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• W2025962058 abstract "•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 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. 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. Infection with human T cell leukemia virus type 1 (HTLV-1) affects approximately 20 million people worldwide (Cook et al., 2013Cook L.B. Elemans M. Rowan A.G. Asquith B. HTLV-1: persistence and pathogenesis.Virology. 2013; 435: 131-140Crossref PubMed Scopus (78) Google Scholar) and is a major cause of mortality and morbidity in endemic areas such as southern Japan, the Caribbean basin, Central/South America, and Western Africa (Ragin et al., 2008Ragin C. Edwards R. Heron D.E. Kuo J. Wentzel E. Gollin S.M. Taioli E. Prevalence of cancer-associated viral infections in healthy afro-Caribbean populations: a review of the literature.Cancer Invest. 2008; 26: 936-947Crossref PubMed Scopus (11) Google Scholar). Most infected individuals are asymptomatic carriers of the virus, although they remain at risk for opportunistic infections (Verdonck et al., 2007Verdonck K. González E. Van Dooren S. Vandamme A.M. Vanham G. Gotuzzo E. Human T-lymphotropic virus 1: recent knowledge about an ancient infection.Lancet Infect. Dis. 2007; 7: 266-281Abstract Full Text Full Text PDF PubMed Scopus (499) Google Scholar). Chronic HTLV-1 infection can lead to a number of severe pathologies associated with poor prognosis, including the aggressive adult T cell leukemia (ATL), progressive HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), uveitis, and infective dermatitis in children (Cook et al., 2013Cook L.B. Elemans M. Rowan A.G. Asquith B. HTLV-1: persistence and pathogenesis.Virology. 2013; 435: 131-140Crossref PubMed Scopus (78) Google Scholar, Yamano and Sato, 2012Yamano Y. Sato T. Clinical pathophysiology of human T-lymphotropic virus-type 1-associated myelopathy/tropical spastic paraparesis.Front Microbiol. 2012; 3: 389Crossref PubMed Scopus (121) Google Scholar). HTLV-1 has a preferential tropism for CD4+ T cells, while both CD4+ and CD8+ T cells constitute viral reservoirs in HAM/TSP patients (Cook et al., 2013Cook L.B. Elemans M. Rowan A.G. Asquith B. HTLV-1: persistence and pathogenesis.Virology. 2013; 435: 131-140Crossref PubMed Scopus (78) Google Scholar). Unlike most retroviruses, cell-free HTLV-1 is poorly infectious and does not stably infect its primary CD4+ T lymphocyte target. Rather, HTLV-1 utilizes various cell-to cell transmission strategies, including transfer of viral assemblies, formation of virological synapses, or formation of intracellular conduits (Igakura et al., 2003Igakura T. Stinchcombe J.C. Goon P.K. Taylor G.P. Weber J.N. Griffiths G.M. Tanaka Y. Osame M. Bangham C.R. Spread of HTLV-I between lymphocytes by virus-induced polarization of the cytoskeleton.Science. 2003; 299: 1713-1716Crossref PubMed Scopus (573) Google Scholar, Pais-Correia et al., 2010Pais-Correia A.M. Sachse M. Guadagnini S. Robbiati V. Lasserre R. Gessain A. Gout O. Alcover A. Thoulouze M.I. Biofilm-like extracellular viral assemblies mediate HTLV-1 cell-to-cell transmission at virological synapses.Nat. Med. 2010; 16: 83-89Crossref PubMed Scopus (234) Google Scholar, Van Prooyen et al., 2010Van Prooyen N. Gold H. Andresen V. Schwartz O. Jones K. Ruscetti F. Lockett S. Gudla P. Venzon D. Franchini G. Human T-cell leukemia virus type 1 p8 protein increases cellular conduits and virus transmission.Proc. Natl. Acad. Sci. USA. 2010; 107: 20738-20743Crossref PubMed Scopus (117) Google Scholar). HTLV-1 also infects cells of the myeloid lineage, which play critical roles in the host innate response to viral infection. Previous studies have shown that cell-free HTLV-1 particles can productively infect DC, which then participate in viral transmission