EXPRESSION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 TAT RESULTS IN DOWN-REGULATION OF BCL-2 AND INDUCTION OF APOPTOSIS IN HEMATOPOIETIC-CELLS

Infection by human immunodeficiency virus type 1 (HIV-1) is characteri zed by progressive loss of various cell types, mainly CD4(+) T lymphoc ytes. While a passive role for the virus in cell destruction is recogn ized, it does not account for the vast amount of cell death including those of uninfected 'bystander' cells. Since in the past we and others have demonstrated the capacity of the Tat protein of HIV-1 to modulat e the expression of various cellular genes and that Tat secreted by HI V-infected cells can be readily taken up by various cell types, we hav e investigated the role of Tat on inducing apoptosis. Our results indi cate that T lymphocytes transfected to constitutively express HIV-1 ta t, when grown under serum-free conditions results in rapid apoptosis c haracterized by typical ultrastructural features and DNA fragmentation . Additionally, we observed that in several hematopoietic cell types, including T and B lymphoid cells and monocytoid cells, the expression of HIV-1 tat results in down-regulation of bcl-2, an oncogene with kno wn potential for inhibition of apoptosis. The tat-mediated down-regula tion of bcl-2 was observed at both the transcriptional and translation al levels. Also, tat-transfected cells expressed increased amounts of bax, a bcl-2 family protein known to induce apoptosis. While these res ults support reports in the literature of an active role for tnt in in ducing cell death in HIV-infected individuals, they point to a new mec hanism involving Tat-mediated modulation of bcl-2 and bax.