Pulmonary lymphoproliferative/infiltrative diseases are commonly associated with HIV infection of children and adults, and they often occur prior to the onset of AIDS. As its most common manifestation, ovine lentivirus (OvLV) infection of sheep induces lymphoid interstitial pneumonia (LIP) that is remarkably similar to HIV-associated pulmonary disease; similar histopathologically and in terms of lymphocyte phenotype . These lentiviruses also share similar morphology, genetic organization, capacity to undergo antigenic variation in vivo, and tropism for macrophages, including alveolar macrophages. Because of these similarities, we propose to use the OvLV model to investigate the mechanisms of induction and progression of lymphoid interstitial pneumonia (LIP). Two hypotheses, which are not mutually exclusive, will be tested: l) that lentiviral antigens, presented by MHC molecules, induce T cell proliferation, and 2) that recruitment of T cells contributes to the pulmonary infiltrative disease. To address the first hypothesis, three groups of newborn lambs will be injected intrabronchially with OvLV or sham-inoculated. T lymphocytes from broncho-alveolar fluid, lung lymph, and peripheral blood will be collected serially during acute and chronic stages of the disease process. The T cells collected from these sources from groups of lambs prior to infection and up to 6 months after infection will be phenotyped and analyzed for Vbeta gene heterogeneity and cytokine transcription. Cultures of T cells from the same compartments will be used to study viral antigen specificity, effector function, and MHC class I and class II restriction. If responding T cells are found to be oligoclonal, as assessed by analysis of the Vbeta gene repertoire, the role of viral antigens in driving T cell expansion will be examined. Alternatively, if the proliferating T cells are polyclonal, experiments will be designed to ascertain whether viral proteins act as superantigens. To address the second hypothesis, the capacity of labelled lung lymph T cells from acutely and chronically-infected animals to migrate from the bloodstream into the lung of the same animal or a recently-infected syngeneic twin will be studied. These experiments will provide information on the extent to which pulmonary recruitment and sequestration of activated T lymphocytes contributes to LIP in OvLV-infected animals. Elucidation of the mechanisms of T cell proliferation and pulmonary infiltration in lentivirus-infected sheep may lead to enhanced understanding of the pathogenesis of HIV-associated pulmonary disease and improved measures for its diagnosis, treatment and prevention.
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