Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Human T-lymphotropic virus type I: Virology, pathogenesis, and epidemiology

David T Scadden, MD
Andrew R Freedman, FRCP
Paul Robertson, MRCP, FRCPath
Section Editor
Martin S Hirsch, MD
Deputy Editor
Allyson Bloom, MD


Human T-lymphotropic virus (HTLV-I), the first human retrovirus to be discovered [1], is estimated to infect 5 to 10 million people worldwide [2,3]. This virus is the causative agent of two typically fatal diseases: adult T cell leukemia-lymphoma (ATL) [4-6] and HTLV-I-associated myelopathy (HAM) [7], which is also known as tropical spastic paraparesis (TSP) [8].

The epidemiology, virology, and pathogenic features of HTLV-I will be reviewed here. The diagnosis, disease associations, and treatment are discussed separately. (See "Human T-lymphotropic virus type I: Disease associations, diagnosis, and treatment".)


HTLV-I is an enveloped, single-stranded RNA virus of the Retroviridae family, the only human pathogen of the subfamily oncovirus, which includes HTLV-2, bovine leukemia virus (BLV), simian T cell leukemia virus (STLV) and HTLV-3 and HTLV-4 [9]. It has a diploid genome, comprised of two identical strands of positive sense RNA, each 9032 bp long. The genomic organization is similar to other retroviruses, with two long terminal repeat (LTR) sequences flanking gag, pol, and env genes (figure 1).

However, HTLV-I also possesses a unique 1.6 kb region, termed pX, which is located between env and the 3'LTR [10]. This region encodes a number of regulatory proteins: p40tax (Tax), p27rex, p21rex, p12, p13 and p30. HTLV-1 basic leucine zipper factor (HBZ) is encoded by the minus (complementary) strand of pX region [11]. Of these, Tax and HBZ have been most implicated in viral pathogenesis. (See 'Pathogenesis' below.)

Cell entry and replication — HTLV-I displays CD4 T cell tropism, but virion entry to CD4 T cells occurs most efficiently by direct cell-to-cell contact, rather than from virions free in plasma. Cell-free HTLV-1 can also infect dendritic cells (via heparin sulphate proteoglycans and neuropilin-1) [12] and can subsequently be transmitted from dendritic cells to CD4 T cells [13]. The glucose transporter, glut-1 [14,15], has also been identified as a receptor for the HTLV-1 envelope glycoprotein (env). However, cells lacking GLUT-1 expression can be infected by HTLV-1 [16].


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Jun 21, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Poiesz BJ, Ruscetti FW, Gazdar AF, et al. 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 U S A 1980; 77:7415.
  2. de Thé G, Bomford R. An HTLV-I vaccine: why, how, for whom? AIDS Res Hum Retroviruses 1993; 9:381.
  3. Gessain A, Cassar O. Epidemiological Aspects and World Distribution of HTLV-1 Infection. Front Microbiol 2012; 3:388.
  4. Hinuma Y, Nagata K, Hanaoka M, et al. Adult T-cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera. Proc Natl Acad Sci U S A 1981; 78:6476.
  5. Uchiyama T, Yodoi J, Sagawa K, et al. Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood 1977; 50:481.
  6. Yoshida M, Miyoshi I, Hinuma Y. Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease. Proc Natl Acad Sci U S A 1982; 79:2031.
  7. Osame M, Usuku K, Izumo S, et al. HTLV-I associated myelopathy, a new clinical entity. Lancet 1986; 1:1031.
  8. Gessain A, Barin F, Vernant JC, et al. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet 1985; 2:407.
  9. Mahieux R, Gessain A. The human HTLV-3 and HTLV-4 retroviruses: new members of the HTLV family. Pathol Biol (Paris) 2009; 57:161.
  10. Seiki M, Hattori S, Hirayama Y, Yoshida M. Human adult T-cell leukemia virus: complete nucleotide sequence of the provirus genome integrated in leukemia cell DNA. Proc Natl Acad Sci U S A 1983; 80:3618.