to and transformation of CD4+ T cells (Jones et al., 2008Jones K.S. Petrow-Sadowski C. Huang Y.K. Bertolette D.C. Ruscetti F.W. Cell-free HTLV-1 infects dendritic cells leading to transmission and transformation of CD4(+) T cells.Nat. Med. 2008; 14: 429-436Crossref PubMed Scopus (220) Google Scholar). HTLV-1 infection of DC elicits an early antiviral response mediated by the production of type I interferon (IFN) (Colisson et al., 2010Colisson R. Barblu L. Gras C. Raynaud F. Hadj-Slimane R. Pique C. Hermine O. Lepelletier Y. Herbeuval J.P. Free HTLV-1 induces TLR7-dependent innate immune response and TRAIL relocalization in killer plasmacytoid dendritic cells.Blood. 2010; 115: 2177-2185Crossref PubMed Scopus (53) Google Scholar), although the number of peripheral DC, as well as the IFN response, is reduced in chronically infected asymptomatic and ATL subjects (Hishizawa et al., 2004Hishizawa M. Imada K. Kitawaki T. Ueda M. Kadowaki N. Uchiyama T. Depletion and impaired interferon-alpha-producing capacity of blood plasmacytoid dendritic cells in human T-cell leukaemia virus type I-infected individuals.Br. J. Haematol. 2004; 125: 568-575Crossref PubMed Scopus (73) Google Scholar). Monocyte precursors that would normally replenish the DC population are unable to properly differentiate during chronic HTLV-1 infection, and recent evidence indicates monocyte depletion in HTLV-1 infected patients (Makino et al., 2000Makino M. Wakamatsu S. Shimokubo S. Arima N. Baba M. Production of functionally deficient dendritic cells from HTLV-I-infected monocytes: implications for the dendritic cell defect in adult T cell leukemia.Virology. 2000; 274: 140-148Crossref PubMed Scopus (49) Google Scholar, Nascimento et al., 2011Nascimento C.R. Lima M.A. de Andrada Serpa M.J. Espindola O. Leite A.C. Echevarria-Lima J. Monocytes from HTLV-1-infected patients are unable to fully mature into dendritic cells.Blood. 2011; 117: 489-499Crossref PubMed Scopus (30) Google Scholar). The molecular consequences of de novo HTLV-1 infection on host innate immunity in monocytic cells have yet to be elucidated. Human myeloid and bystander CD4+ T cells are refractory to HIV-1 infection, in part because the host restriction factor SAMHD1 prevents efficient viral DNA synthesis (Baldauf et al., 2012Baldauf H.M. Pan X. Erikson E. Schmidt S. Daddacha W. Burggraf M. Schenkova K. Ambiel I. Wabnitz G. Gramberg T. et al.SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells.Nat. Med. 2012; 18: 1682-1687Crossref PubMed Scopus (452) Google Scholar, Descours et al., 2012Descours B. Cribier A. Chable-Bessia C. Ayinde D. Rice G. Crow Y. Yatim A. Schwartz O. Laguette N. Benkirane M. SAMHD1 restricts HIV-1 reverse transcription in quiescent CD4(+) T-cells.Retrovirology. 2012; 9: 87Crossref PubMed Scopus (263) Google Scholar, Laguette and Benkirane, 2012Laguette N. Benkirane M. How SAMHD1 changes our view of viral restriction.Trends Immunol. 2012; 33: 26-33Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, Laguette et al., 2011Laguette N. Sobhian B. Casartelli N. Ringeard M. Chable-Bessia C. Ségéral E. Yatim A. Emiliani S. Schwartz O. Benkirane M. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx.Nature. 2011; 474: 654-657Crossref PubMed Scopus (1123) Google Scholar). SAMHD1 functions in nondividing cells as a deoxynucleoside triphosphate triphosphohydrolase, which hydrolyzes the endogenous pool of deoxynucleoside triphosphates (dNTP) to levels below the threshold required for reverse transcription (Ayinde et al., 2012Ayinde D. Casartelli N. Schwartz O. Restricting HIV the SAMHD1 way: through nucleotide starvation.Nat. Rev. Microbiol. 2012; 10: 675-680Crossref PubMed Scopus (49) Google Scholar, Goldstone et al., 2011Goldstone D.C. Ennis-Adeniran V. Hedden J.J. Groom H.C. Rice G.I. Christodoulou E. Walker P.A. Kelly G. Haire L.F. Yap M.W. et al.HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase.Nature. 