Abstract

Lentiviruses have common pathogenic mechanisms which give rise to persistent infections of the immune system and slowly progressive disease in natural hosts. The long term goals of this proposal are to continue our studies on the mechanism of persistent infection and chronic disease by these agents. Pathogenesis of the infection in sheep and goats with visna and caprine arthritis-encephalitis lentiviruses will therefore continue to be explored to provide a better understanding of the counterpart human lentivirus infection. Mechanisms of virus-induced lymphadenopathy in infected sheep will be investigated by identifying proliferating subsets of mononuclear cells in the hyperplastic lymph nodes with monoclonal antibodies and assessing the functional ability of the cells in effector cell assays. These ruminant lentiviruses induce a unique interferon (LV-IFN) during interaction between lymphocytes with virus-producing macrophages. While the IFN may auto-regulate its synthesis by restricting virus replication in macrophages its role in immune modulation - enhanced Ia expression in macrophages and suppression of some effector cell functions -- will be investigated as a possible cause of chronic inflammation. Virus-macrophage target cell interactions will be investigated in greater depth to define the role of infected precursor cells in bone marrow in disease causation. Virus receptor sites on macrophages will be investigated with anti-idiotypic antibodies as a mechanism for tropism of the viruses for selective populations of these cells. Virus-cell interactions will be evaluated in particular, with the aim of explaining the mechanism of acute episodic lesions in CNS versus persistent cumulative lesions in non-neural tissues. Finally, anti-idiotype antibodies will be used as vaccines to induce protective neutralizing antibodies. This may be a useful area for exploration in view of the inability of host immune systems to recognize antigenic mutants of these viruses, or even to recognize neutralization epitopes of some of these agents, as seen in arthritis-encephalitis virus of goats and AIDS virus of humans.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS012127-14
Application #
3394729
Study Section
Experimental Virology Study Section (EVR)
Project Start
1978-06-01
Project End
1993-05-31
Budget Start
1988-06-01
Budget End
1989-05-31
Support Year
14
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Singh, D K; Chebloune, Y; Mselli-Lakhal, L et al. (1999) Ovine lentivirus-infected macrophages mediate productive infection in cell types that are not susceptible to infection with cell-free virus. J Gen Virol 80 ( Pt 6):1437-44
Chebloune, Y; Karr, B M; Raghavan, R et al. (1998) Neuroinvasion by ovine lentivirus in infected sheep mediated by inflammatory cells associated with experimental allergic encephalomyelitis. J Neurovirol 4:38-48
Craig, L E; Sheffer, D; Meyer, A L et al. (1997) Pathogenesis of ovine lentiviral encephalitis: derivation of a neurovirulent strain by in vivo passage. J Neurovirol 3:417-27
Chebloune, Y; Karr, B; Sheffer, D et al. (1996) Variations in lentiviral gene expression in monocyte-derived macrophages from naturally infected sheep. J Gen Virol 77 ( Pt 9):2037-51
Karr, B M; Chebloune, Y; Leung, K et al. (1996) Genetic characterization of two phenotypically distinct North American ovine lentiviruses and their possible origin from caprine arthritis-encephalitis virus. Virology 225:1-10
Chebloune, Y; Sheffer, D; Karr, B M et al. (1996) Restrictive type of replication of ovine/caprine lentiviruses in ovine fibroblast cell cultures. Virology 222:21-30
Narayan, O; Joag, S V; Stephens, E B (1995) Selected models of HIV-induced neurological disease. Curr Top Microbiol Immunol 202:151-66
Clements, J E; Wall, R J; Narayan, O et al. (1994) Development of transgenic sheep that express the visna virus envelope gene. Virology 200:370-80
Gorrell, M D; Brandon, M R; Sheffer, D et al. (1992) Ovine lentivirus is macrophagetropic and does not replicate productively in T lymphocytes. J Virol 66:2679-88
Johnson, L K; Meyer, A L; Zink, M C (1992) Detection of ovine lentivirus in seronegative sheep by in situ hybridization, PCR, and cocultivation with susceptible cells. Clin Immunol Immunopathol 65:254-60

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