Forefront studies on htlv-1 oncogenesis

Almost 40 years ago, Takatsuki et al. recognized the existence of a peculiar T cell leukemia in Kyoto, Japan that they named Adult T Leukemia (ATL). They reported a series of 13 patients in 1976 ( Uchiyama et al., 1977 ). In 1980, the group of Gallo reported the discovery of a human oncogenic retrovirus that they named Human T cell Leukemia Virus type 1 (HTLV-1) in cells obtained from two US patients classified as mycosis fungoides and Sezary syndrome ( Poiesz et al., 1980 ), but who were, in retrospect, probably suffering from ATL [for an historical perspective see ( Takatsuki, 2005 )]. Shortly after, the groups of Hinuma ( Miyoshi et al., 1981 ) and of Yoshida ( Yoshida et al., 1982 ) uncovered the presence of HTLV-1 in cells obtained from ATL patients. In 1985–1986, two groups independently reported that a neurological disease named HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) was also caused by HTLV-1 ( Gessain et al., 1985 ; Osame et al., 1986 ). Since then, other inflammatory diseases (uveitis, infective dermatitis) have also been linked to this viral infection. Other members of the HTLV family (i. e., HTLV-2, HTLV-3, and HTLV-4 have also now been reported, none of them being clearly associated so far with an oncogenic process or a neurodegenerative disease ( Kalyanaraman et al., 1982 ; Calattini et al., 2005 ; Wolfe et al., 2005 ).

Almost 10 years ago, ours colleagues Kuan Teh Jeang and Mitsuaki Yoshida organized a special issue on HTLV infection in Oncogene. In setting up this issue, we cannot forget the memory our friend Teh.

We called upon the expertise of different research groups from Europe, Japan, and USA. However, we regret that the format of this issue prevented us from soliciting many other colleagues. The following reviews will deal with many fascinating aspects of viral cycle, but summarizes also new approaches that should allow a better integrated research.

A first group of articles provides information about HTLV-1 epidemiology and associated-pathogenesis. The article from Gessain and Cassar provides an updated view on HTLV-1 distribution, based on data obtained from 1. 5 billion individuals originating from endemic areas ( Gessain and Cassar, 2012 ). Iwanaga et al. focused their review on ATL epidemiology and show its peculiar characteristic [age at onset, risk factor, proviral load, etc. ( Iwanaga et al., 2012 )]. Yamano and Sato provide an interesting perspective on HAM/TSP physiopathology, and remind us that optimal therapeutic treatments are still lacking for those patients ( Yamano and Sato, 2012 ). The review by Kamoi ad Mochizuki summarizes our current knowledge on HTLV-1 uveitis, which is the most common cause of uveitis in endemic areas ( Kamoi and Mochizuki, 2012 ). Going deeper in the pathological mechanisms linked to HTLV-1 infection, Yamagishi and Watanabe summarize recent data showing that ATL cells express abnormally low levels of a cellular oncosuppressor miRNA and display some epigenetic changes on the promoter of genes critical for cell cycle ( Yamagishi and Watanabe, 2012 ).

A second group of articles summarizes the interaction between the virus and the host’s cells. Before causing diseases, HTLV-1 has to enter the cell. However, the mechanisms of HTLV-1 transmission and cell entry have remained elusive for a long period of time. Pique and Jones have summarized recent insights about those mechanisms both at the cell level but also between individuals ( Pique and Jones, 2012 ). HTLV-1 associated diseases are linked to the fact that HTLV-1 evades both adaptative and innate immune responses. Kannagi et al. provide us with an exciting review, which explains us how the virus evades the interferon response, but also that dysfunction of the CTL response might be a risk factor for disease development in infected carriers ( Kannagi et al., 2012 ).

A third group of articles reports data on individual viral proteins that play important roles in the viral cycle and/or in pathogenesis. Nakano and Watanabe remind us the important role played by Rex, which uses cellular pathways to export unspliced or singly spliced viral mRNAs in the cell cytoplasm, therefore allowing expressing of structural proteins ( Nakano and Watanabe, 2012 ). Currer et al., Zhao and Matsuoka focused their attention on Tax and HBZ, two viral proteins that play important roles in the control of viral transcription and oncogenesis ( Currer et al., 2012 ; Zhao and Matsuoka, 2012 ). Finally, Bai and Nicot provide an overview on 4 auxiliary viral proteins (p12, p8, p30, and p13), which are required for establishing a persistent infection in vivo ( Bai and Nicot, 2012 ).

Finally, Duc Dodon and colleagues remind us that studying HTLV-1 pathogenesis requires animal models ( Dodon et al., 2012 ). Rabbits, rats, transgenic mice, and monkeys have been used in the past. However, recent approaches using humanized mice might represent an interesting alternative for studying HTLV-1 associated diseases.


