One line of research in my laboratory is related to understanding human T cell leukemia/lymphoma virus type 1 (HTLV-1) pathogenesis. HTLV-1 is the only known retrovirus that causes human cancer. Epidemiological, molecular, and biochemical evidence suggests that HTLV-1 persistence in the host is associated with T cell clonal expansion and consequent accumulation of genetic lesions, resulting in leukemia. Thus, the understanding of mechanisms of viral persistence is essential to prevent the occurrence of leukemia. We continued to study the function of the p12I and p30II proteins encoded by the 3' end of the viral genome. We hypothesized that they may play an essential role in viral persistence and pathogenesis. We found that p12I affects proximal T cell receptor (TCR) signaling, and phosphorylation of PLC-gamma1, Vav, and linker for activation of T cells (LAT). Consequently, calcium release and nuclear factor of activated T cells (NFAT) transcription are decreased. p12I, like LAT, is located in the lipid rafts and is recruited to the immunological synapse within minutes from TCR ligation. p12I also decreased MHC class I-restricted recognition of targeted cells by cytotoxic T cells. These findings may relate to the immunosuppression and immune evasion observed in HTLV-1 infection. Another exciting new development has been the finding that the p30II protein encoded by the ORF II at the 3' end of the viral genome decreases proviral expression by a novel post-transcriptional mechanism. We found that p30II binds to the doubly spliced Tax/Rex mRNA and retains it in the nucleus. As expected, expression of p30II in HTLV-1-infected T cell lines also decreases viral replication by decreasing the level of Tax. A protein (p28II) with similar function is also found in HTLV-2, a virus genetically related to HTLV-1.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
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Vector Biology Study Section (VB)
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Basic Sciences
United States
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Franchini, Genoveffa (2009) Choosing the right memory T cell for HIV. Nat Med 15:244-6
Fukumoto, Risaku; Andresen, Vibeke; Bialuk, Izabela et al. (2009) In vivo genetic mutations define predominant functions of the human T-cell leukemia/lymphoma virus p12I protein. Blood 113:3726-34
Younis, Ihab; Khair, Lyne; Dundr, Miroslav et al. (2004) Repression of human T-cell leukemia virus type 1 and type 2 replication by a viral mRNA-encoded posttranscriptional regulator. J Virol 78:11077-83
Nicot, Christophe; Dundr, Miroslav; Johnson, Julie M et al. (2004) HTLV-1-encoded p30II is a post-transcriptional negative regulator of viral replication. Nat Med 10:197-201
Franchini, Genoveffa; Nicot, Christophe; Johnson, Julie M (2003) Seizing of T cells by human T-cell leukemia/lymphoma virus type 1. Adv Cancer Res 89:69-132
D'Agostino, D M; Zotti, L; Ferro, T et al. (2000) The p13II protein of HTLV type 1: comparison with mitochondrial proteins coded by other human viruses. AIDS Res Hum Retroviruses 16:1765-70
Takemoto, S; Trovato, R; Cereseto, A et al. (2000) p53 stabilization and functional impairment in the absence of genetic mutation or the alteration of the p14(ARF)-MDM2 loop in ex vivo and cultured adult T-cell leukemia/lymphoma cells. Blood 95:3939-44
Nicot, C; Mahieux, R; Opavsky, R et al. (2000) HTLV-I Tax transrepresses the human c-Myb promoter independently of its interaction with CBP or p300. Oncogene 19:2155-64
Nicot, C; Opavsky, R; Mahieux, R et al. (2000) Tax oncoprotein trans-represses endogenous B-myb promoter activity in human T cells. AIDS Res Hum Retroviruses 16:1629-32
Trovato, R; Cereseto, A; Takemoto, S et al. (2000) Deletion of the p16INK4A gene in ex vivo acute adult T cell lymphoma/leukemia cells and methylation of the p16INK4A promoter in HTLV type I-infected T cell lines. AIDS Res Hum Retroviruses 16:709-13

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