Immune Reconstitution Inflammatory Syndrome

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.

Inflammatory infiltrate in IRIS associated HIV dementia: The pathological features are predominantly of an inflammatory reaction with marked inflammatory infiltration of the perivascular space and infiltration of the cerebral cortex and white matter. The immuno- phenotyping of inflammatory cells demonstrated the presence of predominantly CD8+ lymphocytes (brown) in both the perivascular space (arrows) as well as neuropil and white matter. The panel on the right shows two CD8 cells (brown) attached to a neuron.

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 inflitration 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 channels resulting in neuronal apoptosis. These observations challenge conventional wisdom that GB requires perforin to enter cells and then initiates the apoptotic cascade. We are now defining the mechanisms by which T cells get activated in the setting of HIV infection, and how they recognize and target brain cells. We are also determining the role of voltage gated potassium channels in causing neuronal injury and developing compounds that may block this activity.