The Helicase-Like transcription factor synergizes with HTLV-1 TAX to activate the NF-¿B Pathway

Abstract

The human T-cell leukaemia virus type 1 (HTLV-1) is the first human retrovirus that has been discovered. It induces serious diseases including the adult T-cell leukaemia (ATL) and the HTLV-1-associated myopathy/tropical spastic paraparesis (HAM/TSP). Approximately 20 million people worldwide are infected with this oncogenic retrovirus, but only 5-10% will develop disease related to the infection. Tax, a trans-regulatory, activating nuclear oncoprotein, encoded by HLTV-1, has been identified as essential for cell replication and transformation. Preliminary data have shown that the helicase-like transcription factor (HLTF), a DNA damage tolerance regulator, is a restriction factor able to reduce HTLV-1 infectivity. These studies also demonstrated that HLTF interacts with Tax. The objective of this undergraduate thesis is to evaluate the impact of Tax and HLTF on transcriptional activity directed by the HLTF promoter and the HTLV-1 long terminal repeat (LTR). Activation of the NF-κB pathway will also be evaluated in presence of wild-type and mutants of HLTF and Tax. Data show that Tax mutants defective in NF-κB activation are expressed at lower levels compared to wild-type Tax. Luciferase reporter assays further show that Tax and HLTF mutants do not impact HLTF promoter activity. HLTF mutants do influence neither the transcription directed by the LTR nor the NF-κB pathway. Simultaneous induction of Tax and HLTF produces a synergistic effect on a NF-κB-AP-1-Luc reporter. In summary, this work contributed to a better understanding of the mechanisms involved in the interactions between Tax and HLTF.