The etiology of HIV-related cardiovascular disease (CVD) specially in patients with a history of cocaine use is most likely multifactorial. This is highlighted by the finding that there is an increase in the incidence of CVD in individuals with a history of cocaine abuse who are not HIV-1 infected and a similar increase in CVD in HIV-1 infected individuals who have no history of drug use. In addition, marked vascular lesions have been documented in SIV infected juvenile rhesus macaques who have no history of drug use. Thus, the effects of cocaine and HIV-1 infection leading to CVD may operate by separate but overlapping pathways, synergistically accelerating the disease process. It is our working hypothesis that insult to the vascular endothelium is one of the factor that contributes to CVD in HIV-1 infection which is further exacerbated by the use of drugs such as cocaine. Our lab has been studying the biology of lymphoid-endothelial cell interaction in both humans and non-human primates (NHP) in a variety of settings including responses to viral infections. During this process we have acquired unique sets of reagents, tools, techniques, knowledge, experience and important preliminary data which we submit will aid in defining some of the mechanisms of pathogenesis of HIV and cocaine induced cardiac disease. Specifically, we propose to a) determine if HIV/SIV infected lymphoid cells show increased adherence to human and NHP microvascular endothelial cells (MVEC), respectively in the presence/absence of cocaine/catecholamines using both a static and dynamic culture system b) to define the effect of HIV/SIV infected lymphoid cells in the presence and absence of cocaine/catecholamine on the expression of select cell adhesion/costimulatory molecule (CAM/CSM's), cytokines and chemokines by human and NHP MVEC c) determine if the effect on CAM/CSM's, cytokines and chemokines requires a disease inducing lentivirus isolate d) determine if HIV infected lymphoid cells in the presence/absence of cocaine/catecholamine induces the breakdown of latency in latent CMV infected autologous aortic endothelial cells e) determine if co-culture of MVEC and autologous smooth muscle cells (SMC's) in the presence of cocaine/catecholamine alone, HIV/SIV infected autologous cells alone or in combination leads to SMC proliferation and remodeling and, f) determine whether interaction of HIV-1/SIV infected cells alone and/or in the presence of cocaine/catecholamine leads to the synthesis of metalloproteinases. We reason that such studies may provide unique insights on the relationship between the effects of cocaine and HIV infection in the pathogenesis of cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL063066-01
Application #
2884463
Study Section
Special Emphasis Panel (ZHL1-CSR-Y (F2))
Program Officer
Wang, Lan-Hsiang
Project Start
1999-07-01
Project End
2004-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Mosunjac, Mario I; Sundstrom, J Bruce; Heninger, Michael et al. (2008) Combined pathological effects of cocaine abuse and HIV infection on the cardiovascular system: an autopsy study of 187 cases from the Fulton County Medical Examiner's office. Am J Forensic Med Pathol 29:9-13
Ansari, Aftab Ahmed (2004) Drugs of abuse and HIV--a perspective. J Neuroimmunol 147:9-12
Sundstrom, J Bruce; Mao, Hui; Santoianni, Robert et al. (2004) Magnetic resonance imaging of activated proliferating rhesus macaque T cells labeled with superparamagnetic monocrystalline iron oxide nanoparticles. J Acquir Immune Defic Syndr 35:9-21
Sundstrom, J Bruce; Little, Dawn M; Villinger, Francois et al. (2004) Signaling through Toll-like receptors triggers HIV-1 replication in latently infected mast cells. J Immunol 172:4391-401
Sundstrom, J B; Martinson, D E; Mosunjac, M et al. (2003) Norepinephrine enhances adhesion of HIV-1-infected leukocytes to cardiac microvascular endothelial cells. Exp Biol Med (Maywood) 228:730-40
Ansari, Aftab A; Fett, James D; Carraway, Robert E et al. (2002) Autoimmune mechanisms as the basis for human peripartum cardiomyopathy. Clin Rev Allergy Immunol 23:301-24
Sundstrom, J Bruce; Fett, James D; Carraway, Robert D et al. (2002) Is peripartum cardiomyopathy an organ-specific autoimmune disease? Autoimmun Rev 1:73-7
Sundstrom, J B; Mosunjac, M; Martinson, D E et al. (2001) Effects of norepinephrine, HIV type 1 infection, and leukocyte interactions with endothelial cells on the expression of matrix metalloproteinases. AIDS Res Hum Retroviruses 17:1605-14