Extracellular vesicles from HTLV-1 infected cells modulate target cells and viral spread

Daniel O. Pinto1, Sarah Al Sharif1, Gifty Mensah1, Maria Cowen1, Pooja Khatkar1, James Erickson1, Heather Branscome1, Thomas Lattanze1, Catherine DeMarino1, Farhang Alem1, R. Magni2, Weidong Zhou2, Sandrine Alais, Hélène Dutartre, Nazira El‐Hage3, Renaud Mahieux, Lance A. Liotta2
1Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, USA
2Center for Applied Proteomics and Molecular Medicine; George Mason University; Manassas, VA USA
3Department of Immunology and NanoMedicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA

Tóm tắt

Abstract Background The Human T-cell Lymphotropic Virus Type-1 (HTLV-1) is a blood-borne pathogen and etiological agent of Adult T-cell Leukemia/Lymphoma (ATLL) and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). HTLV-1 has currently infected up to 10 million globally with highly endemic areas in Japan, Africa, the Caribbean and South America. We have previously shown that Extracellular Vesicles (EVs) enhance HTLV-1 transmission by promoting cell–cell contact. Results Here, we separated EVs into subpopulations using differential ultracentrifugation (DUC) at speeds of 2 k (2000×g), 10 k (10,000×g), and 100 k (100,000×g) from infected cell supernatants. Proteomic analysis revealed that EVs contain the highest viral/host protein abundance in the 2 k subpopulation (2 k > 10 k > 100 k). The 2 k and 10 k populations contained viral proteins (i.e., p19 and Tax), and autophagy proteins (i.e., LC3 and p62) suggesting presence of autophagosomes as well as core histones. Interestingly, the use of 2 k EVs in an angiogenesis assay (mesenchymal stem cells + endothelial cells) caused deterioration of vascular-like-tubules. Cells commonly associated with the neurovascular unit (i.e., astrocytes, neurons, and macrophages) in the blood–brain barrier (BBB) showed that HTLV-1 EVs may induce expression of cytokines involved in migration (i.e., IL-8; 100 k > 2 k > 10 k) from astrocytes and monocyte-derived macrophages (i.e., IL-8; 2 k > 10 k). Finally, we found that EVs were able to promote cell–cell contact and viral transmission in monocytic cell-derived dendritic cell. The EVs from both 2 k and 10 k increased HTLV-1 spread in a humanized mouse model, as evidenced by an increase in proviral DNA and RNA in the Blood, Lymph Node, and Spleen. Conclusions Altogether, these data suggest that various EV subpopulations induce cytokine expression, tissue damage, and viral spread.

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Tài liệu tham khảo

Acheson NH. Fundamentals of molecular virology, 2nd Edition. Wiley Global Education; 2011. 528 p.

Gessain A, Cassar O, Domanovic D, Europäisches zentrum für die prävention und die kontrolle von krankheiten. geographical distribution of areas with a high prevalence of HTLV-1 infection. 2015.

Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci USA. 1980;77(12):7415–9.

Gallo RC. History of the discoveries of the first human retroviruses: HTLV-1 and HTLV-2. Oncogene. 2005;24(39):5926–30.

Yodoi J, Takatsuki K, Masuda T. Letter: Two cases of T-cell chronic lymphocytic leukemia in Japan. N Engl J Med. 1974;290(10):572–3.

Uchiyama T, Yodoi J, Sagawa K, Takatsuki K, Uchino H. Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood. 1977;50(3):481–92.

Tagaya Y, Gallo RC. The Exceptional Oncogenicity of HTLV-1. Front Microbiol. 2017. https://doi.org/10.3389/fmicb.2017.01425/full.

Gessain A, Barin F, Vernant JC, Gout O, Maurs L, Calender A, et al. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet. 1985;2(8452):407–10.

Osame M, Usuku K, Izumo S, Ijichi N, Amitani H, Igata A, et al. HTLV-I s. Lancet. 1986;327(8488):1031–2.