  11. Gaudray G, Gachon F, Basbous J, et al. The complementary strand of the human T-cell leukemia virus type 1 RNA genome encodes a bZIP transcription factor that down-regulates viral transcription. J Virol 2002; 76:12813.
  12. Ghez D, Lepelletier Y, Lambert S, et al. Neuropilin-1 is involved in human T-cell lymphotropic virus type 1 entry. J Virol 2006; 80:6844.
  13. Jones KS, Petrow-Sadowski C, Huang YK, et al. Cell-free HTLV-1 infects dendritic cells leading to transmission and transformation of CD4(+) T cells. Nat Med 2008; 14:429.
  14. Coskun AK, Sutton RE. Expression of glucose transporter 1 confers susceptibility to human T-cell leukemia virus envelope-mediated fusion. J Virol 2005; 79:4150.
  15. Manel N, Kim FJ, Kinet S, et al. The ubiquitous glucose transporter GLUT-1 is a receptor for HTLV. Cell 2003; 115:449.
  16. Takenouchi N, Jones KS, Lisinski I, et al. GLUT1 is not the primary binding receptor but is associated with cell-to-cell transmission of human T-cell leukemia virus type 1. J Virol 2007; 81:1506.
  17. Kakuda K, Ikematsu H, Chong WL, et al. Molecular epidemiology of human T lymphotropic virus type 1 transmission in Okinawa, Japan. Am J Trop Med Hyg 2002; 66:404.
  18. Felber BK, Paskalis H, Kleinman-Ewing C, et al. The pX protein of HTLV-I is a transcriptional activator of its long terminal repeats. Science 1985; 229:675.
  19. Sodroski JG, Rosen CA, Haseltine WA. Trans-acting transcriptional activation of the long terminal repeat of human T lymphotropic viruses in infected cells. Science 1984; 225:381.
  20. Uchiyama T. Human T cell leukemia virus type I (HTLV-I) and human diseases. Annu Rev Immunol 1997; 15:15.
  21. Taylor GP, Tosswill JH, Matutes E, et al. Prospective study of HTLV-I infection in an initially asymptomatic cohort. J Acquir Immune Defic Syndr 1999; 22:92.
  22. Etoh K, Yamaguchi K, Tokudome S, et al. Rapid quantification of HTLV-I provirus load: detection of monoclonal proliferation of HTLV-I-infected cells among blood donors. Int J Cancer 1999; 81:859.
  23. Manns A, Miley WJ, Wilks RJ, et al. Quantitative proviral DNA and antibody levels in the natural history of HTLV-I infection. J Infect Dis 1999; 180:1487.
  24. Kwaan N, Lee TH, Chafets DM, et al. Long-term variations in human T lymphotropic virus (HTLV)-I and HTLV-II proviral loads and association with clinical data. J Infect Dis 2006; 194:1557.
  25. Iga M, Okayama A, Stuver S, et al. Genetic evidence of transmission of human T cell lymphotropic virus type 1 between spouses. J Infect Dis 2002; 185:691.
  26. Jeffery KJ, Siddiqui AA, Bunce M, et al. The influence of HLA class I alleles and heterozygosity on the outcome of human T cell lymphotropic virus type I infection. J Immunol 2000; 165:7278.
  27. Grassmann R, Dengler C, Müller-Fleckenstein I, et al. Transformation to continuous growth of primary human T lymphocytes by human T-cell leukemia virus type I X-region genes transduced by a Herpesvirus saimiri vector. Proc Natl Acad Sci U S A 1989; 86:3351.
  28. Grassmann R, Berchtold S, Radant I, et al. Role of human T-cell leukemia virus type 1 X region proteins in immortalization of primary human lymphocytes in culture. J Virol 1992; 66:4570.
  29. Smith MR, Greene WC. Type I human T cell leukemia virus tax protein transforms rat fibroblasts through the cyclic adenosine monophosphate response element binding protein/activating transcription factor pathway. J Clin Invest 1991; 88:1038.
