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 IL2R beta and gamma-c chains and the MHC I. p12I increases Stat5 activation (Nicot et al., Blood 2001) and cell proliferation. Recently, however, we found that p12I is in the raft and downregulates the TCR proximal signaling pathway and is recruited to the immunological synapse. We are 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 data 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 recently uncovered the function of p30II, a negative regulator of viral expression that specifically targets the mRNA. This protein is a negative regulator of viral expression and may be very important for virus concealment in vivo (latency) and allow escape from immune recognition (Nicot et al., Nat Med 2004). p30II indeed may be a desirable target for therapeutic intervention. References: Harrod et al. J Biol Chem 2003; Johnson et al. in Sugamura K et al.: Two Decades of Adult T-Cell Leukemia and HTLV-1 Research. 2003; Franchini et al Int J Hematol 2003; Younis et al. J Virol. 2004.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005645-15
Application #
7038611
Study Section
Vector Biology Study Section (VB)
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2004
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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
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
Johnson, J M; Mulloy, J C; Ciminale, V et al. (2000) The MHC class I heavy chain is a common target of the small proteins encoded by the 3' end of HTLV type 1 and HTLV type 2. AIDS Res Hum Retroviruses 16:1777-81
Dekaban, G A; Peters, A A; Mulloy, J C et al. (2000) The HTLV-I orfI protein is recognized by serum antibodies from naturally infected humans and experimentally infected rabbits. Virology 274:86-93
Nicot, C; Mahieux, R; Takemoto, S et al. (2000) Bcl-X(L) is up-regulated by HTLV-I and HTLV-II in vitro and in ex vivo ATLL samples. Blood 96:275-81
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

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