against two core proteins and the Avidin-Biotin method of detection. The pathological lesions were in general more severe than observed following infection with the parent strain K1514. Primary demyelination, a late manifestation of infection with K1514, was detected. Thus, in addition to causing more severe pathological lesions, these neurovirulent strains apparently have an increased potential to induce primary demyelination. Viral antigens were detected in lymphocytes, plasma cells, macrophages, endothelial cells, pericytes, fibroblasts and choroidal epithelial cells. Neurons and glial cells were antigen negative. The spectrum of infected cells in the brain was similar to that observed in infections with human immunodeficiency virus. These results do not support the view that the demyelination is caused by immunological damage to infected oligodendrocytes. A perturbation of the function of oligodendrocytes through a non-productive infection could be the underlying pathogenetic mechanism and/or a non-specific demyelination due to the intense inflammatory reaction.

Immunohistochemical staining of cells in the brain of a patient with acquired immune deficiency syndrome (AIDS) with a monoclonal antibody to visna virus.

Several monoclonal antibodies to different epitopes of the two major core proteins of visna virus, p25 and p15, were tested with the Avidin-Biotin immunostaining method on formaldehyde-fixed and paraffin-embedded sections of brains from patients with acquired immune deficiency syndrome (AIDS) who had shown neurological symptoms at death. In one of five AIDS cases a few cells, mainly inflammatory cells, showed a positive staining with a monoclonal antibody to the p25 core protein of visna.