  30. Tanaka A, Takahashi C, Yamaoka S, et al. Oncogenic transformation by the tax gene of human T-cell leukemia virus type I in vitro. Proc Natl Acad Sci U S A 1990; 87:1071.
  31. Seiki M, Eddy R, Shows TB, Yoshida M. Nonspecific integration of the HTLV provirus genome into adult T-cell leukaemia cells. Nature 1984; 309:640.
  32. Yoshida M. Multiple viral strategies of HTLV-1 for dysregulation of cell growth control. Annu Rev Immunol 2001; 19:475.
  33. Jeang KT, Widen SG, Semmes OJ 4th, Wilson SH. HTLV-I trans-activator protein, tax, is a trans-repressor of the human beta-polymerase gene. Science 1990; 247:1082.
  34. Jin DY, Spencer F, Jeang KT. Human T cell leukemia virus type 1 oncoprotein Tax targets the human mitotic checkpoint protein MAD1. Cell 1998; 93:81.
  35. Satou Y, Yasunaga J, Yoshida M, Matsuoka M. HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells. Proc Natl Acad Sci U S A 2006; 103:720.
  36. Zhao T, Yasunaga J, Satou Y, et al. Human T-cell leukemia virus type 1 bZIP factor selectively suppresses the classical pathway of NF-kappaB. Blood 2009; 113:2755.
  37. Arnold J, Zimmerman B, Li M, et al. Human T-cell leukemia virus type-1 antisense-encoded gene, Hbz, promotes T-lymphocyte proliferation. Blood 2008; 112:3788.
  38. Manns A, Murphy EL, Wilks R, et al. Detection of early human T-cell lymphotropic virus type I antibody patterns during seroconversion among transfusion recipients. Blood 1991; 77:896.
  39. Kira J, Koyanagi Y, Yamada T, et al. Increased HTLV-I proviral DNA in HTLV-I-associated myelopathy: a quantitative polymerase chain reaction study. Ann Neurol 1991; 29:194.
  40. Kamihira S, Toriya K, Amagasaki T, et al. Antibodies against p40tax gene product of human T-lymphotropic virus type-I (HTLV-I) under various conditions of HTLV-I infection. Jpn J Cancer Res 1989; 80:1066.
  41. Kannagi M, Harada S, Maruyama I, et al. Predominant recognition of human T cell leukemia virus type I (HTLV-I) pX gene products by human CD8+ cytotoxic T cells directed against HTLV-I-infected cells. Int Immunol 1991; 3:761.
  42. Parker CE, Nightingale S, Taylor GP, et al. Circulating anti-Tax cytotoxic T lymphocytes from human T-cell leukemia virus type I-infected people, with and without tropical spastic paraparesis, recognize multiple epitopes simultaneously. J Virol 1994; 68:2860.
  43. Niewiesk S, Daenke S, Parker CE, et al. Naturally occurring variants of human T-cell leukemia virus type I Tax protein impair its recognition by cytotoxic T lymphocytes and the transactivation function of Tax. J Virol 1995; 69:2649.
  44. Jacobson S, Reuben JS, Streilein RD, Palker TJ. Induction of CD4+, human T lymphotropic virus type-1-specific cytotoxic T lymphocytes from patients with HAM/TSP. Recognition of an immunogenic region of the gp46 envelope glycoprotein of human T lymphotropic virus type-1. J Immunol 1991; 146:1155.
  45. Arnulf B, Thorel M, Poirot Y, et al. Loss of the ex vivo but not the reinducible CD8+ T-cell response to Tax in human T-cell leukemia virus type 1-infected patients with adult T-cell leukemia/lymphoma. Leukemia 2004; 18:126.
  46. Wodarz D, Hall SE, Usuku K, et al. Cytotoxic T-cell abundance and virus load in human immunodeficiency virus type 1 and human T-cell leukaemia virus type 1. Proc Biol Sci 2001; 268:1215.
  47. Sabouri AH, Usuku K, Hayashi D, et al. Impaired function of human T-lymphotropic virus type 1 (HTLV-1)-specific CD8+ T cells in HTLV-1-associated neurologic disease. Blood 2008; 112:2411.
