The main thrust of our work is to use in vitro models of transformation of T-cells by human viruses to understand the role of viral and cellular proteins in T-cell transformation. In the case of HTLV-1, we have focused on two viral proteins, p12I and p30II, encoded by the ORFs I and II of the viral genome, respectively. p12I is a small oncogene that binds to receptors such as the IL-2R beta and gamma-c chains and the MHC I. p12I increases STAT5 activation (Nicot et al., Blood, 2001) and cell proliferation. Recently, however, we have found that p12I is in the raft and downregulates the TCR proximal signaling pathway, and we are at present working on the identification of the cellular partner of p12I for this effect. p12I binds to the free MHC I heavy chain and interferes with its association with the beta-2 microglobulin (Johnson et al., J. Virol., 2001). Biochemical and biological indicate that the alteration in maturation and trafficking of MHC I in the presence of p12I results in decreased antigen presentation and decreased CTL recognition. We have recently uncovered the function of p30II, a negative regulator of viral expression that specifically targets the mRNA. This protein is a positive regulator of viral expression. Thus, p30II may be very important to suppress at least partially viral replication in vivo (latency?) and allow escape from immune surveillance of HTLV-1-infected cells (Nicot et al., submitted, 2003). p30II may prove to be a worthwhile target for therapeutic intervention. We have continued our research on a new virus (HVMNE) isolated from a pig-tailed macaque with Sezary syndrome. This virus, like the human EBV, phylogenetically belongs to the lymphocryptoviruses. 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 T-cell lymphomas with high frequency (Ferrari et al., Blood, 2001), thus providing a small-animal model for lymphoma whereby to assess therapeutic approaches and the genetic determinants involved in T-cell transformation that may help in the treatment of human lymphoma. More recently, we have demonstrated that the virus causes transformation of T-cells in nonhuman primates in vitro as well (Ferrari et al., Virology, in press).

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
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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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