Pathogenesis: Co-Infection and Other Viruses
Thursday, 1:30 - 3:30 pm
Background: Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of an aggressive and fatal disease termed adult T-cell leukemia (ATL) and of the neurodegenerative disease tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). ATL is an aggressive malignancy of mature activated CD4+ T-cells associated with human T-cell leukemia virus type 1 (HTLV-1) infection.
The understanding of ATL pathogenesis remains incomplete, and one leading hypothesis is that virus-induced chronic T-cell proliferation results in the accumulation of genetic defects in a single T-cell clone, which culminates in overt leukemia.
Methods: We hypothesize that SH2 homology-containing protein-tyrosine phosphatases-1 (SHP-1) downregulation is of central importance to HTLV-1 leukemogenesis. To verify this, we cloned the full-length, hematopoietic cell-specific SHP-1 promoter (P2) and identified the core promoter region by 5’- and 3’- deletional assay. The core SHP-1 promoter, which has a length of 277 base pairs, has an equivalent promoter activity in lymphocyte cell lines. We then checked the effects of wild type (WT) tax on the core promoter function.
Results: We demonstrate that: (1) Tax is able to inhibit both WT promoter and core promoter. This inhibition is dose-dependent. (2) The inhibition effect can be increased by co-transfection of histone deacetylase-1 (HDAC1) plasmid and can be decreased by addition of HDAC1 inhibitor trichostatin A (TSA).
Conclusions: These studies should provide new insights into biochemical mechanisms of HTLV-1 leukemogenesis and aid in the development of new treatments for this fatal disease.
Keywords: HTLV-1; Tax; SHP-1