  48. Fox JM, Mutalima N, Molyneux E, et al. Seroprevalence of HTLV-1 and HTLV-2 amongst mothers and children in Malawi within the context of a systematic review and meta-analysis of HTLV seroprevalence in Africa. Trop Med Int Health 2016; 21:312.
  49. Blattner WA, Saxinger C, Riedel D, et al. A study of HTLV-I and its associated risk factors in Trinidad and Tobago. J Acquir Immune Defic Syndr 1990; 3:1102.
  50. Mueller N, Okayama A, Stuver S, Tachibana N. Findings from the Miyazaki Cohort Study. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 13 Suppl 1:S2.
  51. Murphy EL, Watanabe K, Nass CC, et al. Evidence among blood donors for a 30-year-old epidemic of human T lymphotropic virus type II infection in the United States. J Infect Dis 1999; 180:1777.
  52. Taylor GP, Bodéus M, Courtois F, et al. The seroepidemiology of human T-lymphotropic viruses: types I and II in Europe: a prospective study of pregnant women. J Acquir Immune Defic Syndr 2005; 38:104.
  53. Chang YB, Kaidarova Z, Hindes D, et al. Seroprevalence and demographic determinants of human T-lymphotropic virus type 1 and 2 infections among first-time blood donors--United States, 2000-2009. J Infect Dis 2014; 209:523.
  54. Murphy EL, Figueroa JP, Gibbs WN, et al. Sexual transmission of human T-lymphotropic virus type I (HTLV-I). Ann Intern Med 1989; 111:555.
  55. Manns A, Hisada M, La Grenade L. Human T-lymphotropic virus type I infection. Lancet 1999; 353:1951.
  56. Gessain A, Gallo RC, Franchini G. Low degree of human T-cell leukemia/lymphoma virus type I genetic drift in vivo as a means of monitoring viral transmission and movement of ancient human populations. J Virol 1992; 66:2288.
  57. Nerurkar VR, Song KJ, Saitou N, et al. Interfamilial and intrafamilial genomic diversity and molecular phylogeny of human T-cell lymphotropic virus type I from Papua New Guinea and the Solomon Islands. Virology 1993; 196:506.
  58. Liu HF, Vandamme AM, Kazadi K, et al. Familial transmission and minimal sequence variability of human T-lymphotropic virus type I (HTLV-I) in Zaire. AIDS Res Hum Retroviruses 1994; 10:1135.
  59. Biggar RJ, Ng J, Kim N, et al. Human leukocyte antigen concordance and the transmission risk via breast-feeding of human T cell lymphotropic virus type I. J Infect Dis 2006; 193:277.
  60. Plancoulaine S, Gessain A, Tortevoye P, et al. A major susceptibility locus for HTLV-1 infection in childhood maps to chromosome 6q27. Hum Mol Genet 2006; 15:3306.
  61. Kinoshita K, Hino S, Amagaski T, et al. Demonstration of adult T-cell leukemia virus antigen in milk from three sero-positive mothers. Gan 1984; 75:103.
  62. Yamanouchi K, Kinoshita K, Moriuchi R, et al. Oral transmission of human T-cell leukemia virus type-I into a common marmoset (Callithrix jacchus) as an experimental model for milk-borne transmission. Jpn J Cancer Res 1985; 76:481.
  63. Hirata M, Hayashi J, Noguchi A, et al. The effects of breastfeeding and presence of antibody to p40tax protein of human T cell lymphotropic virus type-I on mother to child transmission. Int J Epidemiol 1992; 21:989.
  64. Tsuji Y, Doi H, Yamabe T, et al. Prevention of mother-to-child transmission of human T-lymphotropic virus type-I. Pediatrics 1990; 86:11.
  65. Takahashi K, Takezaki T, Oki T, et al. Inhibitory effect of maternal antibody on mother-to-child transmission of human T-lymphotropic virus type I. The Mother-to-Child Transmission Study Group. Int J Cancer 1991; 49:673.
