Recent studies suggest that HIV patients are at increased risk for cardiovascular events; however, the mechanisms underlying this increased risk remain unclear. Our group was one of the first to demonstrate that HIV infection is independently associated with accelerated atherosclerosis, as measured by carotid artery-intima media thickness (IMT), and that HIV- associated inflammation may be driving this accelerated atherosclerosis. The mechanism by which HIV disease independent of any drug-specific toxicity increases the risk of cardiovascular disease during HAART is not known. We hypothesize that even well controlled HIV infection is independently associated with cardiovascular risk and that further decreasing HIV-associated inflammation adding newer antiretroviral agents will also decrease cardiovascular risk. We will perform a cross-sectional study of 300 treated and suppressed HIV-infected patients and 75 uninfected controls (Aim 1) and two small clinical trials of 50 HIV-infected patients each (Aims 2,3) to study the relationship between HIV infection, inflammation, thrombosis, atherogenic lipoproteins, and measures of atherosclerosis. We propose the following specific aims:
Aim 1 : To determine the influence of traditional and novel markers of inflammation on endothelial function and IMT progression;
Aim 2 : To determine if "intensification" with raltegravir in subjects on long-term antiretroviral therapy with clinically undetectable HIV RNA levels will improve endothelial function, and to determine if this effect is mediated by alterations in inflammatory markers, lipoproteins and/or thrombotic factors;
and Aim 3 : To determine the potentially beneficial aspects of CCR5 inhibition on inflammation and endothelial function as measured by brachial artery reactivity. This application combines (1) the ability to rapidly recruit subjects from existing cohorts of HIV-infected subjects;(2) a dedicated and successful cardiology research imaging laboratory, (3) a laboratory that pioneered study of pro-atherosclerotic lipoprotein in infection, and (4) the collaboration of senior investigators from NIAID performing innovative immunology assays.

Public Health Relevance

Understanding cardiovascular disease pathogenesis in HIV infection will provide essential information for the prediction, management, and therapy of HIV and HAART- associated complications, an increasingly important issue as aging occurs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095130-05
Application #
8322015
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
$990,050
Indirect Cost
$515,348
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Chow, Felicia C; Boscardin, W John; Mills, Claire et al. (2016) Cerebral vasoreactivity is impaired in treated, virally suppressed HIV-infected individuals. AIDS 30:45-55
Parikh, Rushi V; Ma, Yifei; Scherzer, Rebecca et al. (2016) Endothelin-1 Predicts Hemodynamically Assessed Pulmonary Arterial Hypertension in HIV Infection. PLoS One 11:e0146355
Parikh, Victoria N; Park, Joseph; Nikolic, Ivana et al. (2015) Brief Report: Coordinated Modulation of Circulating miR-21 in HIV, HIV-Associated Pulmonary Arterial Hypertension, and HIV/Hepatitis C Virus Coinfection. J Acquir Immune Defic Syndr 70:236-41
Waldo, Stephen W; Brenner, Daniel A; McCabe, James M et al. (2015) A Novel Minimally-Invasive Method to Sample Human Endothelial Cells for Molecular Profiling. PLoS One 10:e0126062
Lange, David C; Glidden, David; Secemsky, Eric A et al. (2015) Mitral Annular and Coronary Artery Calcification Are Associated with Mortality in HIV-Infected Individuals. PLoS One 10:e0130592
Secemsky, Eric A; Scherzer, Rebecca; Nitta, Elaine et al. (2015) Novel Biomarkers of Cardiac Stress, Cardiovascular Dysfunction, and Outcomes in HIV-Infected Individuals. JACC Heart Fail 3:591-9
Waldo, Stephen W; Brenner, Daniel A; McCabe, James M et al. (2015) A novel minimally-invasive method to sample human endothelial cells for molecular profiling. PLoS One 10:e0118081
Moyers, Brian S; Secemsky, Eric A; Vittinghoff, Eric et al. (2014) Effect of left ventricular dysfunction and viral load on risk of sudden cardiac death in patients with human immunodeficiency virus. Am J Cardiol 113:1260-5
Chow, Felicia C; Bacchetti, Peter; Kim, Anthony S et al. (2014) Effect of CD4+ cell count and viral suppression on risk of ischemic stroke in HIV infection. AIDS 28:2573-7
Parikh, Rushi V; Scherzer, Rebecca; Nitta, Elaine M et al. (2014) Increased levels of asymmetric dimethylarginine are associated with pulmonary arterial hypertension in HIV infection. AIDS 28:511-9

Showing the most recent 10 out of 28 publications