The Role of Interferon-alpha in HIV-associated Neurocognitive Disorders Öffentlichkeit
Kessing, Cari Fritz (2013)
Published
Abstract
Elevated levels of interferon-alpha (IFN-alpha) in the central nervous system (CNS) are linked to cognitive dysfunction in patients with inflammatory CNS diseases, most prominently in HIV-associated neurocognitive disorders (HAND). Nearly half of the roughly 34 million HIV-infected patients worldwide suffer from HAND and the prevalence of HAND continues to rise. Antiretroviral therapies are not very effective in treating HAND and people develop HAND even while on antiretroviral therapy.
This research focuses on investigating the signaling mechanisms involved in IFN-alpha neurotoxicity and testing potential therapeutics based on evidence that strongly suggests that IFN-alpha is prominently involved in HAND pathogenesis. We hypothesize that better treatments can be developed for HAND by blocking IFN-alpha or associated downstream signaling.
In order to test this hypothesis, we utilized an HIVE/SCID mouse model to assess the efficacy of a novel IFN-alpha blocker, B18R. We found that treating HIVE/SCID mice with B18R blocked the toxic effects of IFN-alpha on neurons and subsequently prevented pathology associated with HAND. To compliment this in vivo work, we also used a primary rat neuronal culture system to assess alternatative therapeutic targets involved in IFN-alpha signaling. We found that IFN-alpha exposure causes decreased neuronal dendritic length and branching within 24 hours. We determined that the IFN-alpha receptor was only partially responsible for IFN-alpha induced neurotoxicity and that blocking the NR2A subunit of the NMDA receptor also partially prevents neurotoxicity after exposure to IFN-alpha.
The results of these studies provide better insight into the mechanism(s) of IFN-alpha induced neurotoxicity and provide potential therapeutic targets for HAND and possibly other inflammatory central nervous system diseases.
Table of Contents
Table of Contents
Abstract, Dedication, Acknowledgements
Chapter 1: Introduction to IFNalpha Neurotoxicity .............................................................................................. 2
Chapter 2: B18R crosses the BBB and decreases ISG signaling in SV infected mice - B18R preliminary data .................... 26
Chapter 3: B18R neutralizes interferon alpha and alleviates histopathological complications in HIVE mice ....................... 40
Chapter 4: IFNalpha induces neurotoxicity through activation of the type I interferon receptor and the NMDA receptor.... 69
Chapter 5: Discussion and Implications of IFNalpha Neurotoxicity........................................................................... 104
About this Dissertation
| School | |
|---|---|
| Department | |
| Degree | |
| Submission | |
| Language |
|
| Research Field | |
| Stichwort | |
| Committee Chair / Thesis Advisor | |
| Committee Members |
Primary PDF
| Thumbnail | Title | Date Uploaded | Actions |
|---|---|---|---|
|
|
The Role of Interferon-alpha in HIV-associated Neurocognitive Disorders () | 2018-08-28 10:46:59 -0400 |
|
Supplemental Files
| Thumbnail | Title | Date Uploaded | Actions |
|---|