Description
- Abstract:
- JC virus (JCV) is the causative agent of Progressive Multifocal Leukoencephalopathy, a fatal demyelinating disease of the central nervous system (CNS). This disease is caused by reactivation of JCV from peripheral sites within the body to the CNS, where it lytically destroys the myelin-producing oligodendrocytes. As this reactivation is triggered by immunosupression, AIDS patients are most at risk. JCV binds to cells using an ?(2-3)- or ?(2-6)-linked sialic acid and the serotonin receptor 5-HT2A. The goal of this work was to determine the cellular and host-cell factors JCV requires to facilitate delivery of its genome to the nucleus and produce its gene products. Our results show JCV requires a low pH environment during the first two to three hours of its infection. Although this environment is not required for cathepsin activation or conformational change, it is critical to the continued trafficking of JCV. As JCV moves through the cell, it encounters additional environments. We show ER calcium is critical for JCV infection. We also demonstrate JCV infection can be enhanced by loosening its capsid with trypsin prior to infection. This is likely due to an increase in the rate of uncoating. Once inside the nucleus, JCV large T is produced and accumulates in its own viral microdomain. This microdomain is adjacent to ND-10 components PML, Sp100, and Daxx. However, the large T accumulations do not require the presence of these proteins. JCV infection can proceed in the absence of PML protein and is enhanced when it is removed. Additionally, JCV does not actively remove PML during its infection. Lastly, we evaluated viral factors critical for JCV lifecycle. We determined both Vp2 and Vp3 were needed for JCV infectivity. We also showed the myristoylation moiety was critical and could not be replaced by an alternate large, bulky group. The minor proteins are also important for proper packaging of the virus. Additionally, the minor proteins make important contacts inside the virion and will likely be shown to play a critical role in virus uncoating and genome delivery in future experiments.
- Notes:
- Thesis (Ph.D.) -- Brown University (2009)
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Citation
Gasparovic, Megan L.,
"Viral and Host-Cell Factors Critical for JC Virus Infection"
(2009).
Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations, Biology and Medicine Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://doi.org/10.7301/Z0GQ6W7T
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