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Retrovirology highlights a quarter century of HTLV-I research


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 [1]. Shortly afterward, in 1910, Rous demonstrated that chicken sarcomas were infectious and when inoculated into healthy birds induced tumors [2]. 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 [3] 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).

Figure 1
figure 1

Panels A, B, and C show the three accepted ways by which a retrovirus may transform cells: capture of a c-onc and over-expression of v-onc by the provirus (A); promoter insertion upstream of a growth controlling cellular gene (B); and enhancer insertions either upstream or downstream of growth controlling cellular genes (C). Panel D shows the stepwise ways in which HTLV-I Tax oncoprotein may transform cells by i) inactivating checkpoints to induce tolerance of damaged DNA, and ii) permitting the accumulation of unrepaired DNA lesions which ultimately convert a normal cell to a transformed cell.

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 [4]. Tax has no cellular homologue; and it works in trans to disrupt cellular checkpoints and destabilize genome integrity [5] 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.

Two articles in this month's Retrovirology describe respectively the discovery of adult T-cell leukemia [6] and HTLV-I [7].


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I thank Anthony Elmo for help with preparation of manuscript.

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Correspondence to Kuan-Teh Jeang.

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Jeang, KT. Retrovirology highlights a quarter century of HTLV-I research. Retrovirology 2, 15 (2005).

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