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Oncogene (2005) 24, 5931–5937 & 2005 Nature Publishing Group All rights reserved 0950-9232/05 $30.00 www.nature.com/onc Discovery of HTLV-1, the first human retrovirus, its unique regulatory mechanisms, and insights into pathogenesis Mitsuaki Yoshida*,1 1Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Ohkubo, Tsukuba, Ibaraki 300-2611, Japan I briefly review the discovery and characterization of the In Japan something was there, but it was not clear first human retrovirus, human T-cell leukemia virus type 1, focusing on contributions from Japanese researchers. Discovery of ATL The unique regulatory mechanisms for the viral regulation The first key event for human retrovirus was the with Tax and Rex, etiology of ATL and possible discovery of adult T-cell leukemia (ATL) by Kiyoshi leukemogenic mechanism with Tax are also discussed Takatsuki and his colleagues in Japan in 1976 (Uchi- briefly. et al Oncogene (2005) 24, 5931–5937. doi:10.1038/sj.onc.1208981 yama ., 1977). The reports from his laboratory described unique characteristics of the leukemia such as Keywords: HTLV-1; transcription; tumor-suppressor unusual morphology of leukemic cells with lobulated genes; cell cycle; epidemiology nuclei and surface phenotypes. The most striking feature of the disease was the Kyushu (West part of Japan) origin of most of the patients who were identified in Kyoto where Takatsuki’s group performed their research. Takatsuki’s findings were later confirmed by extensive epidemiology and a clear clustering of Introduction ATL cases in the Kyushu area strongly suggested a unique etiology (Hinuma et al., 1981a). At the time, When virologists and oncologists are challenged to this novel discovery elicited enormous attention from identify human tumor viruses, they dream of the physicians, virologists, epidemiologists and oncologists, contribution of such viruses towards understanding but still there was no clue as to how to search for an cancers and answering questions such as how and why etiology. cancers develop and how to prevent viral infection in order to prevent cancers. There was a time when retroviruses were a particular focus because retroviruses Establishment of cell lines had been isolated as tumor viruses from many animal Isao Miyoshi who was interested in karyotype of tumor species in the 1970s. Such studies provided the cells tried to establish cell lines from peripheral conceptual revolution in understanding cancers, ulti- lymphoid cells of ATL patients (Miyoshi et al., 1980). mately contributing to the proposition of a ‘viral Prior to the availability of purified lymphokines, a cell oncogene’. Indeed, over the course of research, it line MT-1 was established from the sample of an ATL became apparent that viral oncogenes originated from patient using cocultivation with cord blood lympho- their host cell ‘proto-oncogenes’, which are widely cytes. Similar attempts then led to the establishing conserved in many animal species. Thus, ‘the oncogene’ of MT-2 and MT-4 cells, and these established lines became the ‘key player’ in cancer research linking exhibited extremely high chromosomal abnormalities. findings between animals and humans and also the Otherwise, at that time, not much additional informa- different origins of cancers. However, the daunting tion was captured from these cell lines. Nevertheless, worldwide challenge remained to identify and isolate a these cell lines later became essential tools for diagnosis bona fide retrovirus in a human cancer. of ATL and identification of the retrovirus, providing The discovery of the first human retrovirus proceeded reproducible and consistent biological materials that rather independently in Japan and the USA. Below, I could be propagated in large quantity. Surprisingly, first summarize the history of discovery from Japanese some of these cell lines turned out to be of cord- researchers and then discuss human T-cell leukemia blood origin and not of ATL origin according to virus type 1 (HTLV-1) regulatory and pathogenic chromosome analysis (Miyoshi et al., 1981). These mechanisms. unexpected results were later explained by the transmis- sion of retrovirus from ATL cells into cord-blood cells and subsequent immortalization of the de novo *Correspondence: M Yoshida; E-mail: [email protected] infected cell. Discovery of HTLV-1, the first human retrovirus M Yoshida 5932 Identification of a unique antibody in ATL patients competent genomic structure is frequently deleted by acquisition of a cellular proto-oncogene resulting in the Identification of unique serum antibodies in ATL formation of a transforming, but replication defective, patients was another key criterion for a new retrovirus. virus. The newly isolated HTLV-1 was unusual in that it Postulating a viral infection in ATL patients, Yorio has a complete undeleted replication competent genome, Hinuma et al. (1981b) applied an indirect immunofluor- but it contained an additional pX sequence which could escence assay to