The HTLV-1 Tax oncoprotein targets the HLTF E3 ubiquitin ligase, a tumor suppressor that regulates innate immunity and DNA damage tolerance pathways

Abstract

The human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus inducing adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Approximately 20 million people worldwide are infected with this oncogenic retrovirus. Two viral proteins (Tax and HBZ) have been identified as key players in viral replication and cell transformation. Restriction factors are antiviral proteins involved in intrinsic immunity. They counteract the action of viral proteins acting at different steps of the virus life cycle. Recently, the helicase-like transcription factor (HLTF), a regulator of DNA damage tolerance pathways, has been identified as restriction factor in the human immunodeficiency virus (HIV). The goal of this project is to examine the role of HLTF as restriction factor in HTLV-1. Microarray data analysis reveals a high variability of HLTF expression within ATL patients compared to healthy donors, indicating a HLTF expression dysregulation in ATL patients. In HTLV-1 infected cell lines, co-culture experiments show that increased levels of HLTF reduce HTLV-1 infectivity, suggesting that HLTF is a restriction factor. Co-immunoprecipitation experiments showed that HLTF interacts with Tax, indicating a role of viral proteins in this mechanism. Results also reveal that the abundance of Tax and HLTF are inversely correlated, independently of HBZ levels. These findings suggest that HLTF is a restriction factor that mediates HTLV-1 infection.