Thesis advisor: Welkin Johnson / HIV-associated comorbidities including neurological disorders (HAND) and cardiovascular diseases (CVD) persist in people living with HIV (PLWH) regardless of adherence to antiretroviral therapies (ART). The development of these comorbidities correlates with increased monocyte/macrophages activation and accumulation. Studies report that the development of CVD and HAND are connected in PLWH, but few studies have examined the roles that monocyte/macrophages activation have in their co-development. We first asked how frequently CD8+ T lymphocyte depleted, SIV-infected rhesus macaques with AIDS co-developed cardiac pathology and SIV encephalitis (SIVE) compared to animals that developed CVD or SIVE alone, and animals with no significant cardiac pathology (NSF) and SIV with no encephalitis (SIVnoE) (Chapter 2). We sought to determine whether animals with concomitant CVD and SIVE had more monocyte activation, cardiac macrophages accumulation, and productively infected SIV-RNA+ and SIV- gp41+ cells in the heart and brain compared to animals with CVD or SIVE alone, and animals with NSF and SIVnoE. We found that animals with AIDS co-developed CVD and SIVE more frequently than animals developed CVD or SIVE alone, and NSF and SIVnoE. Animals with CVD and SIVE had increased biomarkers of monocyte activation, cardiac macrophages inflammation, and productively infected macrophages in the brain. We found that the quantity of SIV-RNA+ cells in the heart was sparse compared to the brain. When detected, cardiac SIV-RNA+ cells are CD68+ and CD206+ cardiac macrophages. Levels of plasma soluble CD163 (sCD163) correlated with plasma galectin-3 (Gal-3), galectin-9, and interleukin-18 (IL-18), more so than plasma viral load. We then assessed cardiac tissues from PWLH with HIV encephalitis (HIVE) and HIV no encephalitis (HIVnoE). We found that PLWH with HIVE had more cardiac inflammation and fibrosis than PLWH with HIVnoE. These findings indicate that CVD and HAND pathogenesis are connected, and that the level of myeloid cell activation correlates with the development and severity of concomitant CVD and HAND. The findings from this study emphasize the importance that macrophages accumulation has in developing AIDS-related comorbidities. Our findings highlight the importance of targeting monocyte/macrophages activation and accumulation in future HIV therapies. The persistence of CVD in the post-ART era suggests that ART successfully inhibits AIDS pathogenesis and HIV replication, but fails to block monocyte activation and macrophages accumulation correlated with CVD pathogenesis. We hypothesize that the optimal therapeutic approach for HIV-infection includes blocking AIDS pathogenesis and viral replication, and inhibiting monocyte/macrophages activation. Methylglyoxal-bis-guanylhydrazone (MGBG) is a polyamine biosynthesis inhibitor selectively taken up by monocytes and macrophages. MGBG treatment blocks monocyte/ macrophages activation in vitro, AIDS pathogenesis, and decreases inflammation in cardiac and brain tissues of SIV- infected rhesus macaques. We asked whether animals treated with ART and adjunct MGBG (ART+MGBG) had an additive decrease in monocyte activation and turnover, cardiac macrophages inflammation and collagen deposition compared to animals on ART, and untreated animals (Chapter 3). We found that animals on ART+MGBG had lower percentages of cardiac collagen deposition than animals on ART. Animals on ART, and ART+MGBG did not develop AIDS, and had decreased cardiac inflammation and collagen, and monocyte activation and turnover compared to untreated animals. Finally, we identified two populations of Gal-3 expressing (Gal-3+) cells in the heart, CD163+ Gal-3+ cardiac macrophages and CD163- Gal-3+ cells. Animals on ART, and ART+MGBG had decreased numbers of CD163+ Gal-3+ cardiac macrophages compared to untreated animals. All animals had similar numbers of CD163- Gal-3+ cells, and low frequencies of SIV-RNA+ cardiac macrophages regardless of treatment. These data suggests that blocking AIDS pathogenesis with ART, and ART+MGBG correlates with decreased monocyte activation and cardiac inflammation and collagen deposition. Overall, we did not find an additive effect in animals on ART+MGBG compared to animals on ART. Our findings show how targeting monocyte/macrophages activation with ART+MGBG blocks AIDS pathogenesis and decreases cardiac macrophages inflammation. This study demonstrates the advantages of therapeutic strategies blocking myeloid cell activation in conjunction with ART. / Thesis (MS) — Boston College, 2024. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.
| Identifer | oai:union.ndltd.org:BOSTON/oai:dlib.bc.edu:bc-ir_109947 |
| Date | January 2024 |
| Creators | White, Kevin Suresh |
| 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. This work is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0). |
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