Poiesz BJ, Ruscetti FW, Reitz MS, Kalyanaraman VS, Gallo RC. Isolation of a new type C retrovirus (HTLV) in primary uncultured cells of a patient with Sézary T-cell leukaemia. Nature. 1981;294(5838):268–71.

Aoki T, Hamada C, Ohno S, Miyakoshi H, Koide H, Robert-Guroff M, et al. Location of human T-cell leukemia virus (HTLV) p19 antigen on virus-producing cells. Int J Cancer. 1984;33(2):161–5.

Kondo T, Kono H, Miyamoto N, Yoshida R, Toki H, Matsumoto I, et al. Age- and sex-specific cumulative rate and risk of ATLL for HTLV-I carriers. Int J Cancer. 1989;43(6):1061–4.

Hirai H, Fujisawa J, Suzuki T, Ueda K, Muramatsu M, Tsuboi A, et al. Transcriptional activator Tax of HTLV-1 binds to the NF-kappa B precursor p105. Oncogene. 1992;7(9):1737–42.

Coffin JM. The discovery of HTLV-1, the first pathogenic human retrovirus. Proc Natl Acad Sci USA. 2015;112(51):15525–9.

Bangham CRM, Araujo A, Yamano Y, Taylor GP. HTLV-1-associated myelopathy/tropical spastic paraparesis. Nature Reviews Disease Primers. 2015;1:15012.

Kaplan JE, Osame M, Kubota H, Igata A, Nishitani H, Maeda Y, et al. The risk of development of HTLV-I-associated myelopathy/tropical spastic paraparesis among persons infected with HTLV-I. J Acquir Immune Defic Syndr. 1990;3(11):1096–101.

Naito T, Yasunaga J, Mitobe Y, Shirai K, Sejima H, Ushirogawa H, et al. Distinct gene expression signatures induced by viral transactivators of different HTLV-1 subgroups that confer a different risk of HAM/TSP. Retrovirology. 2018;15(1):72.

Einsiedel L, Woodman RJ, Flynn M, Wilson K, Cassar O, Gessain A. Human T-Lymphotropic Virus type 1 infection in an Indigenous Australian population: epidemiological insights from a hospital-based cohort study. BMC Public Health. 2016;16:787.

Martin F, Tagaya Y, Gallo R. Time to eradicate HTLV-1: an open letter to WHO. Lancet. 2018;391(10133):1893–4.

Van Prooyen N, Gold H, Andresen V, Schwartz O, Jones K, Ruscetti F, et al. Human T-cell leukemia virus type 1 p8 protein increases cellular conduits and virus transmission. Proc Natl Acad Sci USA. 2010;107(48):20738–43.

Gross C, Thoma-Kress AK. Molecular Mechanisms of HTLV-1 Cell-to-Cell Transmission. Viruses. 2016;8:3.

Bracq L, Xie M, Benichou S, Bouchet J. Mechanisms for Cell-to-Cell Transmission of HIV-1. Front Immunol. 2018. https://doi.org/10.3389/fimmu.2018.00260/full.

Omsland M, Pise-Masison C, Fujikawa D, Galli V, Fenizia C, Parks RW, et al. Inhibition of Tunneling Nanotube (TNT) Formation and Human T-cell Leukemia Virus Type 1 (HTLV-1) Transmission by Cytarabine. Sci Rep. 2018;8(1):11118.

Clapham P, Nagy K, Cheingsong-Popov R, Exley M, Weiss RA. Productive infection and cell-free transmission of human T-cell leukemia virus in a nonlymphoid cell line. Science. 1983;222(4628):1125–7.

Fan N, Gavalchin J, Paul B, Wells KH, Lane MJ, Poiesz BJ. Infection of peripheral blood mononuclear cells and cell lines by cell-free human T-cell lymphoma/leukemia virus type I. J Clin Microbiol. 1992;30(4):905–10.

Derse D, Hill SA, Lloyd PA, Chung H, Morse BA. Examining human T-lymphotropic virus type 1 infection and replication by cell-free infection with recombinant virus vectors. J Virol. 2001;75(18):8461–8.

Alais S, Mahieux R, Dutartre H. Viral source-independent high susceptibility of dendritic cells to human T-cell leukemia virus type 1 infection compared to that of T lymphocytes. J Virol. 2015;89(20):10580–90.

