The immune reconstitution inflammatory syndrome (IRIS) is a frequent complication of antiretroviral therapy in HIV+ individuals. IRIS is described as an inflammatory reaction at the site of infection with numerous opportunistic pathogens, caused by a recovery of the immune system. Although IRIS appears to be immune-mediated, the pathogenesis of this syndrome has not been studied in detail. Progressive Multifocal Leukoencephalopathy (PML) occurring in the context of IRIS is characterized by contrast enhancement, swelling and even mass effect that may prove lethal and may require treatment with steroids. While JC virus, the causative agent of PML, infects oligodendrocytes and astrocytes in the CNS white matter, newly recognized JCV-infected cerebellar granule cell neurons may also act as a target of the immune response in IRIS. Furthermore, we have identified intracortical lesions of PML and, for the first time, observed JCV infection of cerebral hemispheric cortical neurons. As anti-HIV medications become more potent, PML IRIS is likely to become more prominent clinically. We have defined the cellular immune response to JCV mediated by CD8+ T lymphocytes. While CD4+ T cell-mediated immune recovery appears to be of importance in IRIS, whether these cells react specifically against JCV has not been characterized in detail. In addition, the prevalence of JCV infection of neurons, and whether these cells can be recognized by the immune system and participate to IRIS, remains unknown. We hypothesize that rather than the absolute rise of CD4+ T cells during HAART, the frequency of JCV-specific CD4+ T cells will predict the development of IRIS in PML patients. PML lesions will have a different metabolic profile in IRIS cases by proton MR spectroscopy (1H-MRS) and reversible inflammation will be differentiated from permanent demyelination using magnetization transfer, diffusion and perfusion imaging. We predict that intracortical lesions of PML are an important part of the disease burden, including in some cases JCV-infected cortical neurons. Absence of MHC class I antigens on JCV-infected neurons may promote escape from immune recognition in IRIS. To test these hypotheses, we propose to perform the following experiments: 1) Analyze JCV-specific CD4+ T cells by Enzyme-linked immuno-spot (ELISPOT) and intracellular cytokine staining (ICS) assays in PML patients with and without IRIS 2) Evaluate the metabolism and differentiate inflammation from demyelination in PML lesions and adjacent gray matter of patients with an without IRIS with contrast-enhanced MRI, 1H-MRS, Magnetization Transfer, Diffusion and Perfusion Imaging 3) Explore whether JCV-infected neurons in cerebral cortex and granule cell layer of the cerebellum can be recognized by the immune system, determine their prevalence and characterize the molecular determinants of JCV tropism for these cells

Public Health Relevance

JC virus (JCV) causes a demyelinating disease of the brain in immunosuppressed individuals called Progressive Multifocal Leukoencephalopathy (PML). In these studies, we will characterize the mechanisms leading to the potentially lethal immune reconstitution inflammatory syndrome (IRIS), which occurs frequently in HIV+ PML patients after initiation of antiretroviral therapy. The knowledge we will gain from these studies will greatly expand our understanding of JCV pathogenesis and will have a direct impact on patient care.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047029-09
Application #
8319409
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2003-07-01
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
9
Fiscal Year
2012
Total Cost
$416,500
Indirect Cost
$171,500
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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
Dang, Louis; Dang, Xin; Koralnik, Igor J et al. (2014) JC polyomavirus granule cell neuronopathy in a patient treated with rituximab. JAMA Neurol 71:487-9
Siddiqi, Omar K; Ghebremichael, Musie; Dang, Xin et al. (2014) Molecular diagnosis of central nervous system opportunistic infections in HIV-infected Zambian adults. Clin Infect Dis 58:1771-7
Agnihotri, Shruti P; Dang, Xin; Carter, Jonathan L et al. (2014) JCV GCN in a natalizumab-treated MS patient is associated with mutations of the VP1 capsid gene. Neurology 83:727-32
Schwenk, Hayden; Ramirez-Avila, Lynn; Sheu, Shu-Hsien et al. (2014) Progressive multifocal leukoencephalopathy in pediatric patients: case report and literature review. Pediatr Infect Dis J 33:e99-105
Lach, Boleslaw; Connolly, Barbara; Wuthrich, Christian et al. (2014) Inflammatory infratentorial progressive multifocal leukoencephalopathy in a patient with rheumatoid arthritis. Neuropathology 34:39-44
Tan, Chen Sabrina; Broge Jr, Thomas A; Ngo, Long et al. (2014) Immune reconstitution after allogeneic hematopoietic stem cell transplantation is associated with selective control of JC virus reactivation. Biol Blood Marrow Transplant 20:992-9
Agnihotri, Shruti P; Wuthrich, Christian; Dang, Xin et al. (2014) A fatal case of JC virus meningitis presenting with hydrocephalus in a human immunodeficiency virus-seronegative patient. Ann Neurol 76:140-7
Chalkias, Spyridon; Dang, Xin; Bord, Evelyn et al. (2014) JC virus reactivation during prolonged natalizumab monotherapy for multiple sclerosis. Ann Neurol 75:925-34
Khoury, Michael N; Alsop, David C; Agnihotri, Shruti P et al. (2014) Hyperintense cortical signal on magnetic resonance imaging reflects focal leukocortical encephalitis and seizure risk in progressive multifocal leukoencephalopathy. Ann Neurol 75:659-69

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