Host restriction factor SAMHD1 limits Human T-cell Leukemia Virus Type 1 (HTLV-1) infection of monocytes through STING-mediated apoptosis

摘要

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T cell leukemia and HTLV-1-associated myelopathies. HTLV-1 virions are poorly infectious and do not stably infect CD4⁺ T lymphocytes; however, HTLV-1 does efficiently infect cells of the myeloid lineage. Here, we investigate the mechanisms underlying monocyte depletion driven by HTLV-1 infection, and demonstrate that exposure of monocytes to HTLV-1 results in an abortive infection, accompanied by apoptosis that is dependent on the host restriction factor SAMHD1. Reverse transcription intermediates (RTI), produced in the presence of SAMHD1, induced IRF3- mediated antiviral and apoptotic responses. The viral RTI complexed with the DNA sensor STING, resulting in the formation of a pro-apoptotic IRF3-Bax complex leading to apoptosis. Overall, this study provides a mechanistic explanation for abortive retroviral infection of monocytes and reports a link between SAMHD1 restriction, sensing of retroviral HTLV-1 RTI by STING, and initiation of IRF3-Bax driven apoptosis.