T-cell Transformation by Oncoviruses

点击翻译按钮获取中文摘要

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.