Thesis advisor: Welkin Johnson / HIV associated cardiovascular disease is likely due to multiple factors ranging from accelerated aging, the direct effects of HIV proteins, and increased inflammation and immune activation. Monocytes/macrophages play roles in the development and progression of HIV and cardiovascular disease. Increased monocyte/macrophage inflammation and immune activation associated with HIV infection likely contributes to the increased risk of cardiovascular disease development associated with HIV infection. To further understand the role of monocytes/macrophages in the development of HIV-associated cardiovascular disease we: 1) assessed monocyte activation longitudinally to determine if they correlate with and can be predictive of cardiac fibrosis and inflammation; 2) we examined cardiac tissues from the SIV-infected CD8+ T-lymphocyte depleted animals to determine the effects of monocyte/macrophage inflammation on cardiac fibrosis; 3) in parallel we examined cardiovascular tissues from HIV+ individuals on durable cART to determine if aortic and cardiac inflammation persists with infection and if soluble factors (sCD163) correlated with intima-media thickness and fibrosis; 4) we next examined the effects of blocking leukocytes trafficking to the heart on SIV-associated cardiac inflammation and fibrosis; 5) and finally we examined if targeting monocyte/macrophage activation (as opposed to traffic) directly using MGBG decreases SIV-associated cardiovascular pathology, inflammation and fibrosis. We found that early increased monocyte activation was predictive of animals that developed cardiac fibrosis and SIV encephalitis (SIVE). Animals with both cardiac fibrosis and SIVE had increased macrophage inflammation in the heart, suggesting that there is a link between cardiac and CNS inflammation seen with HIV infection (Chapter 2). We found in a SIV-infected CD8+ T-lymphocyte depletion model of rapid AIDS increased prevalence of cardiac disease compared to nondepleted animals, and increased cardiac inflammation that correlated with cardiac fibrosis. Monocyte/macrophage traffic to the heart occurred later with SIV infection, possibly with the development of AIDS (Chapter 3). In post-mortem human tissues studies we found that inflammation in aorta and heart correlated with increased soluble CD163, and correlated with aortic intima-media thickness and cardiac fibrosis with HIV infection (Chapter 4). Blocking leukocyte traffic to the heart using an anti-α4 antibody decreased macrophage inflammation in the heart that correlated with decreased cardiac fibrosis (Chapter 5). Using MGBG, a polyamine biosynthesis inhibitor that directly targets monocyte/macrophage activation, we found decreased inflammation in the carotid artery and heart correlated with decreased carotid artery intima-media thickness and cardiac fibrosis (Chapter 6). Overall these studies provide evidence for ongoing monocyte/macrophage cardiovascular inflammation with HIV and SIV infection. Macrophage inflammation correlates with markers of cardiovascular disease (fibrosis and intima-media thickness, cardiomyocyte damage). Directly targeting monocyte/macrophage traffic (anti-α4 antibody) and activation (MGBG) decreased cardiovascular pathology, inflammation, fibrosis, and intima-media thickness. Taken together, the data in this thesis indicate that targeting monocytes/macrophages in conjunction with combination anti-retroviral therapy could alleviate cardiovascular disease in HIV-infected individuals. / Thesis (PhD) — Boston College, 2016. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.
| Identifer | oai:union.ndltd.org:BOSTON/oai:dlib.bc.edu:bc-ir_107030 |
| Date | January 2016 |
| Creators | Walker, Joshua Aaron |
| Publisher | Boston College |
| Source Sets | Boston College |
| Language | English |
| Detected Language | English |
| Type | Text, thesis |
| Format | electronic, application/pdf |
| Rights | Copyright is held by the author, with all rights reserved, unless otherwise noted. |
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