Sebastian Millen

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C6 Effects of Tax and p8 proteins on cell-to-cell transmission of Human T-cell lymphotropic virus type 1 (HTLV-1)

Principal investigator
Andrea Thoma-Kress

Mentor
Alexander Steinkasserer

Inhibition of signal transduction during Tax-induced transmission of Human T-cell lymphotropic virus type I (HTLV-1)

The δ-retrovirus Human T-cell lymphotropic virus type I (HTLV-1) is the causative agent of severe diseases, including adult T-cell leukemia/lymphoma (ATLL) and the neurodegenerative HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The virus primarily infects CD4+ T-cells eventually resulting in a lifelong persistence. Cell-free transmission of HTLV-1 has been proven to be very inefficient whilst it is dependent on cell-cell-contacts. Thus, the main routes of transmission are represented by blood or cell-containing blood products, sexual contacts and breastfeeding. On the molecular level, transmission pathways can be separated into the formation of the virological synapse and transmission via biofilms or actin-containing cellular protrusions, the latter being induced by the viral accessory protein p8. Overall, the Tax oncoprotein plays a pivotal role for the interplay between HTLV-1 and target cells. Next to its transforming oncogenic potential, Tax is able to interfere with or induce cellular signaling like NF-κB, resulting in deregulation of several cellular pathways and thus, contributing to viral spread. However, the role of Tax in terms of cellular signaling and transmission has not been elucidated in detail. Consequently, a major aim of my PhD thesis will be to identify and describe specific signaling pathways activated by Tax in order to facilitate transmission. Additionally, previous work of our group showed that the actin-bundling protein Fascin is induced by Tax, dependent on NF-κB signaling, as well as it plays a role in virus transmission (see Christine Gross). Next to this actin-bundling protein, microarray analysis identified COL4A1 and COL4A2 (Collagen type IV alpha 1/alpha 2) transcripts to be induced by Tax. Collagen type IV is exclusively expressed in Tax-positive T-cells and thus, being a part of viral biofilms, is a highly attractive target to study. In order to further investigate the hypothesis of a potential role for Collagen type IV during Tax-mediated HTLV-1 transmission I will focus on signaling pathways altered by Tax as well as on the physiological consequences for the infected cells, including effects on their morphology, the formation of biofilms and the capability of transmission (see figure).

Figure: Model of Tax-induced transmission of HTLV-1. In HTLV-1 infected cells, the viral oncoprotein Tax is expressed. Tax induces Fascin via NF-κB signaling and an additional, promoter-independent pathway, which is sensitive to PP2, in order to increase viral transmission. Tax serves as an interaction platform with several cellular partners which remain largely unidentified in regard of their role on transmission. Thus, Tax interferes with cellular signaling pathways eventually resulting in the activation of target genes. In my PhD thesis I am going to investigate which cellular pathways are deregulated by Tax as well as whether a potential induction of COL4A1/2 by Tax might contribute to an elevated cell-to-cell-transmission of HTLV-1.

 

Publications

 

Presentations

October 2016 8th Annual Retreat, Erlangen School of Molecular Communication, Schloss Schney, Lichtenfels, Germany
“COL4A1 and COL4A2: Novel HTLV-1 Tax targets playing a role in virus transmission”
Talk