2011; 480: 379-382Crossref PubMed Scopus (610) Google Scholar, Lahouassa et al., 2012Lahouassa H. Daddacha W. Hofmann H. Ayinde D. Logue E.C. Dragin L. Bloch N. Maudet C. Bertrand M. Gramberg T. et al.SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates.Nat. Immunol. 2012; 13: 223-228Crossref PubMed Scopus (620) Google Scholar). SAMHD1 was initially characterized in the context of the autoimmune disorder Aicardi-Goutières syndrome, and genetic mutations that render SAMHD1 nonfunctional result in uncontrolled inflammatory and type I IFN responses against self DNA (Rice et al., 2009Rice G.I. Bond J. Asipu A. Brunette R.L. Manfield I.W. Carr I.M. Fuller J.C. Jackson R.M. Lamb T. Briggs T.A. et al.Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response.Nat. Genet. 2009; 41: 829-832Crossref PubMed Scopus (534) Google Scholar). Primary cells from these patients are highly susceptible to HIV-1 infection (Baldauf et al., 2012Baldauf H.M. Pan X. Erikson E. Schmidt S. Daddacha W. Burggraf M. Schenkova K. Ambiel I. Wabnitz G. Gramberg T. et al.SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells.Nat. Med. 2012; 18: 1682-1687Crossref PubMed Scopus (452) Google Scholar, Berger et al., 2011Berger A. Sommer A.F. Zwarg J. Hamdorf M. Welzel K. Esly N. Panitz S. Reuter A. Ramos I. Jatiani A. et al.SAMHD1-deficient CD14+ cells from individuals with Aicardi-Goutières syndrome are highly susceptible to HIV-1 infection.PLoS Pathog. 2011; 7: e1002425Crossref PubMed Scopus (206) Google Scholar, Descours et al., 2012Descours B. Cribier A. Chable-Bessia C. Ayinde D. Rice G. Crow Y. Yatim A. Schwartz O. Laguette N. Benkirane M. SAMHD1 restricts HIV-1 reverse transcription in quiescent CD4(+) T-cells.Retrovirology. 2012; 9: 87Crossref PubMed Scopus (263) Google Scholar). The Vpx accessory protein of HIV-2 and its counterpart in certain strains of SIV antagonize SAMHD1 by inducing proteasome-dependent degradation (Ayinde et al., 2012Ayinde D. Casartelli N. Schwartz O. Restricting HIV the SAMHD1 way: through nucleotide starvation.Nat. Rev. Microbiol. 2012; 10: 675-680Crossref PubMed Scopus (49) Google Scholar, Laguette et al., 2012Laguette N. Rahm N. Sobhian B. Chable-Bessia C. Münch J. Snoeck J. Sauter D. Switzer W.M. Heneine W. Kirchhoff F. et al.Evolutionary and functional analyses of the interaction between the myeloid restriction factor SAMHD1 and the lentiviral Vpx protein.Cell Host Microbe. 2012; 11: 205-217Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). HIV-1 restriction mediated by SAMHD1 is overcome by silencing its expression with Vpx or by the addition of exogenous dN (deoxynucleosides) (Baldauf et al., 2012Baldauf H.M. Pan X. Erikson E. Schmidt S. Daddacha W. Burggraf M. Schenkova K. Ambiel I. Wabnitz G. Gramberg T. et al.SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells.Nat. Med. 2012; 18: 1682-1687Crossref PubMed Scopus (452) Google Scholar, Descours et al., 2012Descours B. Cribier A. Chable-Bessia C. Ayinde D. Rice G. Crow Y. Yatim A. Schwartz O. Laguette N. Benkirane M. SAMHD1 restricts HIV-1 reverse transcription in quiescent CD4(+) T-cells.Retrovirology. 2012; 9: 87Crossref PubMed Scopus (263) Google Scholar, Laguette et al., 2011Laguette N. Sobhian B. Casartelli N. Ringeard M. Chable-Bessia C. Ségéral E. Yatim A. Emiliani S. Schwartz O. Benkirane M. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx.Nature. 2011; 474: 654-657Crossref PubMed Scopus (1123) Google Scholar, Lahouassa et al., 2012Lahouassa H. Daddacha W. Hofmann H. Ayinde D. Logue E.C. Dragin L. Bloch N. Maudet C. Bertrand M. Gramberg T. et al.SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates.Nat. Immunol. 