1996 — 1998 |
Fiala, Milan |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cocaine, Blood-Brain Barrier and Disease Progression @ University of California Los Angeles |
1 |
1999 — 2001 |
Fiala, Milan |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cardiomyopathy, Hiv1 and Chemokines @ University of California Los Angeles
Cardiomyopathy, HIV-1 and chemokines With greater survival, HIV-1 infection is increasingly complicated by cardiomyopathy, which is associated with inflammatory infiltrates and HIV-1 nucleic acids in the heart tissues. The overall objective of this proposal is to determine the roles of HIV-1, chemokines and chemokine receptors in HIV-1 cardiomyopathy. Our preliminary work shows the presence of CCR5, CXCR4, and other chemokine receptors on coronary artery endothelial cells (CAEC) and in heart tissues, and chemokine secretion by CAEC and monocytes upon appropriate stimulation. Our data also indicate that HIV-1 infects CAEC abortively and induces IL-6. Chemokine receptors are likely to determine this abortive infection. Following on this abortive infection. Following on this abortive infection, chemokines released by CAEC may by crucial mediators of monocyte/macrophage infiltration of the heart and IL-6 may impair the barrier function of CAEC. Our hypothesis are that in viral cardiomyopathy (a) HIV-1 causes abortive infection of endothelial cells and transcytotic invasions of subendothelial tissues, both of which may be determined by the presence of chemokine receptors on CAEC, (b) in the endothelial and subendothelial heart tissues, HIV-1 induces chemokines, which attract immigration of monocytes and lymphocytes, and (c) infected monocyte/macrophages release toxic factors, which cause cardiomyocyte inflammation and apoptosis, and possibly cardiac hypertrophy. The specific aims are to: #1 localize in vivo and in vitro the expression of chemokine receptors in CAEC and the myocardium in basal state and after stimulation with HIV-1 or HIV-1 peptides, and to determine their role in abortive infection, #2 demonstrate the role of CC- and CXC-chemokines in monocyte transmigration across the CAEC barrier; #3 identify the factors in the supernatants from monocyte and macrophages stimulated by HIV-1 infection or recombinant viral proteins that are responsible for inflammation and apoptosis of cardiomyocytes. This work will elucidate (1) the role of abortive HIV-1 infection and chemokines in transmigration of monocytes into heart tissues, (2) the mechanisms of damage to myocytes in HIV-1 cardiomyopathy caused by putative monocyte/macrophage-derived toxins or direct toxic effects of viral proteins, (3) the contribution of chemokines, cytokines and other products secreted by stimulated myocytes to myocardial injury. The results of this research could lead to development of new strategies for preventing or ameliorating the effects of HIV infection on the heart.
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1 |
1999 — 2002 |
Fiala, Milan |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cocaine and Hiv1 in Coronary Endothelium @ University of California Los Angeles
DESCRIPTION: (Adapted from Applants Abstracts) This project will examine the effects of cocaine on HIV-1 infection of coronary artery endothelial cells (CAEC). Recent pivotal data suggest that HIV-1 infects CAEC and brain microvascular endothelial cells (BMVEC) in an abortive fashion leading to strong-stop DNA synthesis, cocaine increases this abortive infection with the JR-FL strain, and microvascular endothelial cells display modulation of CD4+, CXCR4 and CCR5. In CAEC and BMVEC, cocaine and HIV-1 induce IL-6 and cell adhesion molecules, and increases endothelial permeability. These effects may lead to microvascular endothelial leaks and to increased HIV-1 invasion and leukocyte transmigration into the heart interstitium. Preliminary studies: They have previously demonstrated that TNF-alpha and cocaine cause the microvascular endothelial barriers to allow HIV-1 invasion by a para- or transcellular route and have recently observed that HIV-1 infects CAEC abortively leading to reverse transcription of R/U5 without further steps of reverse transcription but with intracellular signaling, IL-6 induction and increase in cell permeability. They have noted that cocaine and inflammatory cytokines modulate the abortive infection by HIV-1JR-FL. They hypothesize that 1) the abortive infection and increased permeability of CAEC are mediated by cocaine's induction of IL-6 and modulation of CXCR4 and CCR5, and 2) the effects of the abortive HIV-1 infection, cocaine, and IL-6 result in an impairment of endothelial barrier function. Specific Aims: They will determine 1) the effects of cocaine on the abortive infection of CAEC, 2) the effects of cocaine on passage and route of HIV-1 across CAEC, 3) cocaine's signaling, cocaine's signaling for IL-6, and the effects of cocaine, HIV-1 and IL-6 on CCR5 and CXCR4 expression, and 4) the effects of cocaine, HIV-1 and IL-6 on permeability, transendothelial electrical resistance, and procoagulant activity in CAEC.
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