HIV associated cardiac pathology is being recognized increasingly as patients with chronic HIV infection who survive to live productive lives. HIV associated cardiomyopathy is among the most common cardiac specific manifestation of chronic HIV infection and was observed in between 6-12% of patients that succumb to AIDS. However, cardiovascular involvement has emerged as more than a pathologic curiosity, but rather as a significant cause of morbidity as individuals live longer, more productive lives with HIV. Increased use of HAART therapy has served to unmask HIV associated predispositions to cardiac involvement. Despite the increased recognition, the risks factors for, the pathogenesis of, and the specific treatments required in HIV associated cardiac disease remain unknown. The nonhuman primate model of SIV infection in rhesus macaques affords an unparalleled opportunity to study these critical features. Prior work from our laboratory has characterized the time course, the role of CIM counts, and the pleomoprhic cardiac manifestations in simian AIDS. The work has demonstrated the need to consider both viral and host factors in identifying those at increased risk and to create a consistent, reproducible model of cardiac involvement for further investigation. We have determined that macrophage-tropic strains of SIV are most commonly associated with lymphocytic myocarditis. SIV is localized to the myocardium in approximately one third of cases of cardiac involvement, and when present, always co-localizes to cells of the macrophage lineage, either tissue macrophages or cardiac dendritic cells. TNFalpha, produced by activated macrophages, mediates both up-regulation of NOS2 in cardiac myocytes and the expression of Fas (CD95) receptors leading to cardiac myocyte apoptosis. As such, we have shown that cytokines play a central mechanistic role in both reversible LV dysfunction (increased NF-kappaB NOS2 expression) and irreversible myocardial injury (Fas-FasL mediated apoptosis). In addition, lymphocytic infiltrates are frequently perivascular and associated with coronary vascular lesions characterized by endothelial activation, smooth muscle proliferation, and thrombotic occlusions, leading to acute ischemic injury. These pathological features are mirrored in the lung where lymphocytic interstitial pneumonia and pulmonary vasculopathy are observed and contribute to increased right ventricular dysfunction. We plan to explore both host and viral factors that lead to SIV transmission into the myocardium (SIV cardiotropism) and SIV mediated injury (cardiovirulence). The identified mechanisms will serve as a prerequisite for exploring specific strategies to prevent cardiac involvement in chronic SIV infection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075836-05
Application #
7251915
Study Section
Special Emphasis Panel (ZHL1-CSR-B (S1))
Program Officer
Mcdonald, Cheryl
Project Start
2003-09-30
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2009-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$635,127
Indirect Cost
Name
Harvard University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Asztalos, Bela F; Mujawar, Zahedi; Morrow, Matthew P et al. (2010) Circulating Nef induces dyslipidemia in simian immunodeficiency virus-infected macaques by suppressing cholesterol efflux. J Infect Dis 202:614-23
Yearley, Jennifer H; Xia, Dongling; Pearson, Christine B et al. (2009) Interleukin-18 predicts atherosclerosis progression in SIV-infected and uninfected rhesus monkeys (Macaca mulatta) on a high-fat/high-cholesterol diet. Lab Invest 89:657-67
Yearley, Jennifer H; Mansfield, Keith G; Carville, Angela A L et al. (2008) Antigenic stimulation in the simian model of HIV infection yields dilated cardiomyopathy through effects of TNFalpha. AIDS 22:585-94
Wachtman, L M; Gualtieri, L; Wanke, C et al. (2008) Viral and host correlates of serum resistin in simian AIDS. AIDS Res Hum Retroviruses 24:34-42
Mansfield, Keith G; Carville, Angela; Wachtman, Lynn et al. (2007) A diet high in saturated fat and cholesterol accelerates simian immunodeficiency virus disease progression. J Infect Dis 196:1202-10
Yearley, Jennifer H; Pearson, Christine; Shannon, Richard P et al. (2007) Phenotypic variation in myocardial macrophage populations suggests a role for macrophage activation in SIV-associated cardiac disease. AIDS Res Hum Retroviruses 23:515-24
Poornima, Indu G; Parikh, Pratik; Shannon, Richard P (2006) Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ Res 98:596-605
Yearley, Jennifer H; Pearson, Christine; Carville, Angela et al. (2006) SIV-associated myocarditis: viral and cellular correlates of inflammation severity. AIDS Res Hum Retroviruses 22:529-40