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Retrovirology highlights a quarter century of HTLV-I research
Retrovirologyvolume 2, Article number: 15 (2005)
In 1977, Takatsuki and co-workers described in Japan a human malignant disease termed adult T-cell leukemia (ATL). Three years later, in 1980, Gallo and colleagues reported the identification of the first human retrovirus, human T-cell leukemia virus type I (HTLV-I), in a patient with cutaneous T-cell lymphoma. This month, Retrovirology commemorates these two land mark findings by publishing separate personal recollections by Takatsuki and Gallo respectively on the discovery of ATL and HTLV.
Retrovirology as a medical study first emerged in the early 1900s. In 1908, Ellermann and Bang reported on the transmissibility of avian leucosis by cell-free filtrates, suggesting the involvement of a virus . Shortly afterward, in 1910, Rous demonstrated that chicken sarcomas were infectious and when inoculated into healthy birds induced tumors . Today, a plethora of oncogenic animal retroviruses including bovine leukemia virus, feline leukemia virus, gibbon ape leukemia virus, Jaagsiektse sheep retrovirus, murine leukemia virus, mouse mammary tumor virus, reticuloendotheliosis virus, simian T-cell lymphotropic virus, and Walleye dermal sarcoma virus has been described.
Understanding how retroviruses cause cancer took a major step forward with the development of the cellular oncogene hypothesis in 1976. Thus Varmus, Bishop and colleagues  demonstrated that the viral oncogenes (v-onc) encoded by many retroviruses were captured originally from cellular sequences (i.e. c-onc). To date, three general models of retroviral transformation are accepted: a) over-expression of v-onc; b) cis-oncogenic effect from promoter insertion; and c) cis-oncogenic effect from enhancer insertion (Fig. 1A, B, C).
Although not yet fully understood, HTLV-I is believed to transform human T-cells neither through the acquisition of a c-onc nor by cis-insertion effects on the cellular genome. Pioneering molecular biology studies by Mitsuaki Yoshida and colleagues led to the delineation of the HTLV-I transforming gene, Tax . Tax has no cellular homologue; and it works in trans to disrupt cellular checkpoints and destabilize genome integrity  leading to transformation (Fig. 1D). A more extensive discussion of the molecular biology of HTLV-I and its transforming function will be in an upcoming comprehensive review by Masao Matsuoka to be published in Retrovirology.
Ellerman V, Bang O: Experimentelle Leukämie bei Hühnern. Zentralbl Bakteriol Parasitenkd Infectionskr Hyg Abt Orig. 1908, 46: 595-
Rous P: A transmissible avian neoplasm. (Sarcoma of the common foul). J Exp Med. 1910, 12: 696-10.1084/jem.12.5.696.
Stehelin D, Varmus H, Bishop JM, Vogt PK: DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature. 1976, 260: 170-173.
Yoshida M: Multiple viral strategies of HTLV-1 for dysregulation of cell growth control. Annu Rev Immunol. 2001, 19: 475-496. 10.1146/annurev.immunol.19.1.475.
Jeang KT, Giam CZ, Majone F, Aboud M: Life, death, and Tax: role of HTLV-I oncoprotein in genetic instability and cellular transformation. J Biol Chem. 2004, 279: 31991-31994. 10.1074/jbc.R400009200.
Takatsuki K: Discovery of adult T-cell leukemia. Retrovirology. 2005, 2: 16-10.1186/1742-4690-2-16.
Gallo RC: The discovery of the first human retrovirus: HTLV-1 and HTLV-2. Retrovirology. 2005, 2: 17-10.1186/1742-4690-2-17.
I thank Anthony Elmo for help with preparation of manuscript.
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