We are interested in the mechanism of HTLV-I induced T-cell proliferation and the main thrust of our work is to use HTLV-I in vitro to understand the viral and cellular factors involved in T-cell transformation. In the case of HTLV-I, we have focused on a viral protein (p12I) of 12 kD, which is a small oncogene and binds to the IL-2R b and gc chains. We have found that this interaction results in an increase of STAT5 activation and hypothesized that this effect may be important in vivo. In addition, we have demonstrated that p12I exists in two alleles in nature (found in patient samples): one carries in position 88 a Lysine and is ubiquitinated and has a half-life of a half of an hour whereas the other natural allele carries an Arginine in position 88 and is very stable. p12I also is recognized by antibodies in sera of HTLV-I infected cells. A new finding is that p12I binds to the free MHC I heavy chain and interferes with its association with the b 2 microglobulin. Biochemical studies are in progress to understand the alteration in maturation and trafficking of MHC I in the presence of p12I. Very recently we have identified the function of another HTLV-I small protein, p30II. This protein interferes with several of p53's functions and together with Tax may help the virus to circumvent checkpoints of cell growth. During this year, we also discovered a new virus in a pig-tailed macaque with Sezary syndrome. This virus, like the human EBV, phylogenetically belongs to the lymphocryptoviruses. This virus (HVMNE) was isolated from lymphomatous CD8+ T-cell lines, generated from the blood and skin of this diseased animal. Upon inoculation in rabbits, HVMNE causes lymphomas with high frequency, thus providing a small-animal model for lymphoma whereby to assess therapeutic approaches.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
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Basic Sciences
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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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