2012; 13: 223-228Crossref PubMed Scopus (620) Google Scholar). Recognition of evolutionarily conserved molecular structures shared by pathogens, known as pathogen-associated molecular patterns (PAMP), is critical for the initiation of innate immune responses (Kumar et al., 2011Kumar H. Kawai T. Akira S. Pathogen recognition by the innate immune system.Int. Rev. Immunol. 2011; 30: 16-34Crossref PubMed Scopus (1467) Google Scholar). Multiple surface and cytosolic pathogen recognition receptors (PRR) (Kawai and Akira, 2011Kawai T. Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity.Immunity. 2011; 34: 637-650Abstract Full Text Full Text PDF PubMed Scopus (2590) Google Scholar) have now been identified that sense and respond to microbial infection. Toll-like receptors (TLR) detect distinct PAMP such as lipopolysaccharide (TLR4), single-stranded (ss) and double-stranded (ds) RNA (TLR7/8 and TLR3, respectively), and CpG DNA (TLR9) (Blasius and Beutler, 2010Blasius A.L. Beutler B. Intracellular toll-like receptors.Immunity. 2010; 32: 305-315Abstract Full Text Full Text PDF PubMed Scopus (873) Google Scholar, Kawai and Akira, 2011Kawai T. Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity.Immunity. 2011; 34: 637-650Abstract Full Text Full Text PDF PubMed Scopus (2590) Google Scholar). The retinoic acid-inducible gene-I (RIG-I)-like receptors (RLR), which include RIG-I and MDA5, represent another PRR family that recognizes cytosolic viral RNA (Blasius and Beutler, 2010Blasius A.L. Beutler B. Intracellular toll-like receptors.Immunity. 2010; 32: 305-315Abstract Full Text Full Text PDF PubMed Scopus (873) Google Scholar, Kawai and Akira, 2011Kawai T. Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity.Immunity. 2011; 34: 637-650Abstract Full Text Full Text PDF PubMed Scopus (2590) Google Scholar). PRR responsible for the detection of cytosolic DNA include DAI, DDX41, cGAS, and IFI16, all of which trigger IFN production, as well as AIM2 that stimulates an inflammasome-dependent secretion of the proinflammatory IL-1β cytokine (Barber, 2011Barber G.N. Innate immune DNA sensing pathways: STING, AIMII and the regulation of interferon production and inflammatory responses.Curr. Opin. Immunol. 2011; 23: 10-20Crossref PubMed Scopus (193) Google Scholar, Sun et al., 2013Sun L. Wu J. Du F. Chen X. Chen Z.J. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway.Science. 2013; 339: 786-791Crossref PubMed Scopus (2508) Google Scholar). The endoplasmic reticulum resident adaptor STING functions as a DNA sensor for bacterial cyclic GTP (Burdette and Vance, 2013Burdette D.L. Vance R.E. STING and the innate immune response to nucleic acids in the cytosol.Nat. Immunol. 2013; 14: 19-26Crossref PubMed Scopus (341) Google Scholar) and mediates detection of viral DNA (Ishikawa and Barber, 2008Ishikawa H. Barber G.N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling.Nature. 2008; 455: 674-678Crossref PubMed Scopus (1945) Google Scholar, Ishikawa et al., 2009Ishikawa H. Ma Z. Barber G.N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity.Nature. 2009; 461: 788-792Crossref PubMed Scopus (1664) Google Scholar, Zhong et al., 2008Zhong B. Yang Y. Li S. Wang Y.Y. Li Y. Diao F. Lei C. He X. Zhang L. Tien P. Shu H.B. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation.Immunity. 