A Computational Model of Progressive Multifocal Leukoencephalopathy (Update 2)

As my fourth week of summer research draws to a close, I wanted to provide another update on my progress. I’ve been working on a computational model showing the cellular interactions that allow the reactivation and spread of the JC virus, which is the cause of the opportunistic infection Progressive Multifocal Leukoencephalopathy. For the past two weeks, my primary focus has been on transcription factors and the role they play in viral infection. Specifically, I looked at transforming growth factor beta 1 (TGF-B1), tumor necrosis factor alpha (TNFa), and nuclear factor kappa beta (NFkB). All three of these factors promote viral transcription, furthering the spread of the JC virus throughout the body, and most devastatingly, the brain.

When I began investigating TGF-B1, I found myself surprised at how crucial this transcription factor is to viral spread as well at the complexity of the pathway. TGF-B1 binds to a receptor on the cell surface, which then triggers the phosphorylation and activation of Smads, a family of signal transducers that translocate to the nucleus and target specific viral genes. Also involved in this protein network are mitogen activated protein kinases (MAPKs), which further consist of extracellular signal-regulated kinases 1 and 2 (ERK1/2). As depicted in the model (Fig. 1), TGF-B1 also activates ERK1/2, stimulating JC virus multiplication and transcription. TGF-B1 does this as part of a complex with the protein Tat, which I previously modeled.

Fig. 1

(Fig. 1) TGF-B1 Model (Click to zoom.)

While researching TNFa, I noticed that NFkB was frequently referenced in literature about the other transcription factors. This led me to focus on NFkB in my next model, and it reminded me that though I am using separate models for clarity purposes, all of these factors act simultaneously and aggregately in the body. For this reason, my current model of NFkB (Fig. 2) also involves TNFa, Tat, and Rad51 (which I plan to research more in the coming weeks). In this model, we see the formation of a crucial complex from two existing complexes. The first consists of the transcription factor TNFa and its receptor, among other binding proteins. The second is the IKK complex, which becomes activated and phosphorylates the inhibitor of kappa beta (IkB). This step is extremely important, because it allows NFkB to dissociate from IkB and then translocate to the nucleus. Once in the nucleus, NFkB associates with Rad51 and promotes viral transcription.

(Fig. 2) NFkB Model

(Fig. 2) NFkB Model

Going forward, I plan to research Rad51 in more detail. I will then continue looking at other transcription factors such as C/EBPB and AP1, which have both been mentioned in literature concerning NFkB. I look forward to improving upon my transcription factor model, which has grown significantly¬†just¬†within the past week. (See Fig. 3 and 4 for earlier versions of this model – there’s definitely been an improvement!)

(Fig. 4) TNFa early model

(Fig. 3) TNFa early model

(Fig. 3) NFkB early model

(Fig. 4) NFkB early model


Cited below are some of the sources I relied on to build these models.


Chen, X., Weisberg, E., Fridmacher, V., Watanabe, M., Naco, G., & Whitman, M. (1997). Smad4 and FAST-1 in the assembly of activin-responsive factor. Nature, 389(6646), 85-89.

Cohen, M. M. (2003). TGFB/Smad signaling system and its pathologic correlates. American Journal of Medical Genetics, 116A, 1-10.

DuShane, J. K., Wilczek, M. P., Mayberry, C. L., & Maginnis, M. S. (2018). ERK is a critical regulator of JC polyomavirus infection. Journal of Virology, 92(7).

TNFa and NFkB:

Karin, M. & Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of NFkB activity. (2000). Annual Review of Immunology, 18, 621-623.

Kumar, A., Abbas, W., & Herbein, G. (2013). TNF and TNF receptor superfamily members in HIV infection: new cellular targets for therapy? Mediators of Inflammation, 2013.

Sanz, L., Sanchez, P., Lallena, M., Diaz-Meco, M. T., & Moscat, J. (1999). The interaction of p62 with RIP links the atypical PKCs to NFkB activation. The EMBO Journal, 18(11), 3044-3053.

White, M. K., Ibba, G., Pietropaolo, V., Palamara, A. T., & Wollebo, H. S. (2017). The DNA damage response promotes polyomavirus JC infection by nucleus to cytoplasm NFkB activation. Virology Journal, 14(31).