Human T lymphotropic virus Type 1 (HTLV‐1) was the first human retrovirus discovered. Like the related virus human immunodeficiency virus Type‐1 (HIV‐1), HTLV‐1 persists lifelong in the host. HIV‐1 causes disease in over 99% of untreated infected people, whereas HTLV‐1 causes disease in only 2–8%: either a fatal leukaemia or lymphoma, or a disabling chronic inflammatory disease of the nervous system that causes paralysis of the legs. There is no satisfactory treatment for the malignant or inflammatory diseases, and no vaccine. HTLV‐1 is thought to have existed in the human population for over 50 thousand years; it is widely but unevenly distributed in the tropics and in some subtropical areas. A highly dynamic equilibrium is established in each infected person between persistent HTLV‐1 replication and the host immune response. The increasing understanding of this equilibrium has led to discoveries and conclusions of wide significance for virology, immunology and persistent infections.

Key Concepts:

  • Viral load and risk of HTLV‐1‐associated diseases are determined by the efficiency of the host's cell‐mediated immune response.

  • Immunological efficiency is determined by host genetic polymorphisms – chiefly HLA – and by targeting critical weak points in the pathogen's life cycle.

  • An immunodominant antigen is not necessarily the antigen recognised by the protective host immune response.

  • Attributes of T cells such as phenotype, frequency and function do not correlate with their efficiency in protecting against a pathogen in a persistent infection at equilibrium.

  • Viruses that target mobile cells such as leukocytes can use the mobility of the host cell to spread within and between hosts: they do not need to release large numbers of cell‐free virus particles.

  • Some viruses, such as HTLV‐1, can spread from one cell to another by an active, triggered process that involves formation of a specialised cell‐to‐cell contact called a virological synapse.

Keywords: retrovirus; HTLV‐1; cytotoxic T lymphocyte (CTL); virological synapse (VS); persistent infection; tropical spastic paraparesis; CTL efficiency; leukaemia; viral oncogenesis

Figure 1.

Origin, spread, and prevalence of HTLV‐1. Origin and spread hypothesis based on phylogenetic and anthropological data. PTLV () originated in African primates and migrated to Asia where it evolved into STLV‐1. This early STLV‐1 lineage spread to India, Japan, Indonesia and back to Africa (arrows 1). It crossed the simian–human barrier in Indonesian human beings who migrated to Melanesia, resulting in the HTLV‐1c subtype (arrows 2). In Africa, STLV‐1 evolved through several interspecies transmissions into HTLV‐1a, HTLV‐1b, HTLV‐1d, HTLV‐1e, and HTLV‐1f (arrows 3). Because of the slave trade and increased mobility, HTLV‐1a was introduced in the New World, Japan, the middle east and north Africa (arrows 4). Colours indicate current prevalence estimates based on population surveys and on studies in pregnant women and blood donors. In some countries, HTLV‐1 infection is limited to certain population groups or areas. (Reproduced with permission from Figure 4 in Verdonck et al., .)

Figure 2.

Structure and coding potential of plus‐ and minus‐strand HTLV‐1 mRNAs. (Reproduced with permission from Figure 1a in Rende et al., . © The American Society of Hematology.)

Figure 3.

The virological synapse (VS). HTLV‐1 Gag protein (red), and the host cell protein talin (green), which associates with the adhesion molecule LFA‐1, accumulate at the cell–cell interface at the VS. (a) Lateral view of conjugate formed between two lymphocytes from an HTLV‐1‐infected person. (b) z‐Axis image reconstruction of cell–cell interface. (Reproduced with permission from Figure 2b and c in Igakura et al., .)

Figure 4.