2008; 29: 538-550Abstract Full Text Full Text PDF PubMed Scopus (1010) Google Scholar). STING can also directly complex with ss and ds cytoplasmic viral DNA to initiate antiviral signaling (Abe et al., 2013Abe T. Harashima A. Xia T. Konno H. Konno K. Morales A. Ahn J. Gutman D. Barber G.N. STING recognition of cytoplasmic DNA instigates cellular defense.Mol. Cell. 2013; 50: 5-15Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). In the present study, we characterized de novo infection of primary human monocytes by HTLV-1 and demonstrated that HTLV-1 infection induces SAMHD1-mediated apoptosis in monocytic cells. We further showed that production of HTLV-1 reverse transcription intermediates (RTI), generated in the presence of SAMHD1, complexed with the innate immune sensor STING and initiated IRF3-Bax-directed apoptosis. These results elucidate the mechanism of HTLV-1 abortive infection of monocytes and link the host restriction factor SAMHD1, the sensing of retroviral RTI by STING, and the initiation of IRF3-Bax-driven apoptosis. To characterize the impact of HTLV-1 infection on the host antiviral response in primary human monocytes, we first assessed the percentage of HTLV-1-infected monocytes at 3 hr postinfection (hpi), using increasing concentrations of purified HTLV-1 (0–5 μg/ml). Virus binding to monocytes was dependent on the quantity of HTLV-1, as illustrated by surface staining with anti-Env (gp46) monoclonal antibodies (Figure 1A); for subsequent experiments, an HTLV-1 concentration of 2 μg/ml was used, since >90% of the cells displayed virus binding (Figure 1A) (91.7 ± 4.8% gp46+ cells; p > 0.05; n = 5). HTLV-1 particles were efficiently internalized by monocytes, as determined by intracellular HTLV-1 viral RNA (vRNA) detection at 3 hpi, with the viral RNA load gradually decreasing over the 120 hr time course (Figure 1B). HTLV-1 internalization was further demonstrated by intracellular staining (ICS) for the viral matrix protein p19 at 24 hpi (Figure 1C, blue histograms) (86.7 ± 6.2% of p19+ monocytes; p < 0.01 compared to uninfected cells; n = 5). Importantly, viral binding and internalization were eliminated by pretreating HTLV-1 with anti-gp46 neutralizing mAb or pretreating monocytes with 0.1% trypsin (Jones et al., 2005Jones K.S. Petrow-Sadowski C. Bertolette D.C. Huang Y. Ruscetti F.W. Heparan sulfate proteoglycans mediate attachment and entry of human T-cell leukemia virus type 1 virions into CD4+ T cells.J. Virol. 2005; 79: 12692-12702Crossref PubMed Scopus (153) Google Scholar) (Figure 1C) (p < 0.01 compared to infected cells). The absence of intracellular Tax protein and virion release indicated that monocytes were not productively infected by HTLV-1 (Figure 1C and Figure S1, respectively). Monocyte-derived DC, on the other hand, were productively infected with HTLV-1 (40.6 ± 5.7% Tax+ cells at 24 hpi) (data not shown). Despite the nonproductive infection by HTLV-1, monocytes generated a robust innate immune response, as illustrated by the induction of multiple parameters of antiviral signaling. An early increase in phosphorylated interferon regulatory factor 3 (P-IRF3) was detected at 3 hpi (Figure 1D), while increased expression of STAT1, phosphorylated STAT1 (P-STAT1), interferon-stimulated gene 56 (ISG56), and RIG-I were observed at 24 and 48 hpi. We next evaluated the level of apoptosis in HTLV-1-infected CD14+ monocytes by Annexin-V staining. At 24 hpi, infected monocytes displayed higher levels of apoptosis than uninfected cultures (Figure 2A) (22.9 ± 3.5% versus 8.6 ± 1.3%, respectively; p < 0.01; n = 5), and by 72 hr the percentage of HTLV-1 infected apoptotic cells increased to over 45%. Infection of monocytes with a low dose of HTLV-1 (0.1 μg/ml) also resulted in apoptosis in the p19+ population (Figure S2A). Apoptosis was accompanied by the generation of cleaved caspase-3 (Figure 2B and Figure S2B) (33.4 ± 12.3% and 11.4 ± 2%, for HTLV-1-infected and uninfected cells, respectively; p < 0.01; n = 5) and loss of mitochondrial potential as shown by reduced DiOC6(3) intensity (Figure 2C and Figure S2C) (p < 0.01; n = 5). The pan-caspase inhibitor Z-VAD or the blocking α-gp46 mAb prevented CLcaspase-3-mediated apoptosis (Figure 2B) and mitochondrial depolarization (Figure 2C). Z-VAD did not interfere with the internalization of HTLV-1, as