Ritonavir-boosted atazanavir (ATV/RTV) + Truvada [tenofovir disoproxil fumarate/emtricitabine (TDF/FTC)] combination is currently recommended as one of the first line HAART therapy for the antiretroviral-naive patients. This regimen, while being effective to suppress HIV-1 replication, may prove to have hyperlipidemia/endothelial oxidative stress, renal toxicity and injurious cardiac effects when chronically used in HIV-1 patients. We recently demonstrate that AZT alone or RTV alone can cause enhanced cardiac inflammation and dysfunction in rats;RTV further caused hyperlipidemia and eNOS down-regulation. Importantly, we have demonstrated that dietary Mg-supplementation alone diminished most of the AZT- or RTV-side effects. Since HIV-1 protein expression may separately lead to significant systemic and cardiovascular inflammation, we hypothesize that HAART-mediated chronic cardiovascular side effects are enhanced further during HIV-1 infection, and Mg-supplementation may be protective. To pursue these hypotheses, we propose to use an established HIV-1 transgenic rat model and the parent Fischer 344 rats for the following specific Aims: 1) Determine if HAART combination treatment further promotes systemic oxidative/nitrosative stress, hyperlipidemia and cardiac pathology and dysfunction in HIV-1 Transgenic Rats compared with HAART treatment in control rats. 2) Determine if Mg-supplementation attenuates HAART-mediated systemic inflammation, pathology, and cardiac dysfunction in HIV-1 Tg and control rats. Oxidative/nitrosative, lipid metabolic and pathological indices will be quantified by biochemical and immunohistochemical techniques;HAART/HIV-1 induced eNOS down-regulation and Mg effects will be assessed by qRT-PCR and western blot and by NO metabolites. Cardiac function will be determined in situ by echocardiography. The projected results may have a major impact on choosing Mg- supplementation as an effective and safe co-therapy against chronic cardiovascular toxicity induced by most current HAART regimens in HIV patients.

Public Health Relevance

HIV-1 infection and use of highly active antiretroviral therapy (HAART) agents may separately cause systemic side effects. The proposed project will help to determine if chronic treatment with a currently preferred HAART drug combination enhances cardiovascular toxic effects in HIV-1 transgenic rats;furthermore the potential protective benefits of dietary Mg- supplementation will be determined.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL125038-01
Application #
8790053
Study Section
Special Emphasis Panel (ZHL1-CSR-B (M3))
Program Officer
Kirby, Ruth
Project Start
2014-08-06
Project End
2016-05-31
Budget Start
2014-08-06
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$237,750
Indirect Cost
$87,750
Name
George Washington University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052