Illustration of possible routes of HTLV‐1 spread between cells in vivo. (a) cell‐to‐cell transmission via intercellular synaptic cleft surrounded by a tight cell–cell contact between the donor and recipient cell, 1. Cell‐free particles can be internalised by dendritic cells and are then transferred to lymphocyte only by cell‐to‐cell contact, 2. Virus particles can be retained on the cell surface in a biofilm‐like structure before lateral transfer to the recipient outside the cell–cell contact region, 3. (b) In an isolated HTLV‐1‐infected lymphocyte, the viral proteins are not polarised. (Reproduced with permission from Figure 3 in Nejmeddine and Bangham, .)



Asquith B and Bangham CR (2007) Quantifying HTLV‐I dynamics. Immunology & Cell Biology 85: 280–286.

Asquith B, Mosley AJ, Heaps A et al. (2005) Quantification of the virus–host interaction in human T lymphotropic virus I infection. Retrovirology 2: 75.

Azakami K, Sato T, Araya N et al. (2009) Severe loss of invariant NKT cells exhibiting anti‐HTLV‐1 activity in patients with HTLV‐1‐associated disorders. Blood 114(15): 3208–3215.

Bangham CR (2009) CTL quality and the control of human retroviral infections. European Journal of Immunology 39(7): 1700–1712.

Bangham CR and Osame M (2005) Cellular immune response to HTLV‐1. Oncogene 24(39): 6035–6046.

Bangham CR and Toulza F (2011) Adult T cell leukemia/lymphoma: FoxP3(+) cells and the cell‐mediated immune response to htlv‐1. Advances in Cancer Research 111: 163–182

Bangham CRM (2008) Human T‐lymphotropic virus type 1 (HTLV‐1)‐associated diseases. In: Kaslow RA, McNicholl JM and Hill AVS (eds) Genetic Susceptibility to Infectious Diseases, pp. 303–317. Oxford, UK: Oxford University Press.

Bangham CRM, Meekings K, Toulza F et al. (2009) The immune control of HTLV‐1 infection: selection forces and dynamics. Frontiers in Bioscience 14: 2889–2903.

Bazarbachi A, Plumelle Y, Carlos Ramos J et al. (2010) Meta‐analysis on the use of zidovudine and interferon‐alfa in adult T‐cell leukemia/lymphoma showing improved survival in the leukemic subtypes. Journal of Clinical Oncology 28(27): 4177–4183.

Bittencourt AL and de Oliveira M (2010) Cutaneous manifestations associated with HTLV‐1 infection. International Journal of Dermatology 49(10): 1099–1110.

Boxus M and Willems L (2009) Mechanisms of HTLV‐1 persistence and transformation. British Journal of Cancer 101(9): 1497–1501.

Calattini S, Chevalier SA, Duprez R et al. (2005) Discovery of a new human T‐cell lymphotropic virus (HTLV‐3) in Central Africa. Retrovirology 2: 30.

Cavrois M, Gessain A, Wain‐Hobson S et al. (1996) Proliferation of HTLV‐1 infected circulating cells in vivo in all asymptomatic carriers and patients with TSP/HAM. Oncogene 12(11): 2419–2423.

Coffin J, Hughes SE and Varmus HE (eds) (1997) Retroviruses. Plainview, NY: Cold Spring Harbor Laboratory Press.

Cruickshank EK (1956) A neuropathic syndrome of uncertain origin; review of 100 cases. West Indian Medical Journal 5(3): 147–158.

de The G and Bomford R (1993) An HTLV‐I vaccine: why, how, for whom? AIDS Research and Human Retroviruses 9(5): 381–386.

Gabet AS, Mortreux F, Talarmin A et al. (2000) High circulating proviral load with oligoclonal expansion of HTLV‐1 bearing T cells in HTLV‐1 carriers with strongyloidiasis. Oncogene 19(43): 4954–4960.

Gaudray G, Gachon F, Basbous J et al. (2002) The complementary strand of the human T‐cell leukemia virus type 1 RNA genome encodes a bZIP transcription factor that down‐regulates viral transcription. Journal of Virology 76(24): 12813–12822.

Gessain A, Barin F, Vernant JC et al. (1985) Antibodies to human T‐lymphotropic virus type‐I in patients with tropical spastic paraparesis. Lancet 2(8452): 407–410.