Tanaka M, Tanaka K, Ida C, Oue A, Yamashita S, Yao J, et al. Conflicting effects of poly(ADP-ribose) polymerase inhibitor on cell-mediated and virion-mediated HTLV-1 infection. Virus Res. 2019;270:197653.

Clark MC, Baum LG. T cells modulate glycans on CD43 and CD45 during development and activation, signal regulation, and survival. Ann N Y Acad Sci. 2012;1253(1):58–67.

Mazurov D, Ilinskaya A, Heidecker G, Filatov A. Role of O-Glycosylation and Expression of CD43 and CD45 on the Surfaces of Effector T Cells in Human T Cell Leukemia Virus Type 1 Cell-to-Cell Infection. J Virol. 2012;86(5):2447–58.

Pais-Correia A-M, Sachse M, Guadagnini S, Robbiati V, Lasserre R, Gessain A, et al. Biofilm-like extracellular viral assemblies mediate HTLV-1 cell-to-cell transmission at virological synapses. Nat Med. 2010;16(1):83–9.

Barnard AL, Igakura T, Tanaka Y, Taylor GP, Bangham CRM. Engagement of specific T-cell surface molecules regulates cytoskeletal polarization in HTLV-1-infected lymphocytes. Blood. 2005;106(3):988–95.

Nejmeddine M, Barnard AL, Tanaka Y, Taylor GP, Bangham CRM. Human T-lymphotropic virus, type 1, tax protein triggers microtubule reorientation in the virological synapse. J Biol Chem. 2005;280(33):29653–60.

Nejmeddine M, Negi VS, Mukherjee S, Tanaka Y, Orth K, Taylor GP, et al. HTLV-1–Tax and ICAM-1 act on T-cell signal pathways to polarize the microtubule-organizing center at the virological synapse. Blood. 2009;114(5):1016–25.

Pinto DO, DeMarino C, Pleet ML, Cowen M, Branscome H, Al Sharif S, et al. HTLV-1 extracellular vesicles promote cell-to-cell contact. Front Microbiol. 2019;10:2147.

Pleet ML, Mathiesen A, DeMarino C, Akpamagbo YA, Barclay RA, Schwab A, et al. Ebola VP40 in exosomes can cause immune cell dysfunction. Front Microbiol. 2016;7:1765.

Pleet ML, DeMarino C, Lepene B, Aman MJ, Kashanchi F. The Role of Exosomal VP40 in Ebola Virus Disease. DNA Cell Biol. 2017;36(4):243–8.

Pleet ML, Branscome H, DeMarino C, Pinto DO, Zadeh MA, Rodriguez M, et al. Autophagy, EVs, and infections: a perfect question for a perfect Time. Front Cell Infect Microbiol. 2018;8:18.

Barclay RA, Schwab A, DeMarino C, Akpamagbo Y, Lepene B, Kassaye S, et al. Exosomes from uninfected cells activate transcription of latent HIV-1. J Biol Chem. 2017;292(36):14764.

Ojha CR, Lapierre J, Rodriguez M, Dever SM, Zadeh MA, DeMarino C, et al. Interplay between autophagy, exosomes and HIV-1 associated neurological disorders: new insights for diagnosis and therapeutic applications. Viruses. 2017;9:7.

Anderson MR, Pleet ML, Enose-Akahata Y, Erickson J, Monaco MC, Akpamagbo Y, et al. Viral antigens detectable in CSF exosomes from patients with retrovirus associated neurologic disease: functional role of exosomes. Clin Transl Med. 2018;7(1):24.

DeMarino C, Pleet ML, Cowen M, Barclay RA, Akpamagbo Y, Erickson J, et al. Antiretroviral drugs alter the content of extracellular vesicles from HIV-1-Infected Cells. Sci Rep. 2018;8:1.

Branscome H, Paul S, Khatkar P, Kim Y, Barclay RA, Pinto DO, et al. Stem cell extracellular vesicles and their potential to contribute to the repair of damaged CNS Cells. Journal of Neuroimmune Pharmacology. 2019. https://doi.org/10.1007/s11481-019-09865-y.