Bai, X. T., and Nicot, C. (2012). Overview on HTLV-1 p12, p8, p30, p13, accomplices in persistent infection and viral pathogenesis. Front. Microbiol . 3: 400. doi: 10. 3389/fmicb. 2012. 00400

Calattini, S., Chevalier, S. A., Duprez, R., Bassot, S., Froment, A., Mahieux, R., et al. (2005). Discovery of a new human T-cell lymphotropic virus (HTLV-3) in Central Africa. Retrovirology 2: 30. doi: 10. 1186/1742-4690-2-30

Currer, R., Van Duyne, R., Jaworski, E., Guendel, I., Sampey, G., Das, R., et al. (2012). HTLV tax: a fascinating multifunctional co-regulator of viral and cellular pathways. Front. Microbiol . 3: 406. doi: 10. 3389/fmicb. 2012. 00406

Dodon, M. D., Villaudy, J., Gazzolo, L., Haines, R., and Lairmore, M. (2012). What we are learning on HTLV-1 pathogenesis from animal models. Front. Microbiol . 3: 320. doi: 10. 3389/fmicb. 2012. 00320

Gessain, A., Barin, F., Vernant, J. C., Gout, O., Maurs, L., Calender, A., et al. (1985). Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet 2, 407–410. doi: 10. 1016/S0140-6736(85)92734-5

Gessain, A., and Cassar, O. (2012). Epidemiological aspects and world distribution of HTLV-1 infection. Front. Microbiol . 3: 388. doi: 10. 3389/fmicb. 2012. 00388

Iwanaga, M., Watanabe, T., and Yamaguchi, K. (2012). Adult T-cell leukemia: a review of epidemiological evidence. Front. Microbiol . 3: 322. doi: 10. 3389/fmicb. 2012. 00322

Kalyanaraman, V. S., Sarngadharan, M. G., Robert-Guroff, M., Miyoshi, I., Golde, D., and Gallo, R. C. (1982). A new subtype of human T-cell leukemia virus (HTLV-II) associated with a T-cell variant of hairy cell leukemia. Science 218, 571–573. doi: 10. 1126/science. 6981847

Kamoi, K., and Mochizuki, M. (2012). HTLV-1 uveitis. Front. Microbiol . 3: 270. doi: 10. 3389/fmicb. 2012. 00270

Kannagi, M., Hasegawa, A., Takamori, A., Kinpara, S., and Utsunomiya, A. (2012). The roles of acquired and innate immunity in human T-cell leukemia virus type 1-mediated diseases. Front. Microbiol . 3: 323. doi: 10. 3389/fmicb. 2012. 00323

Miyoshi, I., Kubonishi, I., Yoshimoto, S., Akagi, T., Ohtsuki, Y., Shiraishi, Y., et al. (1981). Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukaemic T cells. Nature 294, 770–771. doi: 10. 1038/294770a0

Nakano, K., and Watanabe, T. (2012). HTLV-1 Rex: the courier of viral messages making use of the host vehicle. Front. Microbiol . 3: 330. doi: 10. 3389/fmicb. 2012. 00330

Osame, M., Usuku, K., Izumo, S., Ijichi, N., Amitani, H., Igata, A., et al. (1986). HTLV-I associated myelopathy, a new clinical entity. Lancet 1, 1031–1032. doi: 10. 1016/S0140-6736(86)91298-5

Pique, C., and Jones, K. S. (2012). Pathways of cell-cell transmission of HTLV-1. Front. Microbiol . 3: 378. doi: 10. 3389/fmicb. 2012. 00378

Poiesz, B. J., Ruscetti, F. W., Gazdar, A. F., Bunn, P. A., Minna, J. D., and Gallo, R. C. (1980). 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 . 77, 7415–7419. doi: 10. 1073/pnas. 77. 12. 7415

Takatsuki, K. (2005). Discovery of adult T-cell leukemia. Retrovirology 2: 16. doi: 10. 1186/1742-4690-2-16

Uchiyama, T., Yodoi, J., Sagawa, K., Takatsuki, K., and Uchino, H. (1977). Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood 50, 481–492.

Wolfe, N. D., Heneine, W., Carr, J. K., Garcia, A. D., Shanmugam, V., Tamoufe, U., et al. (2005). Emergence of unique primate T-lymphotropic viruses among central African bushmeat hunters. Proc. Natl. Acad. Sci. U. S. A . 102, 7994–7999. doi: 10. 1073/pnas. 0501734102

Yamagishi, M., and Watanabe, T. (2012). Molecular hallmarks of adult T cell leukemia. Front. Microbiol . 3: 334. doi: 10. 3389/fmicb. 2012. 00334

Yamano, Y., and Sato, T. (2012). Clinical pathophysiology of human T-lymphotropic virus-type 1-associated myelopathy/tropical spastic paraparesis. Front. Microbiol . 3: 389. doi: 10. 3389/fmicb. 2012. 00389

Yoshida, M., Miyoshi, I., and Hinuma, Y. (1982). 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 . 79, 2031–2035. doi: 10. 1073/pnas. 79. 6. 2031

Zhao, T., and Matsuoka, M. (2012). HBZ and its roles in HTLV-1 oncogenesis. Front. Microbiol . 3: 247. doi: 10. 3389/fmicb. 2012. 00247