With improving long-term survival after successful suppression of HIV replication, cardiovascular disease (CVD) is an increasingly important health problem facing HIV infected (HIV+) people. Antiretroviral therapy itself, conventional Framingham risk factors, anemia, hepatitis C co-infection, and renal disease are all risk factors among HIV+ people, but these factors do not completely explain the excess risk of CVD among HIV+ compared to uninfected (HIV-) people. Based on insights gained largely from murine models, progressive atherosclerosis largely causes CVD which is in turn caused by inappropriate lipid metabolism and activation of the innate and adaptive immune systems. While alteration in immune cell function is a shared feature of HIV and CVD pathogenesis, it is not known whether the activation, number and or proportion of peripheral circulating monocyte and T cell subsets are associated with incident CVD in humans and explain the excess risk of CVD among HIV+ people compared to HIV- people. To answer these questions, we will leverage the Veterans Aging Cohort Study (VACS) biomarker cohort, a longitudinal, prospective observational cohort of 1525 HIV+ and 853 HIV- Veterans. Important strengths of this cohort include existing stored cryopreserved cells, data on biomarkers of inflammation, coagulation, and monocyte activation;longitudinal survey, Medicare, Medicaid, mortality and national death index data;comprehensive access to the entire VA electronic medical record including pharmacy records;and adjudicated CVD events occurring within and outside the VA. We propose to measure immune cell types and subsets from existing cryopreserved cells collected in 2005-2006 and (2) to adjudicate CVD events (i.e., acute myocardial infarction, coronary heart disease, ischemic stroke, heart failure, and CVD death) from 2005-2017.
Our specific aims are to: (1) Determine the number and proportion of pro and anti-atherosclerotic immune cells as well as naive and memory/effector T cells among HIV+ and HIV- people;(2) Determine if these immune cell types and subsets are independently associated with prevalent and incident CVD;(3) Determine whether they mediate the association between HIV infection and incident CVD. We hypothesize that people with (1) a higher proportion of proatherosclerotic (e.g., intermediate monocytes and TH1 cells) and a lower proportion of anti-atherosclerotic (e.g., TH regulatory cells) immune cells, respectively, and/or (3) increased evidence of immunosenescence (e.g., a low ratio of naive: memory T cells) will have an increased risk of incident CVD and that these types of immune cell subsets will explain the excess risk of CVD among HIV+ people compared to HIV- people. If our hypotheses are true, we will advance our understanding of how immune function contributes to CVD for HIV+ and HIV- people while also potentially identifying new targets for future CVD intervention studies and new risk factors for inclusion into current CVD risk prediction tools. In addition, the VACS biomarker cohort will become a valuable resource for the larger research community interested in immune function and CVD and other lung and blood disorders.

Public Health Relevance

With improving long-term survival after successful suppression of HIV replication, heart disease is now an increasingly important health problem facing HIV infected people. Antiretroviral therapy itself and known cardiovascular risk factors do not explain why HIV infected people have higher risks of heart disease than people without HIV. We know that people with HIV and people with heart disease have changes to their immune system. Whether these changes in the immune system, particularly changes to monocytes and T cells, explain the excess heart disease risk experienced HIV infected people compared to uninfected people is not known. This grant will examine whether changes in monocyte or T cell numbers or the proportion of these cells in the blood are associated with heart disease risk and if these changes explain the increased risk of heart disease among HIV infected compared to uninfected people.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL125032-01
Application #
8790187
Study Section
Special Emphasis Panel (ZHL1-CSR-B (M1))
Program Officer
Kirby, Ruth
Project Start
2014-08-27
Project End
2018-06-30
Budget Start
2014-08-27
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$754,326
Indirect Cost
$127,186
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212