With the reduction in mortality due to combination antiretroviral therapy (cART), cardiovascular disease has emerged as a leading cause of death in HIV-infected patients. Because several antiretrovirals cause insulin resistance and dyslipidemia, the increased risk for atherosclerotic disease has been attributed primarily to these drugs. However, evidence is emerging that suggest untreated HIV infection contributes significantly to the risk for future cardiovascular events. Inflammation and endothelial cell dysfunction are key promoters of atherosclerosis in the general population. Vascular lesions in HIV-infected patients demonstrate increased leukocyte adhesion to the endothelium with elevated levels of monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1). In cART-na?ve patients, levels of these adhesion molecules are increased and endothelial dysfunction is common. cART only partly reduces levels of these molecules and only partly restores endothelial function. Our novel preliminary data suggest that the anti-inflammatory drug pentoxifylline (PTX) may significantly improve flow-mediated dilation of the brachial artery, an in vivo measure of endothelial function, in HIV-infected subjects by inhibiting leukocyte recruitment and adhesion. Using a cellular model, we found that HIV-infected T cells upregulate endothelial MCP-1 and that PTX inhibits endothelial production of MCP-1. We will directly address a specific objective of RFA-HL-08-003, which is to "examine the direct effects of HIV itself on the endothelium and identify any mitigating factors" in the proposed collaborative studies. In this application, we will address the central hypothesis that HIV-related inflammation induces endothelial cell dysfunction that is reversed with pentoxifylline.
Our Specific Aims are (1) To determine the effects of pentoxifylline on endothelial function in HIV-infected subjects and (2) To analyze in vitro mechanisms by which HIV and PTX modulate endothelial cell activation and injury. We will investigate the utility of PTX to improve HIV-related endothelial dysfunction in therapeutic trials. We will also study the mechanism of HIV-induced endothelial dysfunction and the ability of PTX to reverse this process using our in vitro models. This research is both timely and significant because it will move beyond observational clinical research by involving both therapeutic trials and mechanistic investigations to identify novel causal relationships and pathologic mechanisms between inflammation and endothelial function. If pentoxifylline is found to be effective in improving endothelial function in the proposed studies, then this inexpensive, safe, and widely available drug can be studied in larger trials to reduce cardiovascular endpoints in HIV-infected patients.

Public Health Relevance

The proposed research will determine if HIV infection damages the vascular endothelium, the inner lining of blood vessels, by increasing inflammation and if this damage can be reversed with the anti-inflammatory drug pentoxifylline. Both clinical trials and laboratory investigations will address these key issues. These studies will fill a critical gap in our knowledge of endothelial dysfunction in HIV-infected patients and may eventually lead to better preventative and therapeutic interventions to reduce cardiovascular disease in this population.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095149-05
Application #
8312485
Study Section
Special Emphasis Panel (ZHL1-CSR-H (S1))
Program Officer
Mcdonald, Cheryl
Project Start
2008-09-25
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$744,909
Indirect Cost
$248,612
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Wang, Ting; Green, Linden A; Gupta, Samir K et al. (2014) Transfer of intracellular HIV Nef to endothelium causes endothelial dysfunction. PLoS One 9:e91063
Gupta, Samir K; Mi, Deming; Moe, Sharon M et al. (2013) Effects of switching from efavirenz to raltegravir on endothelial function, bone mineral metabolism, inflammation, and renal function: a randomized, controlled trial. J Acquir Immune Defic Syndr 64:279-83
Gupta, Samir K; Mi, Deming; Dube, Michael P et al. (2013) Pentoxifylline, inflammation, and endothelial function in HIV-infected persons: a randomized, placebo-controlled trial. PLoS One 8:e60852
Kim, Chul; Gupta, Samir K; Green, Linden et al. (2011) Abacavir, didanosine and tenofovir do not induce inflammatory, apoptotic or oxidative stress genes in coronary endothelial cells. Antivir Ther 16:1335-9
Gupta, Samir K; Johnson, Raymond M; Mather, Kieren J et al. (2010) Anti-inflammatory treatment with pentoxifylline improves HIV-related endothelial dysfunction: a pilot study. AIDS 24:1377-80