The Acquired Immunodeficiency Disease Syndrome (AIDS) caused by human immunodeficiency retroviruses (HIVs) is obviously a world-wide health problem. Experimental investigation aimed at treatment or prevention of AIDS, such as vaccine development, has been complicated by a number of features of the disease and the causative HIVs including the long latency period between infection and disease symptoms. Coupled with this factor, perhaps the major limitation in the study of AIDS has been the absence of suitable animal model system. Chimpanzees, although considered to be the best choice to date because they can be infected by HIV, do not become immunodeficient and are difficult and expensive to obtain. These problems have led to major gaps in the understanding of the pathogenesis of AIDS, especially with regards to the interaction of HIV with the immune system. Because of these limitations researchers have turned to other animal systems which, although involving retroviruses other than HIV, present a bona fide immunodeficiency. In that murine models have distinctive advantages over large animal studies--such as shorter latency periods; lower costs, ability to perform classic genetic studies, etc.--this application proposes to employ the recently described mouse-AIDS (MAIDS) system caused by the LP-BM5 retrovirus isolate. Both the LP-BM5 retrovirus mixture as well as its component retroviruses, especially the defective genome now thought to be primarily responsible for the immunodeficiency, will be studied. The focus will be on specific antiviral cell-mediated responses caused by T cells, especially cytolytic T lymphocytes (CTL), but also on T helper cells (The) and other lytic cells such as natural killer (NK) cells. These studies are of important due to the frequent observations in man that AIDS progression occurs in spite of the presence of antiviral antibody responses including those capable of neutralization of virus infectivity in vitro. Thus, cell-mediated responses resulting in the destruction of virus-infected cells may be critical to protection. The broad aims of the proposal are to concentrate on LP-BM5 specific responses as demonstrable against both the B cell tumors that arise in MAIDs infected mice and virus-infected, non-transformed cells. The effects of the LP-BM5 related viruses on these responses, the mechanism by which the responses are inhibited, and the fine specificity of these T cell responses for virus and H-2 components are areas that will be emphasized. It is hoped that such information will advance their understanding of the pathogenesis of MAIDS and aid in the construction of rational approaches aimed at immunological intervention in the disease.
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