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.
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