The Role of Interferon-alpha in HIV-associated Neurocognitive Disorders Público

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

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Immunology
Palavra-chave	neurovirology interferon neurotoxicity immunology cytokine
Committee Chair / Thesis Advisor	Tyor, William, Emory University
Committee Members	Tansey, Malu, Emory University Bassell, Gary, Emory University Cummings, Richard, Emory University Evavold, Brian, Emory University

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