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Project A2: Abarna Baheerathan, doctoral researcher (PhD)

Enhancing immunogenicity of Human T-cell leukaemia virus Type 1 (HTLV-1) by interfering with viral transcription

Human T-cell leukaemia virus Type 1 (HTLV-1) is a delta-retrovirus that induces severe lymphoproliferative and/or inflammatory diseases in infected individuals. Upon infection, the virus latently persists in the organism life-long, which is characterized by reduced gene expression of viral proteins such as the immunodominant protein Tax. The reduction of Tax gene expression allows the virus to escape from the CD8+ cytotoxic T-cell (CTL) response directed towards Tax in order to avoid a destruction by the immune system. Hence, new strategies are required to interfere with HTLV-1 latency. Therefore, our aim is to enhance viral gene expression and antigen presentation of Tax in order to promote the CTL-response directed against the viral Tax protein and to expose the latent HTLV-1 reservoir to immune destruction. Previously, we tested the hypothesis whether more recent histone deacetylase inhibitors (HDACi) enhance viral gene expression. We found that the HDACi Romidepsin and Panobinostat significantly enhance viral sense transcription, but viral protein expression was only enhanced moderately. Thus, additional strategies are needed to enhance HTLV-1 gene expression. Furthermore, we have already identified that apart from the well-known positive transcription elongation factor (P-TEFb), the transcription elongation factor ELL2 complexes with Tax which is essential for Tax-mediated transactivation of the HTLV-1 promotor. Yet, the detailed composition of these transcription complexes and their impact on viral reactivation from latency is still undiscovered. Taken together, the aim of this project is to discover the transcription complex guiding HTLV-1 transcription, which is crucial to develop strategies to manipulate HTLV-1 gene expression.