Alexander DE, Leib DA. Xenophagy in herpes simplex virus replication and pathogenesis. Autophagy. 2008;4(1):101–3.

Ku B, Woo J-S, Liang C, Lee K-H, Hong H-S, E X, et al. Structural and Biochemical Bases for the Inhibition of Autophagy and Apoptosis by Viral BCL-2 of Murine γ-Herpesvirus 68. PLOS Pathogens. 2008;4(2):e25.

Chen X, Wang K, Xing Y, Tu J, Yang X, Zhao Q, et al. Coronavirus membrane-associated papain-like proteases induce autophagy through interacting with Beclin1 to negatively regulate antiviral innate immunity. Protein Cell. 2014;5(12):912–27.

Su M, Mei Y, Sanishvili R, Levine B, Colbert CL, Sinha S. Targeting γ-Herpesvirus 68 Bcl-2-mediated Down-regulation of Autophagy. J Biol Chem. 2014;289(12):8029–40.

Campbell GR, Rawat P, Bruckman RS, Spector SA. Human Immunodeficiency Virus Type 1 Nef inhibits autophagy through transcription factor EB Sequestration. PLoS Pathog. 2015;11(6):e1005018.

Fields J, Dumaop W, Eleuteri S, Elueteri S, Campos S, Serger E, et al. HIV-1 Tat alters neuronal autophagy by modulating autophagosome fusion to the lysosome: implications for HIV-associated neurocognitive disorders. J Neurosci. 2015;35(5):1921–38.

Ren T, Takahashi Y, Liu X, Loughran TP, Sun S-C, Wang H-G, et al. HTLV-1 Tax deregulates autophagy by recruiting autophagic molecules into lipid raft microdomains. Oncogene. 2015;34(3):334–45.

Gupta MK, Kaminski R, Mullen B, Gordon J, Burdo TH, Cheung JY, et al. HIV-1 Nef-induced cardiotoxicity through dysregulation of autophagy. Sci Rep. 2017;7(1):8572.

Wang J, Niu Z, Shi Y, Gao C, Wang X, Han J, et al. Bcl-3, induced by Tax and HTLV-1, inhibits NF-κB activation and promotes autophagy. Cell Signal. 2013;25(12):2797–804.

Ahsan NA, Sampey GC, Lepene B, Akpamagbo Y, Barclay RA, Iordanskiy S, et al. Presence of Viral RNA and proteins in exosomes from cellular clones resistant to rift valley fever virus infection. Front Microbiol. 2016;7:139.

Jaworski E, Narayanan A, Van Duyne R, Shabbeer-Meyering S, Iordanskiy S, Saifuddin M, et al. Human T-lymphotropic Virus Type 1-infected Cells Secrete Exosomes That Contain Tax Protein. J Biol Chem. 2014;289(32):22284–305.

Narayanan A, Iordanskiy S, Das R, Van Duyne R, Santos S, Jaworski E, et al. Exosomes derived from HIV-1-infected cells contain trans-activation response element RNA. J Biol Chem. 2013;288(27):20014–33.

Pinto DO, DeMarino C, Vo TT, Cowen M, Kim Y, Pleet ML, et al. Low-level ionizing radiation induces selective killing of HIV-1-infected cells with reversal of cytokine induction using mTOR Inhibitors. Viruses. 2020;12:8.

Sampey GC, Saifuddin M, Schwab A, Barclay R, Punya S, Chung M-C, et al. Exosomes from HIV-1-infected Cells Stimulate Production of Pro-inflammatory Cytokines through Trans-activating Response (TAR) RNA. J Biol Chem. 2016;291(3):1251–66.

Kowal J, Arras G, Colombo M, Jouve M, Morath JP, Primdal-Bengtson B, et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. PNAS. 2016;113(8):E968–77.

Tkach M, Kowal J, Théry C. Why the need and how to approach the functional diversity of extracellular vesicles. Philos Trans R Soc Lond, B, Biol Sci. 2018;373:1737.

