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Project A2: Louisa Rasp, doctoral researcher (MD)

Systematic comparison of latency reversing agents on Transcription of Human T-cell leukaemia virus Type 1

The Human T-cell leukemia virus Type 1 (HTLV-1) is a deltaretrovirus infecting 5-10 million people worldwide. It is highly oncogenic and can cause T-cell leukemia or chronic progressive inflammatory diseases. As no efficient treatment regimens are available against infection or its severe diseases, the work of elucidating novel therapies against this highly oncogenic virus is expected to have a significant impact on helping people threatened by HTLV-1.

Target of the therapeutic approach tested here is to reverse the remarkably long latency period of HTLV-1 infection, which lasts 20-40 years. During this period, a baseline cytotoxic CD8+ T-cell response (CTL) is still detectable in infected patients but not sufficient to eradicate all infected cells. The immunodominant protein which is recognized by the CTL’s is called Tax.

The latency reversing approach is called "kick and kill" strategy. By reactivating the expression of the HTLV-1 protein Tax ("kick") in the infected cells, Tax can be represented via MHC I and recognized by host CD8+ T-cells. If sufficient eradication of infected cells follows, the HTLV-1 proviral load would decline, thus, preventing onset of HTLV-1-induced maladies.

In this project, the latency-reversing agents (LRAs) in single and combined treatments are tested in this project, similar to research on HIV treatments. Promising approaches seek to interfere with the host cell's DNA folding process using histone deacetylase inhibitors (HDACi) and to activate positive transcription elongation factor b (P-TEFb) to increase viral transcription. To develop customized treatments for HTLV-1 using HDACi, the HDAC classes binding the integrated HTVL-1 proviral DNA in the host cell will be studied. Afterward, HDACi targeting those HDAC classes will be tested, as well as novel P-TEFb activators. Further tests will focus on finding combinations of compounds of both LRA classes to sufficiently increase Tax expression to foster eradication of infected cells.