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      40 years of the human T-cell leukemia virus: past, present, and future

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          Abstract

          It has been nearly 40 years since human T-cell leukemia virus-1 (HTLV-1), the first oncogenic retrovirus in humans and the first demonstrable cause of cancer by an infectious agent, was discovered. Studies indicate that HTLV-1 is arguably one of the most carcinogenic agents to humans. In addition, HTLV-1 causes a diverse array of diseases, including myelopathy and immunodeficiency, which cause morbidity and mortality to many people in the world, including the indigenous population in Australia, a fact that was emphasized only recently. HTLV-1 can be transmitted by infected lymphocytes, from mother to child via breast feeding, by sex, by blood transfusion, and by organ transplant. Therefore, the prevention of HTLV-1 infection is possible but such action has been taken in only a limited part of the world. However, until now it has not been listed by the World Health Organization as a sexually transmitted organism nor, oddly, recognized as an oncogenic virus by the recent list of the National Cancer Institute/National Institutes of Health. Such underestimation of HTLV-1 by health agencies has led to a remarkable lack of funding supporting research and development of treatments and vaccines, causing HTLV-1 to remain a global threat. Nonetheless, there are emerging novel therapeutic and prevention strategies which will help people who have diseases caused by HTLV-1. In this review, we present a brief historic overview of the key events in HTLV-1 research, including its pivotal role in generating ideas of a retrovirus cause of AIDS and in several essential technologies applicable to the discovery of HIV and the unraveling of its genes and their function. This is followed by the status of HTLV-1 research and the preventive and therapeutic developments of today. We also discuss pending issues and remaining challenges to enable the eradication of HTLV-1 in the future.

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          Most cited references 124

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          Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma.

          Retrovirus particles with type C morphology were found in two T-cell lymphoblastoid cell lines, HUT 102 and CTCL-3, and in fresh peripheral blood lymphocytes obtained from a patient with a cutaneous T-cell lymphoma (mycosis fungoides). The cell lines continuously produce these viruses, which are collectively referred to as HTLV, strain CR(HTLV(CR)). Originally, the production of virus from HUT 102 cells required induction with 5-iodo-2'-deoxyuridine, but the cell line became a constitutive producer of virus at its 56th passage. Cell line CTCL-3 has been a constitutive producer of virus from its second passage in culture. Both mature and immature extracellular virus particles were seen in thin-section electron micrographs of fixed, pelleted cellular material; on occasion, typical type C budding virus particles were seen. No form of intracellular virus particle has been seen. Mature particles were 100-110 nm in diameter, consisted of an electron-dense core surrounded by an outer membrane separated by an electron-lucent region, banded at a density of 1.16 g/ml on a continuous 25-65% sucrose gradient, and contained 70S RNA and a DNA polymerase activity typical of viral reverse transcriptase (RT; RNA-dependent DNA nucleotidyltransferase). Under certain conditions of assay, HTLV(CR) RT showed cation preference for Mg(2+) over Mn(2+), distinct from the characteristics of cellular DNA polymerases purified from human lymphocytes and the RT from most type C viruses. Antibodies to cellular DNA polymerase gamma and anti-bodies against RT purified from several animal retroviruses failed to detectably interact with HTLV(CR) RT under conditions that were positive for the respective homologous DNA polymerase, demonstrating a lack of close relationship of HTLV(CR) RT to cellular DNA polymerases gamma or RT of these viruses. Six major proteins, with sizes of approximately 10,000, 13,000, 19,000, 24,000, 42,000, and 52,000 daltons, were apparent when doubly banded, disrupted HTLV(CR) particles were chromatographed on a NaDodSO(4)/polyacrylamide gel. The number of these particle-associated proteins is consistent with the expected proteins of a retrovirus, but the sizes of some are distinct from those of most known retroviruses of the primate subgroups.
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            Adult T-cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera.

            Indirect immunofluorescence of certain human sera demonstrated an antigen(s) in the cytoplasm of 1--5% of the cells of a T-cell line, MT-1, from a patient with adult T-cell leukemia (ATL), which is endemic in southwestern Japan. The antigen was not detected in other human lymphoid cell lines, including six T-cell lines, seven B-cell lines, and four non-T non-B cell lines. The antigen did not show cross antigenicity with that of herpesviruses, including Epstein--Barr virus, herpes simplex virus, cytomegalovirus, varicella-zoster virus, herpesvirus saimiri, and Marek disease virus. The proportion of antigen-bearing cells was increased by a factor of approximately 5 on culture in the presence of 5-iodo-2'-deoxyuridine. Antibodies against the antigen in MT-1 cells were found in all 44 patients with ATL examined and in 32 of 40 patients with malignant T-cell lymphomas (most of them had diseases similar to ATL except that leukemic cells were not found in the peripheral blood). The antibodies were also detected in 26% of the healthy adults examined from ATL-endemic areas but in only a few of those examined from ATL-non-endemic areas. On electron microscopy, extracellular type C virus particles were detected in pelleted MT-1 cells cultured in the presence of 5-iodo-2'-deoxyuridine.
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              Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS.

              Peripheral blood lymphocytes from patients with the acquired immunodeficiency syndrome (AIDS) or with signs or symptoms that frequently precede AIDS (pre-AIDS) were grown in vitro with added T-cell growth factor and assayed for the expression and release of human T-lymphotropic retroviruses (HTLV). Retroviruses belonging to the HTLV family and collectively designated HTLV-III were isolated from a total of 48 subjects including 18 of 21 patients wih pre-AIDS, three of four clinically normal mothers of juveniles with AIDS, 26 of 72 adult and juvenile patients with AIDS, and from one of 22 normal male homosexual subjects. No HTLV-III was detected in or isolated from 115 normal heterosexual subjects. The number of HTLV-III isolates reported here underestimates the true prevalence of the virus since many specimens were received in unsatisfactory condition. Other data show that serum samples from a high proportion of AIDS patients contain antibodies to HTLV-III. That these new isolates are members of the HTLV family but differ from the previous isolates known as HTLV-I and HTLV-II is indicated by their morphological, biological, and immunological characteristics. These results and those reported elsewhere in this issue suggest that HTLV-III may be the primary cause of AIDS.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data CurationRole: InvestigationRole: Project AdministrationRole: ResourcesRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – Original Draft PreparationRole: Writing – Review & Editing
                Role: ConceptualizationRole: Data CurationRole: InvestigationRole: ResourcesRole: ValidationRole: VisualizationRole: Writing – Original Draft PreparationRole: Writing – Review & Editing
                Role: ConceptualizationRole: ResourcesRole: ValidationRole: Writing – Original Draft PreparationRole: Writing – Review & Editing
                Journal
                F1000Res
                F1000Res
                F1000Research
                F1000Research
                F1000 Research Limited (London, UK )
                2046-1402
                28 February 2019
                2019
                : 8
                Affiliations
                [1 ]Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
                [2 ]Department of Hematology, Rheumatology and Infectious Diseases, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-0811, Japan
                Author notes

                No competing interests were disclosed.

                Article
                10.12688/f1000research.17479.1
                6396841
                Copyright: © 2019 Tagaya Y et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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                The author(s) declared that no grants were involved in supporting this work.
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