Dissertation
Antiretroviral drug mediated astrocyte senescence as a contributor to HIV-1-associated neurocognitive disorders
Doctor of Philosophy (Ph.D.), Drexel University
Jun 2018
DOI:
https://doi.org/10.17918/D8J66Q
Abstract
Aging, the time dependent deterioration in the physiological integrity of living organisms, has become pertinent to human immunodeficiency virus type 1 (HIV-1) as highly active antiretroviral therapy (HAART) has rendered it from a terminal to chronic illness. Despite this success, HIV-1 patients experience numerous co-morbidities that result in an accelerated aging phenotype, including a series of neurological deficits collectively known as HIV-1-associated neurocognitive disorders (HAND). Targeting mechanisms of aging has therefore been proposed as a novel HIV-1 therapy. One potential hallmark of aging to target is cellular senescence, a state of irreversible growth arrest coupled with set changes to phenotype and gene expression. Senescent cells are more prevalent in aging tissues and increasingly associated with neurodegenerative disease. We therefore hypothesized that one contributor to HAND is premature senescence of astrocytes in response to HAART drugs. Human astrocytes were treated in vitro with clinically relevant combinations of HAART drugs and examined for markers of senescence. Treated cells displayed classical markers including growth inhibition, expression of cell cycle inhibitors, senescence-associated [beta]-galactosidase activity and the senescence-associated secretory phenotype (SASP). Additionally, these cells demonstrated signs of oxidative stress via p38MAPK dependent total and mitochondrial ROS. This stress was accompanied by changes to astrocyte metabolism including increased mitochondrial oxygen consumption and glycolysis. Conditioned media from these cells induced cell death in the neuroblastoma SH-SY5Y cell line. Since astrocytes interact with endothelial cells at the blood brain barrier (BBB), we wanted to examine the impact of HAART drug mediated endothelial cell senescence on astrocytes. HAART-drug treated human umbilical vein endothelial cells (HUVECs) displayed a similar senescent and oxidative stress profile as astrocytes. Furthermore, senescent HUVECs had decreased eNOS activation, suggesting altered physiology. Most importantly, conditioned media from these HUVECs induced paracrine oxidative stress and senescence in astrocytes, which has implications for astrocyte dysfunction at the BBB. Overall, these results suggest HAART-drug mediated senescence is a detrimental contributor to HAND and drugs aimed to intervene the senescence program represent a novel avenue for therapeutics.
Metrics
71 File views/ downloads
17 Record Views
Details
- Title
- Antiretroviral drug mediated astrocyte senescence as a contributor to HIV-1-associated neurocognitive disorders
- Creators
- Justin Zachary Cohen - DU
- Contributors
- Claudio A. Torres (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- ix, 130 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 8123; 991014632848304721