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-I, we have focused on a viral protein (p12I) of 12 kD, which is a small oncogene and binds to the IL-2R beta and gamma-c chains. We have found that this interaction results in an increase of STAT5 activation (Nicot et al., Blood, 2001) 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 beta-2 microglobulin (Johnson et al., J. Virol., 2001). Biochemical studies are in progress to understand the alteration in maturation and trafficking of MHC I in the presence of p12I and the mechanism of STAT5 activation. In addition, very recently we have identified the function of another HTLV-I small protein, p30II. This protein interferes with p53's function and together with Tax may help the virus to circumvent checkpoints of cell growth. We have discovered that p30II is a negative regulator of viral expression and in concert with p12I may allow expansion of infected cells. Thus, efforts to target p30II may prove worthwhile for possible therapeutic intervention. During this year, we also discovered a new virus (HVMNE) in 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 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.
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