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A retrovirus (ATLV) was unequivocally demonstrated in human adult T-cell leukemia (ATL) cell lines by density (1.152-1.155 g/cm3) in a sucrose gradient, reverse transcriptase activity insensitive to actinomycin D, RNA labeled with [3H]uridine, and specific proteins with molecular weights of 11,000, 14,000, 17,000, 24,000, and 45,000. Furthermore, cDNA prepared by endogenous reaction with detergent-treated virions hybridized to 35S RNA containing poly(A), which was inducible by IdUrd treatment of a T-cell line derived from leukemic cells of the ATL, and the integrated form of ATLV proviral DNA was detected in T-cell lines derived from ATL. The ATLV proviral DNA was also detected in fresh peripheral lymphocytes from all five patients with ATL tested so far but not in those from healthy adults. On the other hand, ATLV protein of Mr 42,000 was found to be at least one of the ATL-associated antigen(s) that were previously detected in ATL-leukemic cells by all sera from patients with ATL. These findings on the close association of ATLV protein and proviral DNA with ATL are direct evidence for the possible involvement of the retrovirus ATLV in leukemogenesis of human ATL.
Adult T-cell leukemia-lymphoma (ATL) is a distinct peripheral T-lymphocytic malignancy associated with a retrovirus designated human T-cell lymphotropic virus type I (HTLV-1). The diversity in clinical features and prognosis of patients with this disease has led to its subclassification into the following four categories: acute, lymphoma, chronic, and smoldering types. The chronic and smoldering subtypes are considered indolent and are usually managed with watchful waiting until disease progression, analogous to the management of some patients with chronic lymphoid leukemia (CLL) or other indolent histology lymphomas. Patients with aggressive ATL generally have a poor prognosis because of multidrug resistance of malignant cells, a large tumor burden with multiorgan failure, hypercalcemia, and/or frequent infectious complications as a result of a profound T-cell immunodeficiency. Under the sponsorship of the 13th International Conference on Human Retrovirology: HTLV, a group of ATL researchers joined to form a consensus statement based on established data to define prognostic factors, clinical subclassifications, and treatment strategies. A set of response criteria specific for ATL reflecting a combination of those for lymphoma and CLL was proposed. Clinical subclassification is useful but is limited because of the diverse prognosis among each subtype. Molecular abnormalities within the host genome, such as tumor suppressor genes, may account for these diversities. A treatment strategy based on the clinical subclassification and prognostic factors is suggested, including watchful waiting approach, chemotherapy, antiviral therapy, allogeneic hematopoietic stem-cell transplantation (alloHSCT), and targeted therapies.
Human T cell leukemia virus type 1 (HTLV-1) is a lymphotropic retrovirus whose cell-to-cell transmission requires cell contacts. HTLV-1-infected T lymphocytes form 'virological synapses', but the mechanism of HTLV-1 transmission remains poorly understood. We show here that HTLV-1-infected T lymphocytes transiently store viral particles as carbohydrate-rich extracellular assemblies that are held together and attached to the cell surface by virally-induced extracellular matrix components, including collagen and agrin, and cellular linker proteins, such as tetherin and galectin-3. Extracellular viral assemblies rapidly adhere to other cells upon cell contact, allowing virus spread and infection of target cells. Their removal strongly reduces the ability of HTLV-1-producing cells to infect target cells. Our findings unveil a novel virus transmission mechanism based on the generation of extracellular viral particle assemblies whose structure, composition and function resemble those of bacterial biofilms. HTLV-1 biofilm-like structures represent a major route for virus transmission from cell to cell.