Progressive Multifocal Leukoencephalopathy (PML) is a major life threatening complication in patients with AIDS and in patients undergoing immunotherapy for autoimmune diseases such as multiple sclerosis, Crohn's disease, severe plaque psoriasis, systemic lupus erythematosis, hematologic malignancies, and rheumatoid arthritis. The disease is paradoxically caused by a common human polyomavirus following the loss of normal immune surveillance of the central nervous system (CNS). Significant progress has recently been made in our understanding of PML including the discovery of of JC virus variants in PML brain that no longer recognize known virus receptors, and our recent discovery that macroglial cells in normal brain or in PML brain lack receptors for JC virus and hence do not directly bind virus. In contrast we discovered that choroid plexus epithelial cells and leptomeningeal cells are JC virus receptor positive, bind virus, and are likely playing a critical role in disseminating or maintaining JC virus infection in the CNS. Our research program will focus on understanding how JC virus or JC virus components spread directly from cell to cell giving rise to white matter lesions that are the hallmark of PML.

Public Health Relevance

This proposal focuses on understanding how the JC polyomavirus (JCPyV) invades the human brain to infect oligodendrocytes and astrocytes in the context of HIV/AIDS. JCPyV infects greater than 50% of the human population worldwide and causes a fatal central nervous system disease in humans known as Progressive Multifocal Leukoencephalopathy or PML in individuals with compromised immune systems. Our work should lead to an increased understanding of the basic biology that underpins the development of PML in the context of HIV/AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043097-17
Application #
9625661
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2001-12-15
Project End
2022-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
17
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Brown University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
O'Hara, Bethany A; Gee, Gretchen V; Atwood, Walter J et al. (2018) Susceptibility of Primary Human Choroid Plexus Epithelial Cells and Meningeal Cells to Infection by JC Virus. J Virol 92:
Haley, Sheila A; Atwood, Walter J (2017) Progressive Multifocal Leukoencephalopathy: Endemic Viruses and Lethal Brain Disease. Annu Rev Virol 4:349-367
Assetta, Benedetta; Atwood, Walter J (2017) The biology of JC polyomavirus. Biol Chem 398:839-855
Dimitriadi, Maria; Derdowski, Aaron; Kalloo, Geetika et al. (2016) Decreased function of survival motor neuron protein impairs endocytic pathways. Proc Natl Acad Sci U S A 113:E4377-86
Assetta, Benedetta; De Cecco, Marco; O'Hara, Bethany et al. (2016) JC Polyomavirus Infection of Primary Human Renal Epithelial Cells Is Controlled by a Type I IFN-Induced Response. MBio 7:
Haley, Sheila A; O'Hara, Bethany A; Nelson, Christian D S et al. (2015) Human polyomavirus receptor distribution in brain parenchyma contrasts with receptor distribution in kidney and choroid plexus. Am J Pathol 185:2246-58
Nelson, Christian D S; Ströh, Luisa J; Gee, Gretchen V et al. (2015) Modulation of a pore in the capsid of JC polyomavirus reduces infectivity and prevents exposure of the minor capsid proteins. J Virol 89:3910-21
Maginnis, Melissa S; Nelson, Christian D S; Atwood, Walter J (2015) JC polyomavirus attachment, entry, and trafficking: unlocking the keys to a fatal infection. J Neurovirol 21:601-13
O'Hara, Bethany A; Rupasinghe, Chamila; Yatawara, Achani et al. (2014) Gallic acid-based small-molecule inhibitors of JC and BK polyomaviral infection. Virus Res 189:280-5
Zins, Stephen R; Nelson, Christian D S; Maginnis, Melissa S et al. (2014) The human alpha defensin HD5 neutralizes JC polyomavirus infection by reducing endoplasmic reticulum traffic and stabilizing the viral capsid. J Virol 88:948-60

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