Characterization of the interaction between the HTLV-1 transactivator protein Tax with human transcription elongation factor ELL2 and its impact on viral transcription
The human T-cell lymphotropic Virus Type 1 (HTLV-1) is a highly oncogenic retrovirus causing a type of cancer called adult T-cell leukaemia/lymphoma (ATLL) or an inflammatory disease leading to damage of the spinal cord, known as HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The virus is endemic in Japan, Sub-Saharan Africa, South America and Australia and 5-10 million people are infected worldwide. Due to very inefficient cell-free transmission, the virus is mainly transmitted via the virological synapse, viral biofilm or cellular protrusions. During infection, HTLV-1 integrates into the host cell genome. Interestingly, HTLV-1 can persist over decades in the host without causing symptoms. HTLV-1 infection is not part of sexual health screening in most countries, thus, asymptomatic carriers are mainly unaware of their infection and may pass the virus to other people. During latency, HTLV-1 shows reduced gene expression without expression of the immunodominant viral Tax protein, thus, allowing the virus to escape from the CD8+ cytotoxic T-cell response (CTL) of the host.
The aim of my project is to elucidate the protein complex that guides HTLV-1-transcription and to interfere with this complex to enhance viral transcription. Enhanced viral gene expression should then expose the viral reservoir to immune destruction. The HTLV-1-encoded oncoprotein Tax functions as a transactivator of viral gene expression, is essential for replication of HTLV-1 by recruiting host cell factors like positive transcription elongation factor b (pTEFb) to the viral promotor and interacts with transcription elongation factor ELL2. Starting point of my project is to further characterize the Tax:ELL2 interaction, which will help to gain novel insights into the composition of the protein complex guiding HTLV-1 transcription. ELL2 enhances Tax-mediated transactivation of the viral promotor and plays a role in viral gene regulation. Even though a Tax:ELL2 complex has been described, it is still unknown which domains of Tax and ELL2 are essential for the interaction and how this interaction affects viral gene expression.
