Progressive Multifocal Leukoencephalopathy (PML) is a major life threatening complication in patients with underlying immunosuppressive disorders (e.g. 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 activation from a latent to a lytic phase of growth. There are several critical gaps in our understanding of the basic biology of PML. First, the anatomical site of virus latency is not known but kidney, tonsil, bone marrow, and brain have all been postulated to be involved. Second, the mechanisms that govern latency versus lytic growth of the virus are not well understood. Third, the mechanisms of viral spread to the CNS and within the CNS are not known. We hypothesize that virus induced signals reprogram the cellular environment to promote replication and spread and that epigenetics plays a role in governing the balance between latency and activation. The experiments proposed here will define these signals and the molecular pathways involved in viral pathogenesis. These mechanisms and pathways may be amenable to pharmacological intervention.

Public Health Relevance

This proposal focuses on understanding how the JC polyomavirus (JCV) alters its environment to promote its growth and spread in multiple human tissues. JCV infects greater than 70% 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 the development of therapeutic approaches to prevent or treat JCV induced disease in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043097-11
Application #
8319349
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2001-12-15
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
11
Fiscal Year
2012
Total Cost
$364,500
Indirect Cost
$139,500
Name
Brown University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
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:
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
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
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
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
Carney, Daniel W; Nelson, Christian D S; Ferris, Bennett D et al. (2014) Structural optimization of a retrograde trafficking inhibitor that protects cells from infections by human polyoma- and papillomaviruses. Bioorg Med Chem 22:4836-47
Haley, Sheila A; Atwood, Walter J (2014) An animal model for progressive multifocal leukoencephalopathy. J Clin Invest 124:5103-6
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
Assetta, Benedetta; Maginnis, Melissa S; Gracia Ahufinger, Irene et al. (2013) 5-HT2 receptors facilitate JC polyomavirus entry. J Virol 87:13490-8

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