Immune reconstitution inflammatory syndrome (IRIS) in the brain is a devastating disease that can cause severe encephalitis and death upon initiation of combination antiretroviral therapy particularly in patients with high CSF viral load. As antiretroviral therapy is now becoming available world wide this could emerge as a single most important neurological complication that will have a major impact on the ability to treat large populations with antiretroviral drugs where viral loads cannot be measured easily. Understanding the pathogenesis of this syndrome and developing new approaches for treatment are critically important in our battle against AIDS. Pathological studies suggest that in patients with CNS IRIS there is massive infiltration of T cells within the brain. Preliminary data from our laboratory suggest that granzyme B (GB) is the key molecule released by activated T cells that causes neurotoxicity. Furthermore, we have made a novel observation that GB can cause neurotoxicity by interaction with G-protein coupled receptors (GPCP) on the neuronal cell membrane with activation of a voltage gated potassium channel Kv1 .3 resulting in neuronal apoptosis. These observations challenge conventional wisdom that GB requires perforin to enter cells and then initiates the apoptotic cascade. We also demonstrate for the first time that blockers of the Kv1.3 channels have neuroprotective properties. These observations suggest that it may be possible to develop novel pharmacological approaches that could intervene in this cascade. In this proposal, we focused our efforts on the Kv1.3 channel. Pharmacological blockers of this channel not only protect against GB mediated neurotoxicity but also prevent GB release from activated T cells thus providing a novel therapeutic approach. These observations may also be important for other T cell mediated neuroinflammatory diseases. We thus propose three interrelated specific aims.
Specific aim 1 : To determine if HIV proteins can activate T cells to cause release of GB.
Specific aim 2 : To determine the mechanism of GB mediated neurotoxicity Specific aim 3: To determine the mechanism of neuroprotection with Kv1.3 blockers

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS056884-04
Application #
7625100
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2006-09-30
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
4
Fiscal Year
2009
Total Cost
$348,346
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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