some ATL sera employing a large panel encode multiple proteins using alternative open reading of cells of human origin. After laborious screening, a frames. Thus, HTLV-1 has an ‘LTR-gag-pol-env-pX- single cell line was identified to give a robustly positive LTR’ genomic structure (Figure 1; Seiki et al., 1982, signal. That was the MT-1 cell, and the putative antigens 1983), with constitution similar to that of Rous sarcoma in the cell line were preliminary termed ATL antigens virus. This unique genome structure distinguished (ATLA). Later, MT-2 and -4 were also identified to give HTLV-1 from any other animal retroviruses, thus positive signals in this assay. Without knowing what founding a new retroviral group. Other members of this ATLA were, screening for anti-ATLA was carried out viral group, HTLV-2, STLV or PTLV and BLV, are with sera from various types of leukemias, and the well characterized today. results were importantly informative: anti-ATLA were detected in all ATL patients, also in a minor fraction of healthy individuals restricted to the Kyushu area in Association with ATL and other diseases Japan (Hinuma et al., 1981a, b). Therefore, it was evident that something was there, but it was not clear As described above, unique antibodies that crossreact what was there. with MT-1 cells were detected in all ATL patients, but not in other leukemic or healthy individuals, except for a rare minor population (Shimoyama et al., 1986). The HTLV-1 proteins, p24 and p19, were identified at least The daybreak of HTLV-1 in Japan as a part of the antigens for the unique antibodies in ATL patients; therefore, close association of HTLV-1 Identification of retrovirus infection with ATL was immediately concluded (Yoshida et al., 1982). Furthermore, the epidemiology also During the corresponding period of these years, Robert revealed that the cumulative risk of ATL among virus C Gallo and his group at NIH, USA (Poeisz et al., carriers in Japan was about 3–5%, indicating that most 1980), identified and first reported a retrovirus in a of the HTLV-1 carriers are asymptomatic throughout T-cell line, HUT102, established from a patient with their life (Tajima, 1990). Mycosis fungoides , which was later diagnosed as a case Subsequently, HTLV-1 infection was also discovered of ATL lymphoma. to associate with tropical spastic paraparesis (TSP) in Independently, molecular approaches were being Jamaica by Guy de The and his colleagues (Gessain applied to identify a retrovirus in the MT-2 cell line in et al., 1985) and with HTLV-1-associated myelopathy Japan by Yoshida et al. (1982). MT2 reacted positively (HAM) in Japan by Osame M et al. (1986). TSP and to sera from ATL patients. Particle fraction with similar HAM are now identified as identical myelopathies, density to animal retrovirus was purified from MT-2 which have lesions in the spinal cord. Interestingly, ATL culture fluid, and cDNA was prepared with the reverse and HAM/TSP are mutually exclusive. Onset of either transcriptase activity endogenous to those particles. This disease may depend on HLA types which determine the cDNA preparation was demonstrated to hybridize with magnitude of immune response to HTLV-1, or may cellular DNA of MT-2 but not of other cells. Thus, the depend on modes of infection, mucosal exposure to virus-like particles released from MT-2 cells were shown to contain both RNA templates and reverse transcrip- tase, and MT-2 cells had DNA sequence which hybridized with RNA from the particles, that is, the LTR gag pol env pX LTR integrated provirus DNA. p24 and p19 were also Gag, Pol identified as components of the particles, which are 3 known today as viral core proteins. Thus, a retrovirus Env was convincingly demonstrated in MT-2 cells, and this retrovirus was reported as adult T-cell leukemia virus (ATLV). The US HTLV and Japanese ATLV were later mRNA Repression demonstrated to be identical at the sequence level and Tax 2 Activation named as HTLV-1 (Watanabe et al., 1984). 1 Rex Figure 1 Feed back regulation of HTLV-1 gene expression by Tax Evidences for new retrovirus and Rex. Spontaneous viral expression of Tax from doubly spliced viral transcript. (1) Tax further activates subsequent viral Generally, replication competent retroviruses have their transcription; (2) Rex encoded by the same mRNA as Tax suppresses splicing of viral RNA, (3) thus accumulated unspliced proviral genome organized as LTR-gag-pol-env-LTR, mRNAs express Gag, Pol and Env proteins, and then followed which respectively encode the viral core proteins, reverse by down-regulation of Tax/Rex expression and by shut-off of transcriptase and envelope proteins. The replication transcription Oncogene Discovery of HTLV-1, the first human retrovirus M Yoshida 5933 HTLV-1 or primary viral infection in the peripheral Accordingly, the viral gene expression is efficient at blood (Barmak et al., 2003). More studies are appar- the initial stage of infection/gene expression and then is ently required.

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