Ghez D, Lepelletier Y, Lambert S et al. (2006) Neuropilin‐1 is involved in human T‐cell lymphotropic virus type 1 entry. Journal of Virology 80(14): 6844–6854.

Gillet NA, Malani N, Melamed A et al. (2011) The host genomic environment of the provirus determines the abundance of HTLV‐1‐infected T cell clones. Blood 117: 3113–3122.

Goon PK, Hanon E, Igakura T et al. (2002) High frequencies of Th1‐type CD4(+) T cells specific to HTLV‐1 Env and Tax proteins in patients with HTLV‐1‐associated myelopathy/tropical spastic paraparesis. Blood 99(9): 3335–3341.

Goon PK, Igakura T, Hanon E et al. (2004) Human T cell lymphotropic virus type I (HTLV‐I)‐specific CD4+ T cells: immunodominance hierarchy and preferential infection with HTLV‐I. Journal of Immunology 172(3): 1735–1743.

Gotuzzo E, Terashima A, Alvarez H et al. (1999) Strongyloides stercoralis hyperinfection associated with human T cell lymphotropic virus type‐1 infection in Peru. American Journal of Tropical Medicine and Hygiene 60(1): 146–149.

Hanon E, Stinchcombe JC, Saito M et al. (2000) Fratricide among CD8(+) T lymphocytes naturally infected with human T cell lymphotropic virus type I. Immunity 13(5): 657–664.

Hinuma Y, Nagata K, Hanaoka M et al. (1981) Adult T‐cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera. Proceedings of the National Academy of Sciences of the USA 78(10): 6476–6480.

Hoshida Y, Li T, Dong Z et al. (2001) Lymphoproliferative disorders in renal transplant patients in Japan. International Journal of Cancer 91(6): 869–875.

Igakura T, Stinchcombe JC, Goon PK et al. (2003) Spread of HTLV‐I between lymphocytes by virus‐induced polarization of the cytoskeleton. Science 299(5613): 1713–1716.

Iwasaki Y (1993) Human T cell leukemia virus type I infection and chronic myelopathy. Brain Patholology 3(1): 1–10.

Iwatsuki K, Inoue F, Takigawa M et al. (1990) Exchange of dominant lymphoid cell clones in a patient with adult T‐cell leukemia/lymphoma. Acta Dermato‐Venereologica 70(1): 49–52.

Jeffery KJ, Usuku K, Hall SE et al. (1999) HLA alleles determine human T‐lymphotropic virus‐I (HTLV‐I) proviral load and the risk of HTLV‐I‐associated myelopathy. Proceedings of the National Academy of Sciences of the USA 96(7): 3848–3853.

Jones KS, Petrow‐Sadowski C, Huang YK et al. (2008) Cell‐free HTLV‐1 infects dendritic cells leading to transmission and transformation of CD4(+) T cells. Nature Medicine 14(4): 429–436.

Kalyanaraman VS, Sarngadharan MG, Robert‐Guroff M et al. (1982) A new subtype of human T‐cell leukemia virus (HTLV‐II) associated with a T‐cell variant of hairy cell leukemia. Science 218(4572): 571–573.

Kinpara S, Hasegawa A, Utsunomiya A et al. (2009) Stromal cell‐mediated suppression of human T‐cell leukemia virus type 1 expression in vitro and in vivo by type I interferon. Journal of Virology 83(10): 5101–5108.

LaGrenade L, Hanchard B, Fletcher V et al. (1990) Infective dermatitis of Jamaican children: a marker for HTLV‐I infection. Lancet 336(8727): 1345–1347.

Li M, Kesic M, Yin H et al. (2009) Kinetic analysis of human T‐cell leukemia virus type 1 gene expression in cell culture and infected animals. Journal of Virology 83(8): 3788–3797.