detected by measuring intracellular p19 (Figure 2B, blue histograms) (p > 0.05; n = 5). A strong statistical correlation between (1) caspase-3 activation and (2) mitochondrial depolarization and apoptosis was confirmed by the nonparametric Spearman test (Figure 2D) (r = 0.7845 and 0.9036, respectively, for 1 and 2; p < 0.0001; n = 25). Expression of mitochondrial pro- and antiapoptotic molecules were also analyzed; increased Bax expression and caspase-9 cleavage were observed in infected monocytes (Figure 2E) (p < 0.05 and p < 0.01, respectively; n = 3), while expression of Bcl-2 family members Bim, Noxa, Bcl-2, and Mcl-1 were unchanged. In the above experiments, we did not observe death by necrosis or an effect of necrostatin-1 on infected monocytes (Figure S2D). Cleaved caspase-1 and bioactive IL-1β were detected after infection, indicating activation of the inflammasome (Figure S2E). To investigate caspase-1-associated pyroptosis, HTLV-1-infected cells were treated with YVAD, a selective inhibitor of caspase-1; a minor but significant improvement of cell survival was observed (Figure S2F). The above observations, detailing abortive HTLV-1 infection of monocytes, are reminiscent of the consequences of host restriction by SAMHD1 during HIV-1 infection (Baldauf et al., 2012Baldauf H.M. Pan X. Erikson E. Schmidt S. Daddacha W. Burggraf M. Schenkova K. Ambiel I. Wabnitz G. Gramberg T. et al.SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells.Nat. Med. 2012; 18: 1682-1687Crossref PubMed Scopus (452) Google Scholar, Descours et al., 2012Descours B. Cribier A. Chable-Bessia C. Ayinde D. Rice G. Crow Y. Yatim A. Schwartz O. Laguette N. Benkirane M. SAMHD1 restricts HIV-1 reverse transcription in quiescent CD4(+) T-cells.Retrovirology. 2012; 9: 87Crossref PubMed Scopus (263) Google Scholar, Doitsh et al., 2010Doitsh G. Cavrois M. Lassen K.G. Zepeda O. Yang Z. Santiago M.L. Hebbeler A.M. Greene W.C. Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue.Cell. 2010; 143: 789-801Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar, Laguette et al., 2011Laguette N. Sobhian B. Casartelli N. Ringeard M. Chable-Bessia C. Ségéral E. Yatim A. Emiliani S. Schwartz O. Benkirane M. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx.Nature. 2011; 474: 654-657Crossref PubMed Scopus (1123) Google Scholar), prompting us to investigate whether SAMHD1 functioned similarly to restrict HTLV-1 infection. Small interfering RNA (siRNA)-mediated silencing of SAMHD1 resulted in a 72 ± 11.8% reduction in SAMHD1 expression (Figure 3A), but did not alter HTLV-1 internalization in control or siRNA-transfected monocytes (>95.5%) (Figure 3B, right histograms). Following HTLV-1 infection, induced apoptosis was also reduced by ∼70% in SAMHD1-silenced monocytes compared to control siRNA-treated monocytes (Figure 3B) (p < 0.01; n = 5). The correlation between inhibition of SAMHD1 expression and inhibition of HTLV-1-induced apoptosis in primary monocytes was significant (Figure 3C) (r = 1; p = 0.0167; n = 5, Spearman test). The deoxynucleoside triphosphate triphosphohydrolase function of SAMHD1 blocks reverse transcription of retroviral RNA by depleting the dNTP pool required for complete reverse transcription (Ayinde et al., 2012Ayinde D. Casartelli N. Schwartz O. Restricting HIV the SAMHD1 way: through nucleotide starvation.Nat. Rev. Microbiol. 2012; 10: 675-680Crossref PubMed Scopus (49) Google Scholar, Goldstone et al., 2011Goldstone D.C. Ennis-Adeniran V. Hedden J.J. Groom H.C. Rice G.I. Christodoulou E. Walker P.A. Kelly G. Haire L.F. Yap M.W. et al.HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase.Nature. 2011; 480: 379-382Crossref PubMed Scopus (610) Google Scholar, Hollenbaugh et al., 2013Hollenbaugh J.A. Gee P. Baker J. Daly M.B. Amie S.M. Tate J. Kasai N. Kanemura Y. Kim D.H. Ward B.M. et al.Host factor SAMHD1 restricts DNA viruses in non-dividing myeloid cells.PLoS Pathog. 