Distinctive clinical syndrome involving nervous system, myocardium, and muscle develop in the course of HIV-1 infection. Clinical manifestations of these syndromes, including AIDS-dementia complex, have been attributed to pro-inflammatory molecules and virus-encoded proteins released by leukocytes that migrate into affected tissues. Despite new anti-retroviral therapies, little is achieved in treating extravascular manifestations. The long-term goal of this application is to identify mechanisms whereby HIV-1 infection influences the migration of mononuclear leukocytes (MNLs) across vascular endothelial barrier and the accumulation of infected cells in tissues outside of the vascular compartment. During the previous period of funding the Principal Investigator and coworkers found that the number of HIV-1 infected patients' leukocytes migrating across vascular endothelial cells is determined by the activation state of the leukocytes. The guiding hypothesis in this application is that HIV-1 infection generates cytokines and chemokines that facilitate adhesion between T cells, monocytes, and endothelial cells; increase leukocyte random locomotion; and promote the development of extravascular foci of infected macrophages. Possibly, certain strains of HIV-1 may stimulate migration of the leukocytes they infect. Alternatively, these strains of HIV-1 infect preferentially those leukocytes that are already endowed with ability to migrate across vascular barriers.
Three specific aims are proposed to test these hypotheses: (1) to characterize patients' MNLs that carry HIV-1 across endothelial barriers and identify influences that promote migration of these cells; (2) to determine whether migratory T cells can transmit HIV-1 to co-migrating monocytes and how infection may be modulated by signaling from adjacent endothelial cells, extracellular matrix proteins, and co-migrating MNLs; and (3) to identify the molecular basis for the observed effects of HIV-1 on transendothelial migration of T cells and monocytes.
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