Macatonia SE, Cruickshank JK, Rudge P et al. (1992) Dendritic cells from patients with tropical spastic paraparesis are infected with HTLV‐1 and stimulate autologous lymphocyte proliferation. AIDS Research and Human Retroviruses 8(9): 1699–1706.

MacNamara A, Rowan A, Hilburn S et al. (2010) HLA class I binding of HBZ determines outcome in HTLV‐1 infection. PLoS Pathogens 6(9): e1001117.

Manel N, Kinet S, Battini JL et al. (2003) The HTLV receptor is an early T‐cell activation marker whose expression requires de novo protein synthesis. Blood 101(5): 1913–1918.

Matsuoka M and Jeang KT (2011) Human T‐cell leukemia virus type 1 (HTLV‐1) and leukemic transformation: viral infectivity, Tax, HBZ and therapy. Oncogene 30(12): 1379–1389.

Matsushita K, Arima N, Fujiwara H et al. (1999) Spontaneous regression associated with apoptosis in a patient with acute‐type adult T‐cell leukemia. American Journal of Hematology 61(2): 144–148.

Matutes E (2007) Adult T‐cell leukaemia/lymphoma. Journal of Clinical Pathology 60(12): 1373–1377.

Mazurov D, Ilinskaya A, Heidecker G et al. (2010) Quantitative comparison of HTLV‐1 and HIV‐1 cell‐to‐cell infection with new replication dependent vectors. PLoS Pathogens 6(2): e1000788.

Mochizuki M, Watanabe T, Yamaguchi K et al. (1992) Uveitis associated with human T lymphotropic virus type I: seroepidemiologic, clinical, and virologic studies. Journal of Infectious Diseases 166(4): 943–944.

Morgan OS, Rodgers‐Johnson P, Mora C et al. (1989) HTLV‐1 and polymyositis in Jamaica. Lancet 2(8673): 1184–1187.

Nagai M, Usuku K, Matsumoto W et al. (1998) Analysis of HTLV‐I proviral load in 202 HAM/TSP patients and 243 asymptomatic HTLV‐I carriers: high proviral load strongly predisposes to HAM/TSP. Journal of Neurovirology 4(6): 586–593.

Nakagawa M, Izumo S, Ijichi S et al. (1995) HTLV‐I‐associated myelopathy: analysis of 213 patients based on clinical features and laboratory findings. Journal of Neurovirology 1(1): 50–61.

Ndhlovu LC, Snyder‐Cappione JE, Carvalho KI et al. (2009) Lower numbers of circulating Natural Killer T (NK T) cells in individuals with human T lymphotropic virus type 1 (HTLV‐1) associated neurological disease. Clinical & Experimental Immunology 158(3): 294–299.

Nejmeddine M and Bangham CR (2010) The HTLV‐1 virological synapse. Viruses 2(7): 1427–1447.

Nicot C, Harrod RL, Ciminale V et al. (2005) Human T‐cell leukemia/lymphoma virus type 1 nonstructural genes and their functions. Oncogene 24(39): 6026–6034.

Nishioka K (1996) HTLV‐I arthropathy and Sjogren syndrome. Journal of Acquired Immune Deficiency Syndrome Human Retrovirology 13(suppl. 1): S57–62.

Nishioka K, Maruyama I, Sato K et al. (1989) Chronic inflammatory arthropathy associated with HTLV‐I. Lancet 1(8635): 441.

Osame M, Usuku K, Izumo S et al. (1986) HTLV‐I associated myelopathy, a new clinical entity. Lancet 1(8488): 1031–1032.

Overbaugh J and Bangham CR (2001) Selection forces and constraints on retroviral sequence variation. Science 292(5519): 1106–1109.

Poiesz BJ, Ruscetti FW, Gazdar AF et al. (1980) Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T‐cell lymphoma. Proceedings of the National Academy of Sciences of the USA 77(12): 7415–7419.

Proietti FA, Carneiro‐Proietti AB, Catalan‐Soares BC et al. (2005) Global epidemiology of HTLV‐I infection and associated diseases. Oncogene 24(39): 6058–6068.

