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 to 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.
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.
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