Zijlstra A, Di Vizio D. Size matters in nanoscale communication. Nat Cell Biol. 2018;20(3):228–30.

DeMarino C, Barclay RA, Pleet ML, Pinto DO, Branscome H, Paul S, et al. Purification of high yield extracellular vesicle preparations away from virus. J Vis Exp. 2019;12:151.

Hood JL, San RS, Wickline SA. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res. 2011;71(11):3792–801.

Raimondo S, Saieva L, Corrado C, Fontana S, Flugy A, Rizzo A, et al. Chronic myeloid leukemia-derived exosomes promote tumor growth through an autocrine mechanism. Cell Commun Signal. 2015;13:8.

Gu H, Chen C, Hao X, Wang C, Zhang X, Li Z, et al. Sorting protein VPS33B regulates exosomal autocrine signaling to mediate hematopoiesis and leukemogenesis. J Clin Invest. 2016;126(12):4537–53.

Sullivan R, Maresh G, Zhang X, Salomon C, Hooper J, Margolin D, et al. The emerging roles of extracellular vesicles as communication vehicles within the tumor microenvironment and beyond. Front Endocrinol. 2017. https://doi.org/10.3389/fendo.2017.00194/full.

Pleet ML, Erickson J, DeMarino C, Barclay RA, Cowen M, Lepene B, et al. Ebola Virus VP40 modulates cell cycle and biogenesis of extracellular vesicles. J Infect Dis. 2018;2:99.

Gao T, Guo W, Chen M, Huang J, Yuan Z, Zhang Y, et al. Extracellular vesicles and autophagy in osteoarthritis. Vol. 2016, BioMed Research International:Hindawi; 2016. p. e2428915. https://www.hindawi.com/journals/bmri/2016/2428915/. Accessed 13 Apr 2020.

Xu J, Camfield R, Gorski SM. The interplay between exosomes and autophagy - partners in crime. J Cell Sci. 2018;131:15.

Coly PM, Chatterjee S, Loyer X, Boulanger C. Exploring the crosstalk between endothelial autophagy and extracellular vesicle biology: Potential role in atherosclerosis. /data/revues/18786480/v11i2/S1878648019300448/. 2019. https://www.em-consulte.com/en/article/1282654. Accessed 13 Apr 2020.

Moy RH, Gold B, Molleston JM, Schad V, Yanger K, Salzano M-V, et al. Antiviral autophagy restricts rift valley fever virus infection and is conserved from flies to mammals. Immunity. 2014;40(1):51–65.

Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010;140(3):313–26.

Jackson WT. Viruses and the autophagy pathway. Virology. 2015;479–480:450–6.

Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47(Database issue):D607–13.

To WS, Midwood KS. Plasma and cellular fibronectin: distinct and independent functions during tissue repair. Fibrogenesis Tissue Repair. 2011;4:21.

Fitzgerald W, Freeman ML, Lederman MM, Vasilieva E, Romero R, Margolis L. A system of cytokines encapsulated in extracellular vesicles. Scientific Rep. 2018;8:1.

Vallhov H, Johansson C, Veerman RE, Scheynius A. Extracellular vesicles released from the skin commensal yeast malassezia sympodialis activate human primary keratinocytes. Front Cell Infect Microbiol. 2020;10:e13.

Fitzgerald W, Gomez-Lopez N, Erez O, Romero R, Margolis L. Extracellular vesicles generated by placental tissues ex vivo: a transport system for immune mediators and growth factors. Am J Reprod Immunol. 2018;80(1):e12860.

Wynn TA. Type 2 cytokines: mechanisms and therapeutic strategies. Nat Rev Immunol. 2015;15(5):271–82.

Liew FY, Girard J-P, Turnquist HR. Interleukin-33 in health and disease. Nat Rev Immunol. 2016;16(11):676–89.

Charrin S, Jouannet S, Boucheix C, Rubinstein E. Tetraspanins at a glance. J Cell Sci. 2014;127(17):3641–8.

El-Saghir J, Nassar F, Tawil N, El-Sabban M. ATL-derived exosomes modulate mesenchymal stem cells: potential role in leukemia progression. Retrovirology. 2016;13(1):73.