Rende F, Cavallari I, Corradin A et al. (2011) Kinetics and intracellular compartmentalization of HTLV‐1 gene expression: nuclear retention of HBZ mRNAs. Blood 117(18): 4855–4859.

Saito M, Braud VM, Goon P et al. (2003) Low frequency of CD94/NKG2A+ T lymphocytes in patients with HTLV‐1‐associated myelopathy/tropical spastic paraparesis, but not in asymptomatic carriers. Blood 102(2): 577–584.

Satoh M, Toma H, Sugahara K et al. (2002) Involvement of IL‐2/IL‐2R system activation by parasite antigen in polyclonal expansion of CD4(+)25(+) HTLV‐1‐infected T‐cells in human carriers of both HTLV‐1 and S. stercoralis. Oncogene 21(16): 2466–2475.

Satou Y, Yasunaga J, Yoshida M et al. (2006) HTLV‐I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells. Proceedings of the National Academy of Sciences of the USA 103(3): 720–725.

Satou Y, Yasunaga J, Zhao T et al. (2011) HTLV‐1 bZIP factor induces T‐cell lymphoma and systemic inflammation in vivo. PLoS Pathogens 7(2): e1001274.

Shimoyama M (1991) Diagnostic criteria and classification of clinical subtypes of adult T‐cell leukaemia‐lymphoma. A report from the Lymphoma Study Group (1984–87). British Journal of Haematology 79(3): 428–437.

Silic‐Benussi M, Biasiotto R, Andresen V et al. (2010) HTLV‐1 p13, a small protein with a busy agenda. Molecular Aspects of Medicine 31(5): 350–358.

Slattery JP, Franchini G and Gessain A (1999) Genomic evolution, patterns of global dissemination, and interspecies transmission of human and simian T‐cell leukemia/lymphotropic viruses. Genome Research 9(6): 525–540.

Takezako Y, Kanda Y, Arai C et al. (2000) Spontaneous remission in acute type adult T‐cell leukemia/lymphoma. Leukemia & Lymphoma 39(1–2): 217–222.

Uchiyama T, Yodoi J, Sagawa K et al. (1977) Adult T‐cell leukemia: clinical and hematologic features of 16 cases. Blood 50(3): 481–492.

Vandamme AM, Liu HF, Goubau P et al. (1994) Primate T‐lymphotropic virus type I LTR sequence variation and its phylogenetic analysis: compatibility with an African origin of PTLV‐I. Virology 202(1): 212–223.

Verdonck K, Gonzalez E, Henostroza G et al. (2007a) HTLV‐1 infection is frequent among out‐patients with pulmonary tuberculosis in northern Lima, Peru. International Journal of Tuberculosis and Lung Diseases 11(10): 1066–1072.

Verdonck K, Gonzalez E, Van Dooren S et al. (2007b) Human T‐lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infectious Diseases 7(4): 266–281.

Wolfe ND, Heneine W, Carr JK et al. (2005) Emergence of unique primate T‐lymphotropic viruses among central African bushmeat hunters. Proceedings of the National Academy of Sciences of the USA 102(22): 7994–7999.

Yu F, Itoyama Y, Fujihara K et al. (1991) Natural killer (NK) cells in HTLV‐I‐associated myelopathy/tropical spastic paraparesis‐decrease in NK cell subset populations and activity in HTLV‐I seropositive individuals. Journal of Neuroimmunology 33(2): 121–128.

Further Reading

Sompayrac LM (2002) How Pathogenic Viruses Work. Sudbury, MA: Jones and Bartlett Publishers, Inc.

Sompayrac LM (2012) How the Immune System Works, 4th edn. Oxford, UK: Wiley‐Blackwell.

David AW, Timothy MC and John DF (2010) Oxford Textbook of Medicine, 5th edn. Oxford, UK: Oxford University Press.

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Bangham, Charles RM(Dec 2011) HTLV‐1. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023613]