T-cell Transformation by Oncoviruses

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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.