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Project A2: Annika Schnell, doctoral researcher (MD)

Systematic comparison of compounds manipulating transcription of Human T-cell leukaemia virus Type 1

The Human T-cell leukaemia virus type 1 (HTLV-1), also known as Human T-lymphotropic virus type 1, is marked by a prolonged clinical and viral latency after infection of mainly CD4+ T-cells. Clinical latency refers to the period of infection before the onset of malignant and inflammatory diseases caused by the virus. By now, there is no satisfactory curative therapy for those. One therapeutic approach, called Kick-and-Kill / Shock-and-Kill / Gene Activation Therapy, focuses on reversing viral latency. One of the regulatory factors of viral latency is the protein Tax. This key player is encoded by the pX region of the sense strand of the HTLV-1 genome. The oncoprotein enhances transcription and promotes viral production and spread. Besides, Tax is also the immunodominant protein. Within the scope of the Kick-and-Kill-strategy, we seek to activate the viral gene expression, in particular, to trigger Tax expression, to expose infected cells to the host’s immune response, via a Tax-specific CD8+ T-cell (CTL) response. Latency reversing agents (LRAs) are the subject of research for mainly HIV-1, but also HTLV-1. There are numerous studies on the effect of single or few LRAs in the context of HIV-1, but only little on HTLV-1. In the course of this project, we aim to systematically compare and analyze several rationally selected LRAs on their impact on HTLV-1 latency reversal in different cell models. Taken together, we intend to find successful LRAs, whose effectiveness in provoking a CTL response in peripheral blood mononuclear cells (PBMCs) from HTLV-1 infected patients can be shown.