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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-H (M2))
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Wang, Lan-Hsiang
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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