Host Restriction Factor SAMHD1 Limits Human T Cell Leukemia Virus Type 1 Infection of Monocytes via STING-Mediated Apoptosis

•HTLV-1 infection of primary monocytes is nonproductive and elicits an antiviral response•Host restriction factor SAMHD1 aborts HTLV-1 reverse transcription•HTLV-1 reverse transcription intermediates (RTI) form a complex with STING•RTI sensing by STING generates an IRF3-Bax complex that triggers apoptosis to limit HTLV-1

SummaryHuman T cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T cell leukemia and HTLV-1-associated myelopathies. In addition to T cells, HTLV-1 infects cells of the myeloid lineage, which play critical roles in the host innate response to viral infection. Investigating the monocyte depletion observed during HTLV-1 infection, we discovered that primary human monocytes infected with HTLV-1 undergo abortive infection accompanied by apoptosis dependent on SAMHD1, a host restriction factor that hydrolyzes endogenous dNTPs to below the levels required for productive reverse transcription. Reverse transcription intermediates (RTI) produced in the presence of SAMHD1 induced IRF3-mediated antiviral and apoptotic responses. Viral RTIs complexed with the DNA sensor STING to trigger formation of an IRF3-Bax complex leading to apoptosis. This study provides a mechanistic explanation for abortive HTLV-1 infection of monocytes and reports a link between SAMHD1 restriction, HTLV-1 RTI sensing by STING, and initiation of IRF3-Bax driven apoptosis.

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