description) The endothelial cell is more than a passive boundary between blood and tissues -- it plays an active role in the regulation of immune responses. Endothelial cells control the migration of inflammatory leukocytes into tissues by upregulating the expression of specific cell adhesion molecules (CAMs) in response to various environmental stimuli such as cytokines and chemokines. Recent studies have suggested that interactions between lymphocytes or monocytes and endothelial cells are crucial for HIV infection of organs, but, the mechanisms by which endothelial cells regulate leukocyte migration and acute inflammatory responses to HIV have yet to be elucidated. The overall objective of this application is to identify, using in vitro and complimentary in vivo experiments, the viral and cellular proteins and signal transduction pathways involved in controlling the entry of virus into tissues, and hence, the development of organ-specific disease. The endothelial cell is central to viral entry into tissues. These cells lie between blood and tissue, reacting to the molecular environments in both of these compartments by expressing specific surface molecules and interacting with virus-infected and inflammatory leukocytes to control cellular efflux from blood to tissues. The SIV/macaque model provides a unique and valuable in vivo system in which to examine the effects of acute lentivirus infection and inflammatory responses on leukocytes and Ecs, and to assess their roles in disease progression while dissecting the specific underlying mechanisms using parallel primary cell cultures in vitro. SIV causes clinical and pathological manifestations in macaques that are strikingly similar to HIV infection in humans. Moreover, the SIV model can use specific genotype(s) of virus for infection (molecularly cloned, phenotypically characterized, pathogenic viruses) and the animals can be euthanized at different stages of infection to study tissue changes and virus gene expression. In addition, the role of specific viral genotypes in driving virus infected cells into tissues will be studied. The mechanisms underlying increased expression of cell adhesion molecules, integrins and chemokine receptors and the resulting increase in leukocyte transmigration through endothelial barriers will be examined in vitro. Alteration of specific signal transduction pathways by viral infection will be analyzed. This will be complemented by in vivo studies to identify and quantitate changes in the expression of cell adhesion molecules, integrins and chemokine receptors in tissues during the acute phase of infection.
