Interstitial pneumonia is a major component of disease in HIV-infected children and adults. SIV infection in macaques provides an excellent model for the disease seen in children because juvenile macaques inoculated with appropriate strains of SIV develop lymphocytic interstitial pneumonia similar to that seen in HIV-infected children. The SIV/macaque model is ideal to study the pathogenetic mechanisms of lentivirus-induced pneumonia because animals can be infected with biologically cloned and molecularly characterized virus strains, they can be evaluated throughout the course of infection, and the course of disease is not confounded by drug treatment. In previous studies, a macrophage-tropic strain of SIV was selected after repeated in vivo passage of SIV in macaques. This macrophage-tropic virus was also pneumovirulent because when inoculated into macaques it caused typical lymphocytic interstitial pneumonia characterized by intense infiltrates of lymphocytes, lymphoblasts, plasma cells and macrophages in the interalveolar septae and perivascular and peribronchial interstitium. Our hypotheses are l) that the development of pneumonia requires a strain of virus that replicates preferentially in pulmonary macrophages, and 2) that virus replication in the lung induces local dysregulation of pulmonary cytokine systems that, in turn, leads to increased expression of cell adhesion molecules and lymphocyte infiltration. The goal of this study is to characterize the host and virus factors which contribute to the development and progression of lentivirus- induced pulmonary disease.
The specific aims are l) to characterize the pathobiology of the host pulmonary response to SIV infection, 2) to determine to what extent productive virus replication is associated with the development of disease, 3) to determine whether during infection there is a selection by the lung for a strain of virus that replicates preferentially in alveolar macrophages, and 4) to identify the molecular changes-that are responsible for pneumovirulence. Rhesus macaques will be inoculated with a macrophage-tropic pneumovirulent strain of SIV and examined for the development of pulmonary disease by both bronchoalveolar lavage (BAL) and sequential sacrifice. BAL and tissue samples will be use to identity the infiltrating cells in the lung, to determine what cytokines are produced in the affected lung, to measure the expression of cell adhesion molecules and to measure virus replication and identify virus tropism. In order to understand at the molecular level how the virus induces pulmonary disease, the macrophage-tropic, pneumovirulent strain of SIV will be sequenced and infectious recombinant viruses will be tested to identify the molecular changes that are important for the development of pulmonary disease.
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