Date of Award


Level of Access Assigned by Author

Open-Access Thesis

Degree Name

Doctor of Philosophy (PhD)


Biomedical Sciences


Melissa Maginnis

Second Committee Member

Sally Molloy

Third Committee Member

Robert Gundersen

Additional Committee Members

Melody Neely

Paul Millard


Viruses require a host cell in order to replicate. Infection and the onset of disease result from direct virus-host cell interactions. My dissertation research is focused on understanding how a common human virus, JC polyomavirus (JCPyV), activates specific host cell factors to cause infection. When people are immunocompromised, JCPyV infection may exacerbate into the onset of progressive multifocal leukoencephalopathy (PML), a fatal neurodegenerative disease. Individuals with the greatest risk for the development of PML are those living with multiple sclerosis or infected with HIV. Unfortunately 50-80% of the population is infected by JCPyV, putting individuals at risk for developing PML. Limited therapies exist to treat PML, highlighting the need for effective therapeutics, candidates with the most promise target the initial interactions between JCPyV and host cell receptors, blocking their communication, thus preventing viral attachment, entry, and resultant infection. JCPyV recognizes and interacts with specific proteins, or receptors, on the host cell surface, resulting in the uptake of the virus into the cell. JCPyV requires the serotonin receptor subtype 2 (A, B, and C) family to internalize, however, the cellular proteins that mediate internalization and how they drive viral infection is poorly understood.

This dissertation research aimed to characterize the processes by which JCPyV usurps cellular endocytic machinery to internalize into host cells. The work described herein has demonstrated that proteins central to the clathrin-mediated endocytic pathway are crucial for JCPyV entry and infection,

including clathrin, AP2, β-arrestin, and dynamin. β-arrestin is capable of localizing to, and interacting with, serotonin receptors. Additionally, this work has further characterized the requirement of these contacts through modification of the β-arrestin binding domains within the receptor and through knockdown of the cellular protein, GRK2, responsible for initiating serotonin receptor-β-arrestin communications, both of which block JCPyV entry.

This research demonstrates that direct interaction between serotonin receptors and β-arrestin is a major determinant for JCPyV entry and is critical for driving the infectious process. Understanding the role of these proteins in virus internalization may serve as a platform for the development of novel treatments for PML. Together, this work defines how JCPyV internalization occurs within host cells.

Included in

Virology Commons