There is a fundamental gap in our understanding of the immune reconstitution inflammatory syndrome (IRIS), which occurs frequently in HIV+ patients with progressive multifocal leukoencephalopathy (PML) treated with antiretroviral medications. This poses a difficult diagnostic and therapeutic conundrum, since neurological deterioration associated with inflammation in PML-IRIS cannot be differentiated from the demyelination occurring with the natural evolution of PML. In addition, a growing number of PML patients are developing seizures, thought to originate in the cerebral cortex. How PML, a disease affecting predominantly the CNS white mater triggers seizures is unknown. Our long term goal is to understand the pathogenic mechanisms of PML-IRIS, and the cause of epileptogenesis in PML and its association with IRIS. Our objective is to establish precise criteria to diagnose and track IRIS and predict the development of seizures in PML, which can then be used for preventive and therapeutic purposes. We have shown that the T-cell response to the causative agent of PML, JC virus (JCV), was associated with PML survival. Using proton magnetic resonance spectroscopy (1H-MRS) and arterial spin labeling (ASL) MRI, we have defined differences in the metabolism and perfusion of PML lesions with and without IRIS. Finally, we have identified a novel MRI marker associated with seizures and IRIS. This hyperintense cortical signal (HCS) can be seen on pre- contrast T1-weighted images in cortical gray matter adjacent to PML lesions. We hypothesize that hyperperfusion seen in PML progressors delineates virologically active lesions and is triggered by local production of nitric oxide (NO). We postulate that HCS is caused by an infiltrate of macrophages and astrogliosis in deep layers of the cerebral cortex affected by JCV demyelination, and constitutes the nidus of epileptogenesis in PML. We propose that IRIS is caused by an imbalance between Th1, Th2 and Th17 immune responses. The rationale for the proposed research is that a combination of immunological, neuroradiological and electrophysiological parameters will predict the development of IRIS and seizures in PML, and directly help in the management of these challenging patients. To test these hypotheses, we will pursue the following set of Specific Aims: 1) Characterize immunological and radiological determinants of inflammation and outcome in PML patients with and without IRIS. We will study JCV-specific T-cell responses, MRI, 1H- MRS and perfusion MRI to define further the mechanisms of IRIS and identify surrogate markers of PML progression and survival. 2) Analyze the role of IRIS in PML-associated epileptogenesis. We will determine prospectively the value of HCS and of dense array electroencephalographic findings as predictive markers of IRIS and seizures in PML. 3) Decipher the histopathological substrates of PML progression, epileptogenesis and IRIS. We will characterize histologically the pathogenic mechanisms leading to HCS, hyperperfusion and IRIS. Our multifaceted innovative approach will have direct impact on the management of patients with PML-IRIS and seizures. The knowledge gained will greatly advance the fields of Neuroradiology, Immunology and Epileptology.

Public Health Relevance

The proposed research is relevant to public health because it will have an important positive impact on the clinical management of Progressive Multifocal Leukoencephalopathy patients presenting with Immune Reconstitution Inflammatory Syndrome and seizures, and provide targets for preventive and therapeutic interventions. Once such strategies become available, they will decrease the morbidity and mortality not only in the context of PML and PML-IRIS, but also likely benefit patients with other infectious or inflammatory diseases of the CNS. Thus, the proposed research is relevant to the part of NINDS'mission that pertains to developing fundamental knowledge to alleviate the burdens of neurological diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS047029-10
Application #
8788881
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2003-07-01
Project End
2019-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02215
Miskin, Dhanashri P; Herman, Susan T; Ngo, Long H et al. (2016) Predictors and characteristics of seizures in survivors of progressive multifocal leukoencephalopathy. J Neurovirol 22:464-71
Miskin, Dhanashri P; Ngo, Long H; Koralnik, Igor J (2016) Diagnostic delay in progressive multifocal leukoencephalopathy. Ann Clin Transl Neurol 3:386-91
Crossley, Kate M; Agnihotri, Shruti; Chaganti, Joga et al. (2016) Recurrence of progressive multifocal leukoencephalopathy despite immune recovery in two HIV seropositive individuals. J Neurovirol 22:541-5
Bialasiewicz, Seweryn; Hart, Gareth; Oliver, Kimberly et al. (2016) A Difficult Decision: Atypical JC Polyomavirus Encephalopathy in a Kidney Transplant Recipient. Transplantation :
Miskin, Dhanashri P; Koralnik, Igor J (2015) Novel syndromes associated with JC virus infection of neurons and meningeal cells: no longer a gray area. Curr Opin Neurol 28:288-94
Varma, Gopal; Duhamel, Guillaume; de Bazelaire, Cedric et al. (2015) Magnetization transfer from inhomogeneously broadened lines: A potential marker for myelin. Magn Reson Med 73:614-22
Chalkias, Spyridon G; Gheuens, Sarah; Bord, Evelyn et al. (2015) Brief Report: Role of Thymic Reconstitution in the Outcome of AIDS-Related PML. J Acquir Immune Defic Syndr 70:357-61
Wüthrich, Christian; Batson, Stephanie; Koralnik, Igor J (2015) Lack of Major Histocompatibility Complex Class I Upregulation and Restrictive Infection by JC Virus Hamper Detection of Neurons by T Lymphocytes in the Central Nervous System. J Neuropathol Exp Neurol 74:791-803
Satyanarayana, Gowri; Hammond, Sarah P; Broge Jr, Thomas A et al. (2015) BK polyomavirus reactivation after reduced-intensity double umbilical cord blood cell transplantation. Transpl Immunol 32:116-20
Kaliyaperumal, Saravanan; Wüthrich, Christian; Westmoreland, Susan V et al. (2015) Simian Virus 40 Infection in the Spinal Cord of Simian Immunodeficiency Virus-Immunosuppressed Rhesus Macaques. J Neuropathol Exp Neurol 74:1071-6

Showing the most recent 10 out of 74 publications