Human immunodeficiency virus (HIV) infection is associated with an increased risk of both arterial and venous thrombosis, and as highly active antiretroviral therapy (HAART) is increasing the expected lifespan of HIV/AIDS patients, cardiovascular disease is increasing in prevalence in this population. The recognized drivers of chronic immune activation in HIV disease, including viral replication and microbial products translocated from the damaged gastrointestinal tract, may be playing a crucial role in development of cardiovascular disease and thrombosis within these patients. Monocytes from HIV infected patients have increased expression of tissue factor (TF) compared to levels found on monocytes from uninfected controls. Expression of monocytic tissue factor is related to markers of immune activation (CD38 and HLADR on Tcells), levels of plasma viremia, a marker of microbial translocation (sCD14), and fibrynolysis (D-dimers). The studies outlined in this application will define the mechanistic basis for increased monocyte TF expression in HIV infection and will explore the clinical impact of inflammation on TF expression and on the strikingly increased risk for cardiovascular disease and thrombosis in chronic HIV infection.
The aims of this project are as follows:
Aim 1 A: To determine the molecular basis for the induction of tissue factor expression on monocytes following in vitro exposure to HIV-1.
Aim 1 B: To explore the role of Kruppel-like factor 2 in the regulation of monocyte tissue factor expression in HIV-1 infection Aim 2A: To characterize further the phenotype of activated Tissue Factor-expressing monocytes in HIV-1 infected patients.
Aim 2 B: To evaluate monocyte phenotypes in untreated and treated HIV infection. The phenotype Aim 3: To assess the effects of statin treatment on monocyte activation in HIV disease Support of this project via the K99/R00 award will play a pivotal role in the career development of the applicant, solidifying his research experience through intensive mentorship, technical training, and broad intellectual development. Training during the mentored phase of this proposal will enhance the applicant's knowledge of the linkages between the immune system, inflammation, and cardiovascular disease, expand his technical repertoire, and provide a foundation in translational research that will enable him t achieve his long-term goals as an NIH-funded faculty member. The applicant has been successful at every level of his career, and through the continued mentorship of Dr Michael Lederman, a world leader in clinical trials research, and continued hard work by the applicant, there is no reason to believe that Dr Nicholas Funderburg will not be able to achieve success as an independent scientist.

Public Health Relevance

Highly active antiretroviral therapy (HAART) is increasing the expected lifespan of HIV/AIDS patients and cardiovascular disease (CVD) is increasing in prevalence in this population. The mechanisms behind this increased risk for cardiovascular events are poorly understood and by exploring the potential causes of CVD in HIV infection, perhaps new therapies can be developed.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Career Transition Award (K99)
Project #
5K99HL108743-02
Application #
8463029
Study Section
Special Emphasis Panel (ZHL1-CSR-P (O2))
Program Officer
Carlson, Drew E
Project Start
2012-05-01
Project End
2014-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
2
Fiscal Year
2013
Total Cost
$88,447
Indirect Cost
$6,552
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Hunt, Peter W; Sinclair, Elizabeth; Rodriguez, Benigno et al. (2014) Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection. J Infect Dis 210:1228-38
Martinez-Lopez, Denise G; Funderburg, Nicholas T; Cerissi, Adam et al. (2014) Lipopolysaccharide and soluble CD14 in cord blood plasma are associated with prematurity and chorioamnionitis. Pediatr Res 75:67-74
Funderburg, Nicholas T (2014) Markers of coagulation and inflammation often remain elevated in ART-treated HIV-infected patients. Curr Opin HIV AIDS 9:80-6
Eckard, Allison Ross; Jiang, Ying; Debanne, Sara M et al. (2014) Effect of 24 weeks of statin therapy on systemic and vascular inflammation in HIV-infected subjects receiving antiretroviral therapy. J Infect Dis 209:1156-64
Funderburg, Nicholas T; Jiang, Ying; Debanne, Sara M et al. (2014) Rosuvastatin treatment reduces markers of monocyte activation in HIV-infected subjects on antiretroviral therapy. Clin Infect Dis 58:588-95
Funderburg, Nicholas T; Lederman, Michael M (2014) Coagulation and morbidity in treated HIV infection. Thromb Res 133 Suppl 1:S21-4
Longenecker, Chris T; Jiang, Ying; Yun, Chun-Ho et al. (2013) Perivascular fat, inflammation, and cardiovascular risk in HIV-infected patients on antiretroviral therapy. Int J Cardiol 168:4039-45
Lederman, Michael M; Funderburg, Nicholas T; Sekaly, Rafick P et al. (2013) Residual immune dysregulation syndrome in treated HIV infection. Adv Immunol 119:51-83
Funderburg, Nicholas T; Stubblefield Park, Samantha R; Sung, Hannah C et al. (2013) Circulating CD4(+) and CD8(+) T cells are activated in inflammatory bowel disease and are associated with plasma markers of inflammation. Immunology 140:87-97
Petrov, Velizar; Funderburg, Nicholas; Weinberg, Aaron et al. (2013) Human ? defensin-3 induces chemokines from monocytes and macrophages: diminished activity in cells from HIV-infected persons. Immunology 140:413-20