The helicase-like transcription factor inhibits infectious replication of the human T-cell leukemia virus type 1

The human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that induces adult T-cell leukemia/lymphoma (ATL), an aggressive T-cell tumor, and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a neurodegenerative disorder. Globally, approximately 20 million people are infected with this oncogenic retrovirus. At present, there is unfortunately no universally recognized primary treatment for HTLV-1 infection and its associated diseases. Two crucial viral proteins, Tax and HBZ, have been identified as key factors in both viral replication and cell transformation.
The coevolution of retroviruses and their hosts is characterized by a delicate balance between viral replication and the survival of infected cells. In this equilibrium, infected cells express restriction factors that control various steps of retroviral replication, such as entry, uncoating, nuclear import, expression, or budding. In our study, we describe a new mechanism of restriction against HTLV-1 mediated by the helicase-like transcription factor (HLTF). Our findings indicate reduced RNA and protein levels of HLTF in primary T-cells of HTLV-1-infected subjects, suggesting clinical relevance. We also demonstrate that the viral oncogene Tax represses HLTF transcription through the Enhancer of zeste homolog 2 methyltransferase of the Polycomb repressive complex 2 (EZH2). Additionally, Tax directly interacts with HLTF and induces its proteasomal degradation. RNA interference and gene transduction experiments in HTLV-1-infected cell lines confirm that HLTF acts as a restriction factor. Restoring normal HLTF expression levels induces the dispersal of the Golgi apparatus and overproduction of secretory granules. Through synergizing with Tax-mediated NF-κB activation, physiologically relevant levels of HLTF intensify the autophagic flux. This increased vesicular trafficking results in enlarged lysosomes and the production of large vacuoles containing viral particles. HLTF induction in HTLV-1-infected cells significantly increases the percentage of defective virions. In conclusion, HLTF-mediated activation of the autophagic flux interferes with the infectious replication cycle of HTLV-1, revealing an original mode of viral restriction.