Multiple Sclerosis-Associated Retrovirus Particles Cause T Lymphocyte-Dependent Death with Brain Hemorrhage in Humanized SCID Mice Model

• Published in: Journal of neurovirology Vol. 9; no. 1; pp. 79 - 93
• Main Authors: Firouzi, R, Rolland, A, Michel, M, Jouvin-Marche, E, Hauw, JJ, Malcus-Vocanson, C, Lazarini, F, Gebuhrer, L, Seigneurin, JM, Touraine, JL, Sanhadji, K, Marche, PN, Perron, H
• Format: Journal Article
• Language: English
• Published: London Informa UK Ltd 01.01.2003; Taylor & Francis
• Subjects: Animals; B-Lymphocytes - cytology; B-Lymphocytes - virology; Biological and medical sciences; Blood-Brain Barrier - immunology; Cell Death - immunology; Cells, Cultured; Cerebral Hemorrhage - immunology; Cerebral Hemorrhage - virology; Choroid Plexus - cytology; Choroid Plexus - virology; Cytokines - genetics; Disease Models, Animal; Endogenous Retroviruses - isolation & purification; Endogenous Retroviruses - pathogenicity; Gene Expression; Human viral diseases; Humans; Infectious diseases; Medical sciences; Mice; Mice, SCID; Multiple Sclerosis - immunology; Multiple Sclerosis - virology; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Neurology; Spleen - physiology; Spleen - virology; Superantigens - immunology; T-Lymphocytes - cytology; T-Lymphocytes - virology; Viral diseases; Viral diseases of the nervous system; Virion; Virulence; Animal model; Multiple sclerosis; endogenous retrovirus; Brain death; Cardiovascular disease; Hemorrhage; Inflammatory disease; Vascular disease; T-Lymphocyte; Recombinant protein; Cerebrovascular disease; Human; blood-brain barrier; Intracranial; Meninge; Nervous system diseases; Rodentia; Cytokine; Retroviridae; superantigen; Virus; Vertebrata; Mammalia; Mouse; Animal; Central nervous system disease; Interferon; Combined immune deficiency; Brain (vertebrata)
• ISSN: 1355-0284; 1538-2443
• DOI: 10.1080/13550280390173328

A retroviral element (multiple sclerosis-associated retrovirus, MSRV) defining a family of genetically inherited endogenous retroviruses (human endogenous retrovirus type W, HERV-W) has been characterized in cell cultures from patients with multiple sclerosis. Recently, MSRV retroviral particles or the envelope recombinant protein were shown to display superantigen activity in vitro , but no animal model has yet been set up for studying the pathogenicity of this retrovirus. In the present study, the pathogenicity of different sources of MSRV retroviral particles has been evaluated in a hybrid animal model: severe combined immunodeficiency (SCID) mice grafted with human lymphocytes and injected intraperitoneally with MSRV virion or mock controls. MSRV-injected mice presented with acute neurological symptoms and died within 5 to 10 days post injection. Necropsy revealed disseminated and major brain hemorrhages, whereas control animals did not show abnormalities ( P < .001). In ill animals, reverse transcriptase-polymerase chain reaction (RT-PCR) analyses showed circulating MSRV RNA in serum, whereas overexpression of proinflammatory cytokines such as tumor necrosis factor (TNF)- &#102 and interferon (IFN)- &#110 was evidenced in spleen RNA. Neuropathological examination confirmed that hemorrhages occurred prior to death in multifocal areas of brain parenchyma and meninges. Further series addressed the question of immune-mediated pathogenicity, by inoculating virion to SCID mice grafted with total and T lymphocyte-depleted cells in parallel: dramatic and statistically significant reduction in the number of affected mice was observed in T-depleted series ( P < .001). This in vivo study suggests that MSRV retroviral particles from MS cultures have potent immunopathogenic properties mediated by T cells compatible with the previously reported superantigen activity in vitro , which appear to be mediated by an overexpression of proinflammatory cytokines.