The human T-cell leukemia viruses (HTLV) types I and II are lymphotropic type C retroviruses causally associated with certain human T-cell malignancies. These unique viruses, which do not contain sequences related to known oncogenes, cause acute transformation of human T lymphocytes in vitro. The mechanism of HTLV-I induced leukemogenesis is unknown. The HTLV-I and HTLV-II proviruses have been molecularly cloned. Analyses of nucleic acid sequences in HTLV identified, in addition to the typical structural genes, a region, termed X, located between env and the 3' long terminal repeat (LTR). The HTLV-I and HTLV-II X regions are approximately 1.6 kbp in size and conserve 75% of the distal two-thirds of their sequences. These high homology X sequences are also conserved in HTLV-II deletion mutants that are found in cells with more malignant growth characteristics. Recent data indicates that virtually identical HTLV-I and HTLV-II high homology X sequences are expressed as subgenomic RNA, which encode proteins weighing 40 and 37 kD, respectively. Other studies have suggested that the HTLV LTR, a control element for viral expression, is regulated in-trans by a HTLV-related factor. It is likely that the X-encoded protein is a trans-acting regulator of the HTLV LTR and that this gene product serves an analagous function in the process of leukemic transformation of normal T-cells by regulation of genetic control elements in-trans. The overall goal of this proposal is to determine whether the HTLV X gene product influences the behavior of the HTLV LTR.
The specific aims are: (1) To clone and express both the HTLV-I and HTLV-II X genes; (2) To determine if the X gene product acts in-trans on the HTLV LTR; (3) To compare the effect of the HTLV-I and HTLV-II X gene product on the LTR; (4) To compare the response of the HTLV-I, HTLV-II, and HTLV-II deletion mutant LTRs to the X gene product; (5) To ascertain if X gene product-LTR interaction is modulated by cellular environment in a variety of lymphoid and non-lymphoid cell lines. These studies will further our understanding of HTLV biology and add to fundamental knowledge regarding the mechanism of viral-induced leukemogenesis. Presently, my focus is in the area of hematologic malignancies and the biology of HTLV. The environment at UCLA, where there is an ongoing program focused on the molecular biology of HTLV, is ideal for continuing my development as an academic hematologist-oncologist.
