A Computational Model of Progressive Multifocal Leukoencephalopathy (Update 3)

These past two weeks of research have been interesting, because rather than focusing on larger subtopics as in previous weeks, I was able to look at a greater number of smaller topics. I studied a wide range of transcription factors, including C/EBPB, Sp1, AP-1, YP1, Egr-1, SRSF-1, and NF-1. As Progressive Multifocal Leukoencephalopathy (PML) and the JC virus are still a relatively new discovery, some of these factors have limited research on them. Another problem I ran into was that some of these factors have been linked to the JC virus in literature, though the exact cellular mechanisms and interactions are unknown. Computational modeling directly relies on this knowledge, making my models for these factors less thorough than past transcription factors, like NFkB.

While I didn’t include C/EBPB and Sp1 in my model, I added AP-1, YP1, Egr-1, SRSF-1, and NF-1 to my already existing model of the JC virus life cycle (Fig. 1). These factors all influence viral replication and/or transcription, though in different ways (Fig. 2). NF-1 inhibits DNA replication, while SRSF1 inhibits viral transcription. This interaction can be inhibited by Pur-alpha and large T-antigen, which I studied in previous weeks. YB-1 and Egr-1 stimulate JCV transcription, and agnoprotein inhibits the action of YB-1. So many of these factors relate to other proteins I’ve looked at previously, making these findings that much more relevant.

(Fig. 1) JC Virus Life Cycle

(Fig. 1) Updated JCV life cycle model

(Fig. 2) Newly added transcription factors

(Fig. 2) Newly added transcription factors

Now that I’ve finished studying transcription factors, I am focusing my research on the immune response, which occurs both before and after transcription factors alter viral replication and transcription. My first model on this topic (Fig. 3) shows CD8+ T lymphocytes killing virus-infected cells, which is associated with the containment of PML progression and improved survival. For my last week of research, I plan to continue researching immune response in PML, both adding to this model and creating new ones.

(Fig. 3) CD8+ T lymphocytes kill virus-infected cells

(Fig. 3) CD8+ T lymphocytes kill virus-infected cells

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