  66. Takezaki T, Tajima K, Ito M, et al. Short-term breast-feeding may reduce the risk of vertical transmission of HTLV-I. The Tsushima ATL Study Group. Leukemia 1997; 11 Suppl 3:60.
  67. Wiktor SZ, Pate EJ, Rosenberg PS, et al. Mother-to-child transmission of human T-cell lymphotropic virus type I associated with prolonged breast-feeding. J Hum Virol 1997; 1:37.
  68. Li HC, Biggar RJ, Miley WJ, et al. Provirus load in breast milk and risk of mother-to-child transmission of human T lymphotropic virus type I. J Infect Dis 2004; 190:1275.
  69. Ando Y, Kakimoto K, Tanigawa T, et al. Effect of freeze-thawing breast milk on vertical HTLV-I transmission from seropositive mothers to children. Jpn J Cancer Res 1989; 80:405.
  70. Miyoshi I, Takehara N, Sawada T, et al. Immunoglobulin prophylaxis against HTLV-I in a rabbit model. Leukemia 1992; 6 Suppl 1:24.
  71. Sawada T, Iwahara Y, Ishii K, et al. Immunoglobulin prophylaxis against milkborne transmission of human T cell leukemia virus type I in rabbits. J Infect Dis 1991; 164:1193.
  72. Ando Y, Matsumoto Y, Nakano S, et al. Long-term follow-up study of HTLV-I infection in bottle-fed children born to seropositive mothers. J Infect 2003; 46:9.
  73. Katamine S, Moriuchi R, Yamamoto T, et al. HTLV-I proviral DNA in umbilical cord blood of babies born to carrier mothers. Lancet 1994; 343:1326.
  74. Kazi A, Miyata H, Kamahora T, et al. Deleted HTLV-1 provirus in cord-blood samples of babies born to HTLV-1-carrier mothers. Int J Cancer 1998; 77:701.
  75. Achiron A, Pinhas-Hamiel O, Barak Y, et al. Detection of proviral human T-cell lymphotrophic virus type I DNA in mouthwash samples of HAM/TSP patients and HTLV-I carriers. Arch Virol 1996; 141:147.
  76. Achiron A, Higuchi I, Takenouchi N, et al. Detection of HTLV type I provirus by in situ polymerase chain reaction in mouthwash mononuclear cells of HAM/TSP patients and HTLV type I carriers. AIDS Res Hum Retroviruses 1997; 13:1067.
  77. Miyoshi I, Sawada T, Iwahara Y, et al. Excretion of HTLV-I in saliva. JAMA 1992; 267:236.
  78. Archibald D, Essex M, McLane MF, et al. Antibodies to HTLV-1 in saliva of seropositive individuals from Japan. Viral Immunol 1987-1988; 1:241.
  79. Yamamoto T, Terada K, Nishida N, et al. Inhibitory activity in saliva of cell-to-cell transmission of human T-cell lymphotropic virus type 1 in vitro: evaluation of saliva as an alternative source of transmission. J Clin Microbiol 1995; 33:1510.
  80. Wignall FS, Hyams KC, Phillips IA, et al. Sexual transmission of human T-lymphotropic virus type I in Peruvian prostitutes. J Med Virol 1992; 38:44.
  81. Zunt JR, Dezzutti CS, Montano SM, et al. Cervical shedding of human T cell lymphotropic virus type I is associated with cervicitis. J Infect Dis 2002; 186:1669.
  82. Stuver SO, Tachibana N, Okayama A, et al. Heterosexual transmission of human T cell leukemia/lymphoma virus type I among married couples in southwestern Japan: an initial report from the Miyazaki Cohort Study. J Infect Dis 1993; 167:57.
  83. Kaplan JE, Khabbaz RF, Murphy EL, et al. Male-to-female transmission of human T-cell lymphotropic virus types I and II: association with viral load. The Retrovirus Epidemiology Donor Study Group. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 12:193.