Zitvogel L, Kepp O, Kroemer G. Decoding cell death signals in inflammation and immunity. Cell. 2010;140(6):798–804.

Tran TT, Groben P, Pisetsky DS. The release of DNA into the plasma of mice following hepatic cell death by apoptosis and necrosis. Biomarkers. 2008;13(2):184–200.

Urbonaviciute V, Fürnrohr BG, Meister S, Munoz L, Heyder P, De Marchis F, et al. Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE. J Exp Med. 2008;205(13):3007–18.

Allam R, Scherbaum CR, Darisipudi MN, Mulay SR, Hägele H, Lichtnekert J, et al. Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4. J Am Soc Nephrol. 2012;23(8):1375–88.

Balaj L, Lessard R, Dai L, Cho Y-J, Pomeroy SL, Breakefield XO, et al. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat Commun. 2011;2:180.

Nair RR, Mazza D, Brambilla F, Gorzanelli A, Agresti A, Bianchi ME. LPS-challenged macrophages release microvesicles coated with histones. Front Immunol. 2018;9:1463.

Tucher C, Bode K, Schiller P, Claßen L, Birr C, Souto-Carneiro MM, et al. Extracellular vesicle subtypes released from activated or apoptotic T-lymphocytes carry a specific and stimulus-dependent protein cargo. Front Immunol. 2018;9:534.

Rothaug M, Becker-Pauly C, Rose-John S. The role of interleukin-6 signaling in nervous tissue. Biochimica et Biophysica Acta (BBA) 2016;1863(6, Part A):1218–27.

Russo RC, Garcia CC, Teixeira MM, Amaral FA. The CXCL8/IL-8 chemokine family and its receptors in inflammatory diseases. Expert Review of Clinical Immunology. 2014;10(5):593–619.

Alfaro C, Sanmamed MF, Rodríguez-Ruiz ME, Teijeira Á, Oñate C, González Á, et al. Interleukin-8 in cancer pathogenesis, treatment and follow-up. Cancer Treat Rev. 2017;60:24–31.

Gonzalez-Aparicio M, Alfaro C. Influence of interleukin-8 and neutrophil extracellular Trap (NET) formation in the tumor microenvironment: is there a pathogenic role? J Immunol Res. 2019;2019:13.

Shimauchi T, Caucheteux S, Finsterbusch K, Turpin J, Blanchet F, Ladell K, et al. Dendritic cells promote the spread of Human T-Cell leukemia virus type 1 via bidirectional interactions with CD4+ T Cells. J Invest Dermatol. 2019;139(1):157–66.

Tetta C, Ghigo E, Silengo L, Deregibus MC, Camussi G. Extracellular vesicles as an emerging mechanism of cell-to-cell communication. Endocrine. 2013;44(1):11–9.

Pique C, Jones KS. Pathways of cell-cell transmission of HTLV-1. Front Microbiol. 2012;3:378.

Tang S-W, Chen C-Y, Klase Z, Zane L, Jeang K-T. The Cellular Autophagy Pathway Modulates Human T-Cell Leukemia Virus Type 1 Replication. J Virol. 2013;87(3):1699–707.

Akers JC, Gonda D, Kim R, Carter BS, Chen CC. Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J Neurooncol. 2013;113(1):1–11.

Mathieu M, Martin-Jaular L, Lavieu G, Théry C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol. 2019;21(1):9–17.

Anonymous. AIDS: proposed WHO criteria for interpreting western blot assays for HIV-1, HIV-2, and HTLV-I/HTLV-II. Bull World Health Organ. 1991;69(1):127–9

Mahieux R, Horal P, Mauclère P, Mercereau-Puijalon O, Guillotte M, Meertens L, et al. Human T-Cell Lymphotropic Virus Type 1 Gag Indeterminate Western Blot Patterns in Central Africa: relationship to Plasmodium falciparum infection. J Clin Microbiol. 2000;38(11):4049–57.

