Hypertension, cardiovascular disease and cerebral infarction are common comorbidities encountered in the HIV-infected aging population. Endothelial dysfunction is the initial step in these conditions.
The aim of the research project is to better understand the effect of long-term treated HIV infection on endothelial dysfunction and atherogenesis in older HIV-infected subjects, and the mechanisms behind these effects. The overreaching hypothesis is that in HIV-infected subjects on suppressive antiretroviral therapy, the heightened state of inflammation and immune activation will lead to increases in levels of asymmetric dimethylarginine and perturbation in arginine metabolism, which result in decrease in nitric oxide availability leading to reduced endothelial progenitor cells, endothelial dysfunctin, and worse vascular disease and atherogenesis. The causative relationships will be further investigated in interventional studies in which we hypothesize that by increasing the availability of nitric oxide, rosuvastatin with or without L-arginine supplementation, will increase endothelial progenitor cells and improve endothelial function.
In Specific Aim 1, we will conduct a longitudinal 3-year study on a well characterized cohort of 300 virologically suppressed older population who has been followed since initiation of antiretroviral therapy, and will assess the effect of inflammation and immune activation on serial measures of endothelial function, atherogenesis and vascular disease, and whether this effect is mediated by alterations in arginine metabolism and reduction in endothelial progenitor cells. Then, we will determine the effect of rosuvastatin vs. placebo (Aim 2) and rosuvastatin with or without L-arginine supplementation (Aim 3) on changes in endothelial function, endothelial progenitor cells, immune activation, insulin resistance, systemic blood pressure, and oxidized LDL. This proposal gathers an excellent group of experienced investigators in the areas of pathogenesis of arginine metabolism, HIV immune activation, HIV cardiovascular disease, and vascular imaging, and conduct these highly novel and rigorous studies in the most resource-efficient manner. .

Public Health Relevance

People living with HIV are suffering from several complications like heart disease and increased risk of stroke. These complications are linked to endothelial dysfunction that persists despite successful HIV therapy and undetectable HIV viral load. At the same time, heightened inflammation and abnormal immune activation in treated HIV are common but their relationship to endothelial dysfunction is unclear. We will use a cohort of older participants who are on long term successful HIV treatment, as well as two interventional clinical trials of statin agent with or without L-arginine to carefully and comprehensively study te mechanisms of endothelial dysfunction and possibilities of reversing it with safe readily available intervention.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZHL1-CSR-B (S1))
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Ershow, Abby
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Case Western Reserve University
Schools of Medicine
United States
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Longenecker, Chris T; Sullivan, Claire E; Morrison, Justin et al. (2018) The effects of HIV and smoking on aortic and splenic inflammation. AIDS 32:89-94
Dirajlal-Fargo, Sahera; Sattar, Abdus; Kulkarni, Manjusha et al. (2017) Soluble TWEAK may predict carotid atherosclerosis in treated HIV infection. HIV Clin Trials 18:156-163
Dirajlal-Fargo, Sahera; El Kamari, Vanessa; Sattar, Abdus et al. (2017) Effect of statin on arginine metabolites in treated HIV-infection. Atherosclerosis 266:74-80
Dirajlal-Fargo, Sahera; Alam, Khurshid; Sattar, Abdus et al. (2017) Comprehensive assessment of the arginine pathway and its relationship to inflammation in HIV. AIDS 31:533-537