Human T-cell Leukemia Virus type 1 (HTLV-1)

HTLV-1 is the etiologic agent of the acute T-cell leukemia (ATL). HTLV-1 infection is characterized by viral latency, which is assumed to represent a viral strategy to escape from the host immune response and to allow tumor development. HTLV-1 latency results from the in vivo transcriptional silencing of the RNA polymerase II promoter located in the viral 5'Long Terminal Repeat (5'LTR). The 5’LTR promoter controls the expression of the viral transactivator Tax, which transactivates this promoter by inducing a nucleosomal remodeling nearby the transcription start site. Another HTLV-1 gene is HBZ which is transcribed in the antisense orientation from the 3’LTR and which is the only HTLV-1 gene conserved and expressed in ATL cells.

Role of the cellular factor BCL11b in the transcriptional regulation of HTLV-1

The present research project aims at further understanding the molecular mechanisms regulating HTLV-1 transcription and viral latency in the T lymphocytes by focusing on the role of the cellular factor BCL11b and its involvement in HTLV- 1-mediated tumorigenesis. To this end, we will investigate the recruitment of BCL11b on the HTLV-1 promoters in the latently-HTLV-1 infected cell lines and in PBCMS from ATL patients. Then, we will characterize the interplay between BCL11b and Tax and the involvement of BCL11b in Tax downregulation via the autophagy pathway. To determine the role of BCL11b in HTLV-1 latency, we will study the impact of BCL11b on transcriptional regulation of the HTLV-1 3’LTR and the potential interaction between BCL11b and HBZ. Finally, we will investigate the role of BCL11b in the chromatin accessibility of the HTLV-1 genome by ATAC-seq in BCL11b-knocked-down PBMCs isolated from ATL patients. Altogether, these experiments will contribute to a more detailed understanding of the molecular mechanisms of establishment and maintenance of HTLV-1 latency and thus to the development of novel therapeutic strategies against HTLV-1.