A Computational Model of Progressive Multifocal Leukoencephalopathy (Update 1)

Today marks the start of my third week of on-campus research, so I wanted to provide an update about what I have accomplished so far. I have been working in Professor Coleman’s computational modeling lab, using the computer program Cell Designer to model the chemical reactions and pathways of neurodegenerative diseases. My focus is on Progressive Multifocal Leukoencephalopathy (PML), a relatively rare yet fatal opportunistic disease that can affect HIV/AIDS patients as well as immunosuppressed Multiple Sclerosis and Crohn’s Disease patients who are on certain medications.

PML is caused by infection of the JC polyomavirus, which is often harbored in the kidneys or tonsils in its latent state. The body’s immunosuppressed state then allows this virus to become reactivated and enter the central nervous system, where it causes demyelination that symptomatically presents itself as severe cognitive impairments.

In these first two weeks of research, my efforts have focused on understanding and modeling the life cycle and reactivation of the JC virus. What initially began as small, fifteen species model simply showing viral entry into the cell and the stages of replication, transcription, and translation has now more than tripled in size (Fig. 1). My current model includes more receptors, complexes, catalysts, and inhibitors that are involved in this complicated viral cycle, and it is still far from complete (Fig. 2).

My initial model of the JC virus life cycle.

(Fig. 1) My initial model of the JC virus life cycle. (Click to zoom.)

Here is my current model.

(Fig. 2) Here is my current model. Hopefully it will continue to grow and improve!

In addition to the JC virus cycle, I have also been focusing on some of the proteins that initiate viral replication and late transcription, which allow the JC virus to become reactivated. Specifically, I have begun to model the Tat protein, which is heavily studied in HIV literature. This protein has been found to bind to the protein kinase complex P-TEFb, forming a new complex that promotes cooperative binding to the transactivation response element (TAR) RNA and sequential phosphorylation of RNA Polymerase II. This chain of events stimulates transcriptional activation and elongation, allowing the JC virus to spread further (Fig. 3).

This model depicts the Tat protein and the complexes it interacts with.

(Fig. 3) This model depicts the Tat protein and the complexes it interacts with.

Going forward, I plan to continue to study and model the life cycle and reactivation of the JC virus. Specifically, I will spend the next two weeks looking at transcription factors that encourage viral replication and transcription, such as NFkB. I also plan to research the role of the immune system on cytokine production, as the literature suggests that B cells may play an important role.

Though my primary focus at this point is on reading journal articles and modeling those interactions, our lab is also working on using new programming for the computational aspect of our projects. I will be learning how to eventually use the SBML Squeezer plugin and COPASI (rather than MATLAB as in prior years) to compute and analyze the kinetic reactions I am currently depicting in Cell Designer.

 

Here are some of the sources I have focused on and found most interesting over the past two weeks:

Anand K., Schulte, A., Vogel-Bachmayr, K., Scheffzek, K., & Geyer, M. (2008). Structural insights into the Cyclin T-Tat-TAR RNA transcription activation complex from EIAV. Nature Structural & Molecular Biology, 15(12).

Bagashev, A. & Sawaya, B. E. (2013). Roles and functions of HIV-1 Tat protein in the CNS: an overview. Virology Journal, 10(358).

Maginnis M. S., Nelson, C., & Atwood, W. J. (2016). JC polyomavirus attachment, entry, and trafficking: unlocking the keys to a fatal infection. Journal of Neurovirology.

Saribas, A. S., Ozdemir, A. Lam, C. & Safak, M. (2010). JC virus-induced Progressive Multifocal Leukoencephalopathy. Future Virology, 5(3), 313-323.

 

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