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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS032583-06
Application #
2839364
Study Section
AIDS and Related Research Study Section 7 (ARRG)
Program Officer
Kerza-Kwiatecki, a P
Project Start
1993-12-01
Project End
2000-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
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Birdsall, Holly H; Porter, Wendy J; Green, David M et al. (2004) Impact of fibronectin fragments on the transendothelial migration of HIV-infected leukocytes and the development of subendothelial foci of infectious leukocytes. J Immunol 173:2746-54
Birdsall, Holly H; Siwak, Edward B; Trial, JoAnn et al. (2002) Transendothelial migration of leukocytes carrying infectious HIV-1: an indicator of adverse prognosis. AIDS 16:5-12
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Klysik, J; Kinsey, B M; Hua, P et al. (1997) A 15-base acridine-conjugated oligodeoxynucleotide forms triplex DNA with its IL-2R alpha promoter target with greatly improved avidity. Bioconjug Chem 8:318-26

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