  84. La Rosa AM, Zunt JR, Peinado J, et al. Retroviral infection in Peruvian men who have sex with men. Clin Infect Dis 2009; 49:112.
  85. Chen YC, Wang CH, Su IJ, et al. Infection of human T-cell leukemia virus type I and development of human T-cell leukemia lymphoma in patients with hematologic neoplasms: a possible linkage to blood transfusion. Blood 1989; 74:388.
  86. Okochi K, Sato H, Hinuma Y. A retrospective study on transmission of adult T cell leukemia virus by blood transfusion: seroconversion in recipients. Vox Sang 1984; 46:245.
  87. Kamihira S, Nakasima S, Oyakawa Y, et al. Transmission of human T cell lymphotropic virus type I by blood transfusion before and after mass screening of sera from seropositive donors. Vox Sang 1987; 52:43.
  88. Lu SC, Kao CL, Chin LT, et al. Seroprevalence and demographic characteristics of HTLV-I among blood donors in Taiwan: 1996-1999. Int J Hematol 2001; 74:333.
  89. Chiavetta JA, Escobar M, Newman A, et al. Incidence and estimated rates of residual risk for HIV, hepatitis C, hepatitis B and human T-cell lymphotropic viruses in blood donors in Canada, 1990-2000. CMAJ 2003; 169:767.
  90. Pillonel J, Laperche S, Saura C, et al. Trends in residual risk of transfusion-transmitted viral infections in France between 1992 and 2000. Transfusion 2002; 42:980.
  91. Armstrong MJ, Corbett C, Rowe IA, et al. HTLV-1 in solid-organ transplantation: current challenges and future management strategies. Transplantation 2012; 94:1075.
  92. Glowacka I, Korn K, Potthoff SA, et al. Delayed seroconversion and rapid onset of lymphoproliferative disease after transmission of human T-cell lymphotropic virus type 1 from a multiorgan donor. Clin Infect Dis 2013; 57:1417.
  93. Toro C, Rodés B, Poveda E, Soriano V. Rapid development of subacute myelopathy in three organ transplant recipients after transmission of human T-cell lymphotropic virus type I from a single donor. Transplantation 2003; 75:102.
  94. Zou S, Dodd RY, Stramer SL, et al. Probability of viremia with HBV, HCV, HIV, and HTLV among tissue donors in the United States. N Engl J Med 2004; 351:751.
  95. Giuliani M, Rezza G, Lepri AC, et al. Risk factors for HTLV-I and II in individuals attending a clinic for sexually transmitted diseases. Sex Transm Dis 2000; 27:87.
  96. Poljak M, Bednarik J, Rednak K, et al. Seroprevalence of human T cell leukaemia/lymphoma virus type I (HTLV-I) in pregnant women, patients attending venereological outpatient services and intravenous drug users from Slovenia. Folia Biol (Praha) 1998; 44:23.
  97. Urwijitaroon Y, Barusrux S, Puapairoj C, et al. Seroepidemiology of HTLV-I infection in northeast Thailand: a four year surveillance. J Med Assoc Thai 1997; 80 Suppl 1:S102.
  98. Dourado I, Andrade T, Carpenter CL, Galvão-Castro B. Risk factors for human T cell lymphotropic virus type I among injecting drug users in northeast Brazil: possibly greater efficiency of male to female transmission. Mem Inst Oswaldo Cruz 1999; 94:13.
  99. Hewagama S, Krishnaswamy S, King L, et al. Human T-cell lymphotropic virus type 1 exposures following blood-borne virus incidents in central Australia, 2002-2012. Clin Infect Dis 2014; 59:85.
  100. Filippone C, Betsem E, Tortevoye P, et al. A Severe Bite From a Nonhuman Primate Is a Major Risk Factor for HTLV-1 Infection in Hunters From Central Africa. Clin Infect Dis 2015; 60:1667.
  101. Kazanji M, Mouinga-Ondémé A, Lekana-Douki-Etenna S, et al. Origin of HTLV-1 in hunters of nonhuman primates in Central Africa. J Infect Dis 2015; 211:361.