2013; 9: e1003481Crossref PubMed Scopus (128) Google Scholar, Kim et al., 2012Kim B. Nguyen L.A. Daddacha W. Hollenbaugh J.A. Tight interplay among SAMHD1 protein level, cellular dNTP levels, and HIV-1 proviral DNA synthesis kinetics in human primary monocyte-derived macrophages.J. Biol. Chem. 2012; 287: 21570-21574Crossref PubMed Scopus (160) Google Scholar, Lahouassa et al., 2012Lahouassa H. Daddacha W. Hofmann H. Ayinde D. Logue E.C. Dragin L. Bloch N. Maudet C. Bertrand M. Gramberg T. et al.SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates.Nat. Immunol. 2012; 13: 223-228Crossref PubMed Scopus (620) Google Scholar), an effect reversed by the addition of exogenous dN (Lahouassa et al., 2012Lahouassa H. Daddacha W. Hofmann H. Ayinde D. Logue E.C. Dragin L. Bloch N. Maudet C. Bertrand M. Gramberg T. et al.SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates.Nat. Immunol. 2012; 13: 223-228Crossref PubMed Scopus (620) Google Scholar). To explore the relationship between the triphosphohydrolase activity of SAMHD1 and apoptosis, primary monocytes were infected with HTLV-1 in the presence of increasing concentrations of exogenous dN (0–100 nM). SAMHD1-mediated apoptosis was inhibited by addition of exogenous dN in a dose-dependent manner (Figure 3D), with apoptosis reduced to control levels in monocytes treated with 100 nM dN (>80% inhibition of apoptosis). We did not observe de novo Tax expression following SAMHD1 knockdown or dN treatment in infected monocytes at 48 hpi (n = 3; data not shown). These results demonstrate that nucleotide pool depletion, mediated by SAMHD1 function, correlates directly with HTLV-1-induced apoptosis. Previous studies demonstrated that incomplete synthesis of retroviral DNA triggered a proapoptotic response in HIV-1-infected bystander CD4+ T cells (Doitsh et al., 2010Doitsh G. Cavrois M. Lassen K.G. Zepeda O. Yang Z. Santiago M.L. Hebbeler A.M. Greene W.C. Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue.Cell. 2010; 143: 789-801Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar). To assess the presence of RTI in HTLV-1-infected monocytes, viral DNA was measured in total versus nuclear fractions at 3–120 hpi; HTLV-1 RTI were detected only in the total fraction (Figure 4A and Figures S3A and S3B), indicating that viral DNA synthesis was initiated in the cytosol, but was not fully reverse transcribed and did not reach the nucleus (Nisole and Saïb, 2004Nisole S. Saïb A. Early steps of retrovirus replicative cycle.Retrovirology. 2004; 1: 9Crossref PubMed Scopus (135) Google Scholar). Silencing SAMHD1 expression or treatment with exogenous dN led to the detection of HTLV-1 DNA in the nucleus, as well as integrated provirus, in infected monocytes (Figure 4B and Figure S3C). Several primer pairs were designed to monitor sequential steps in HTLV-1 reverse transcription, including strong-stop DNA (5′utr), and DNA elongation (env or gag) (Figure 4C, upper schematic, and Table S1) (Doitsh et al., 2010Doitsh G. Cavrois M. Lassen K.G. Zepeda O. Yang Z. Santiago M.L. Hebbeler A.M. Greene W.C. Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue.Cell. 2010; 143: 789-801Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar). Primary monocytes were treated with 5μM azidothymidine (AZT), a nucleoside analog reverse transcriptase inhibitor that prevents elongation of reverse-transcribed DNA after initiation (Doitsh et al., 2010Doitsh G. Cavrois M. Lassen K.G. Zepeda O. Yang Z. Santiago M.L. Hebbeler A.M. Greene W.C. Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue.Cell. 2010; 143: 789-801Abstract Full Text Full Text PDF PubMed Scopus (317" @default.
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