Investigating the impact of chronic inflammation on monocyte function in HIV+ individuals and the elderly
Creators: name: Angelovich, Thomas
Publisher: name: RMIT University
Year: 2024

description: Background: Advances in effective combination antiretroviral therapy (cART) have dramatically reduced the incidence of AIDS in HIV+ individuals; however, relatively young HIV+ individuals continue to have higher risk of inflammatory diseases associated with ageing, such as atherosclerosis. In the elderly these diseases are associated with a chronic inflammatory state known as inflamm-ageing. Younger treated HIV+ individuals also show increased low grade inflammation suggesting that this may contribute to disease pathogenesis in a similar manner. Monocytes, key innate immune cells, may contribute to chronic inflammation due to response to increased presence of pathogenic material such as bacterial lipopolysaccharide (LPS) by producing proinflammatory cytokine such as IL-6 and TNF. However, whether this mechanism drives inflammation and age-related disease pathogenesis in HIV+ individuals and the elderly, and whether HIV infection accelerates or potentiates age-related changes to monocytes in the elderly, is unknown. Therefore, the hypothesis underlying this thesis is that chronic monocyte activation drives chronic inflammation and age-related disease pathogenesis in both HIV+ individuals and the elderly.<br><br>Methods: Monocyte phenotype and markers of monocyte activation and response to LPS were measured in monocytes from HIV+ individuals and the elderly primarily using flow cytometry and gene expression analysis. Viremic or cART treated virologically suppressed (VS) HIV+ individuals were recruited from the Alfred Hospital, Melbourne and monocytes were compared to those from age-matched and older HIV- individuals recruited from the community. The propensity of monocytes to form foam cells, lipid-laden macrophage associated with atherosclerotic plaque progression was measured using a novel in vitro model of early atherogenesis.<br><br>Results: Linear regression analyses identified that the percentage of monocyte subsets (intermediate and non-classical) and biomarkers of monocyte activation (CXCL-10, neopterin, sCD163) in HIV+ individuals increased with age at a similar rate as those from HIV- individuals; however, levels of these biomarkers were higher, indicating that HIV infection accentuates age-related changes to monocytes. Monocyte basal activation state and response to LPS in viremic and VS HIV+ individuals was shown to be higher (primed) in comparison to young HIV- controls, and levels of intracellular IL-6 and TNF produced by monocytes were shown to be similar to older HIV- men. However, the mechanism governing priming in HIV+ individuals and the elderly differed, suggesting HIV infection does not prematurely induce age-related changes to monocytes. Finally, monocytes from older HIV- men were shown to have a higher propensity to form foam cells in vivo through both intrinsic and extrinsic mechanisms which may lead to heightened development of atherosclerosis, similar to our previous findings in HIV+ men.<br><br>Discussion: The findings presented in this thesis provide key insight into how monocytes contribute to chronic inflammation, immune activation and age-related disease in young viremic and VS HIV+ individuals and the elderly. Furthermore, these findings raise doubt that HIV infection simply accelerates age-related changes in younger HIV+ individuals. Identifying the mechanism of primed monocyte response to LPS in HIV+ individuals will provide further insight into how chronic inflammation may drive age-related diseases in these individuals.