Cardiovascular disease is highly prevalent among HIV-infected patients, however the distinct mechanisms of atherosclerotic disease development in HIV-infected patients are yet unknown. Chronic HIV infection is associated with loss of gastrointestinal mucosal epithelial integrity and loss of CD4+ T-cells in the intestinal lamina propria, leading to increased microbial translocation across the gastrointestinal tract. The key hypothesis of this grant application is that microbial translocation causes activation of the innate immune system which can induce inflammatory damage in the vasculature, leading to cardiovascular disease. This application proposes to investigate the role of the intestinal mucosal barrier to innate immune activation and downstream effects on atherosclerotic disease in HIV-infected patients.
Aim 1 seeks to study the relationships of intestinal epithelial integrity and microbial translocation to monocyte and macrophage activation and to cardiovascular risk measured by arterial inflammation via FDG-PET (to assess arterial macrophage activity) and coronary cardiac computed tomography angiography (to assess coronary atherosclerotic plaque quantitatively and qualitatively). Transcriptomic analyses in monocytes are proposed to identify novel biological pathways of atherogenesis in HIV-infected patients. To further test the central hypothesis, an interventional study is proposed in Aim 2 to improve the gut epithelial integrity and reduce microbial translocation in order to test effects of such an intervention on cardiovascular inflammation and monocyte function. The intervention of teduglutide, a glucagon-like peptide 2 analog with known trophic and anti-inflammatory effects on the intestinal epithelium, will be investigated in a randomized, double-blind placebo-controlled proof of concept trial in HIV-infected individuals. The hypothesis to be tested is that improvement of gut epithelial integrity will decrease intestinal permeability to microbial products, thus decreasing the stimulus for monocyte and macrophage activation, and therefore decrease macrophage activity in the arterial wall measured by FDG-PET and reduce overall cardiovascular risk.

Public Health Relevance

Cardiovascular disease is an emerging problem among patients living with HIV infection. As HIV-infected patients can have increased intestinal damage leading to excess bacterial products crossing over the intestinal mucosal barrier, which we hypothesize can lead to increased inflammation and thus atherosclerosis. In this grant application, we will examine whether abnormalities in the intestinal mucosal barrier can affect inflammation downstream in the blood vessels of the heart. We will also perform a randomized double-blind placebo-controlled trial to study whether treatment to improve the integrity of the mucosal barrier can help to decrease inflammation in the blood vessels of the heart and thus affect the development of atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL123351-01
Application #
8731433
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Iturriaga, Erin
Project Start
2014-05-07
Project End
2019-04-30
Budget Start
2014-05-07
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$827,188
Indirect Cost
$332,752
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199