Medical Sciences Group/Core LaboratoriesUchimaru Laboratory
(Laboratory of Tumor Cell Biology)
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Professor UCHIMARU Kaoru
ATL (Adult T-cell Leukemia) is caused by the human retrovirus HTLV-1 (Human T-cell leukemia Virus type 1) transmitted mainly through breast milk and infecting infant T cells. ATL has no definitive treatment and is the poorest prognosis hematologic tumor disease.
- Research
keywords - HTLV-1, ATL, HTLV-1 Tax / Rex / HBZ, Host-pathogen interaction, ADC,
Clinical HTLV-1
HTLV-1 is transmitted through mother-to-child transmission, in which HTLV-1-infected mothers pass the virus to their infants mainly through breast milk, and through horizontal transmission, in which HTLV-1 is transmitted through sexual intercourse. HTLV-1 is transmitted from mother to infant through breastfeeding and horizontally through sexual intercourse. However, about 5% develop a refractory hematologic malignancy called adult T-cell leukemia-lymphoma (ATL), and a small percentage develop HTLV-1-associated myelopathy (HAM), HTLV-1 uveitis (HU), and other inflammatory diseases such as HTLV-1-associated myelopathy (HTLV-1). The outcome of ATL with chemotherapy has been very poor, and recently, novel molecularly targeted drugs have been developed and hematopoietic cell transplantation has been used for curative treatment. Another future challenge is to identify high-risk groups of HTLV-1 asymptomatic carriers for early intervention. Dr. Uchimaru treats patients with ATL at the Institute of Medical Science Hospital and has established a specialized outpatient clinic for HTLV-1 asymptomatic carriers to analyze clinical data. He also conducts policy research for the Ministry of Health, Labour and Welfare (MHLW) on HTLV-1 infection, including measures to prevent mother-to-child transmission.
Research from the HTLV-1 virus side
Associate Professor Nakano is interested in the properties of HTLV-1 as an oncogenic virus; HTLV-1 is a single-stranded positive-sense RNA virus belonging to the genus Deltaretrovirus of the family Retroviridae. After infection, the viral genomic RNA undergoes reverse transcription and conversion to double-stranded DNA, and is permanently incorporated into the human genomic DNA of host T cells as an approximately 9 kb provirus with LTR at both ends. The provirus contains all the genetic information necessary for viral replication. After infection, viral replication is carried out for 10 to 14 days using the host cell's transcription and translation mechanisms, followed by a rapid shift to a latent infection state (Fig. 1). The infected cells then become immortalized and are thought to survive for several decades in the carrier body. In the early stages of infection, the provirus transcribes Tax/Rex mRNA, which encodes the major functional proteins Tax and Rex together, from the 5′-LTR, and HBZ mRNA, which encodes HBZ (HTLV-1 basic region leucine-zipper), from the 3′- Tax specifically and potently activates the 5′-LTR and promotes transcription of non-spliced viral mRNAs encoding Gag/Pro/Pol, the structural proteins of the viral particle, and incompletely spliced viral mRNA encoding Env. Rex activates the transcription of these non Rex binds specifically to the RxRE motif in the 3'-UTR of these non/incompletely spliced mRNAs and rapidly transports them out of the nucleus, escorting viral RNA and promoting viral particle formation while intervening in host cell transcription, translation and mRNA quality control mechanisms (Nakano et al. 2013; Viruses 14, 344. 2022; Viruses 14, 407. 2022). HBZ acts antagonistically with Tax to negatively regulate viral gene transcription, while HTLV-1 increases the efficiency of infection and promotes proliferation of infected T cells.