title: Host restriction factor SAMHD1 limits human T cell leukemia virus type 1 infection of monocytes via STING-mediated apoptosis.
abstract: Human 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.
authors.affiliation: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Sze
authors.forename: S Mehdi
authors.initials: SM
authors.lastname: Belgnaoui
authors.forename: David
authors.initials: D
authors.lastname: Olagnier
authors.forename: Rongtuan
authors.initials: R
authors.lastname: Lin
authors.forename: John
authors.initials: J
authors.lastname: Hiscott
authors.forename: Julien
authors.initials: J
authors.lastname: van Grevenynghe
mesh_terms: D017209:Apoptosis; D015368:Human T-lymphotropic virus 1 / Q000276:immunology*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology* / Q000821:virology*; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D000076106:SAM Domain and HD Domain-Containing Protein 1; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000099197:STING Protein
chemical_list: D050838:Interferon Regulatory Factor-3; D008565:Membrane Proteins; D020559:Monomeric GTP-Binding Proteins; D000076106:SAM Domain and HD Domain-Containing Protein 1; D051028:bcl-2-Associated X Protein; C494826:BAX protein, human; C494232:IRF3 protein, human; C532857:STING1 protein, human; D000099197:STING Protein; C484280:SAMHD1 protein, human