Takao S, Ishida T, Bhatia KK, Saha N, Soemantri A, Kayame OW. Seroprevalence of human T-lymphotropic virus type 1 in Papua New Guinea and Irian Jaya measured using different Western blot criteria. J Clin Virol. 2000;16(2):129–33.

Elovaara I, Koenig S, Brewah AY, Woods RM, Lehky T, Jacobson S. High human T cell lymphotropic virus type 1 (HTLV-1)-specific precursor cytotoxic T lymphocyte frequencies in patients with HTLV-1-associated neurological disease. J Exp Med. 1993;177(6):1567–73.

Greten TF, Slansky JE, Kubota R, Soldan SS, Jaffee EM, Leist TP, et al. Direct visualization of antigen-specific T cells: HTLV-1 Tax11–19- specific CD8+ T cells are activated in peripheral blood and accumulate in cerebrospinal fluid from HAM/TSP patients. PNAS. 1998;95(13):7568–73.

Nagai M, Kubota R, Greten TF, Schneck JP, Leist TP, Jacobson S. Increased activated human T cell lymphotropic virus type I (HTLV-I) Tax11-19-specific memory and effector CD8+ cells in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis: correlation with HTLV-I provirus load. J Infect Dis. 2001;183(2):197–205.

Kubota R, Soldan SS, Martin R, Jacobson S. Selected cytotoxic T lymphocytes with high specificity for HTLV-I in cerebrospinal fluid from a HAM/TSP patient. Journal of NeuroVirology. 2002;8(1):53–7.

Tattermusch S, Skinner JA, Chaussabel D, Banchereau J, Berry MP, McNab FW, et al. Systems biology approaches reveal a specific interferon-inducible signature in HTLV-1 Associated Myelopathy. PLoS Pathog. 2012;8(1):e1002480.

Assil S, Futsch N, Décembre E, Alais S, Gessain A, Cosset F-L, et al. Sensing of cell-associated HTLV by plasmacytoid dendritic cells is regulated by dense β-galactoside glycosylation. PLoS Pathog. 2019;15(2):e1007589.

Stanifer ML, Pervolaraki K, Boulant S. Differential Regulation of Type I and Type III Interferon Signaling. Int J Mol Sci. 2019;20(6):1445.

Mahgoub M, Yasunaga J, Iwami S, Nakaoka S, Koizumi Y, Shimura K, et al. Sporadic on/off switching of HTLV-1 Tax expression is crucial to maintain the whole population of virus-induced leukemic cells. PNAS. 2018;2017:15724.

Belrose G, Gross A, Olindo S, Lézin A, Dueymes M, Komla-Soukha I, et al. Effects of valproate on Tax and HBZ expression in HTLV-1 and HAM/TSP T lymphocytes. Blood. 2011;118(9):2483–91.

Giam C-Z, Semmes OJ. HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma-A Tale of Two Proteins: Tax and HBZ. Viruses. 2016;16(8):6.

Akbarin MM, Shirdel A, Bari A, Mohaddes ST, Rafatpanah H, Karimani EG, et al. Evaluation of the role of TAX, HBZ, and HTLV-1 proviral load on the survival of ATLL patients. Blood Res. 2017;52(2):106–11.

Enose-Akahata Y, Vellucci A, Jacobson S. Role of HTLV-1 Tax and HBZ in the Pathogenesis of HAM/TSP. Front Microbiol. 2017;8:2563.

Felderhoff-Mueser U, Schmidt OI, Oberholzer A, Bührer C, Stahel PF. IL-18: a key player in neuroinflammation and neurodegeneration? Trends Neurosci. 2005;28(9):487–93.

Terao S, Yilmaz G, Stokes KY, Russell J, Ishikawa M, Kawase T, et al. Blood cell-derived RANTES mediates cerebral microvascular dysfunction, inflammation, and tissue injury after focal ischemia-reperfusion. Stroke. 2008;39(9):2560–70.

Shigemoto-Mogami Y, Hoshikawa K, Sato K. Activated microglia disrupt the blood-brain barrier and induce chemokines and cytokines in a rat in vitro model. Front Cell Neurosci. 2018. https://doi.org/10.3389/fncel.2018.00494/full.