Human immunodeficiency virus type-1 Tat/co-activator acetyltransferase interactions inhibit p53Lys-320 acetylation and p53-responsive transcription.

Patients with AIDS are at increased risk for developing various neoplasms, including Hodgkin's and non-Hodgkin's lymphomas, Kaposi's sarcomas, and anal-rectal carcinomas, suggestive that human immunodeficiency virus type-1 infection might promote establishment of AIDS-related cancers. Tat, the viral trans-activator, can be endocytosed by uninfected cells and has been shown to inhibit p53 functions, providing a candidate mechanism through which the human immunodeficiency virus type-1 might contribute to malignant transformation. Because Tat has been shown to interact with histone acetyltransferase domains of p300/cAMP-responsive element-binding protein (CREB)-binding protein and p300/CREB-binding protein-associated factor, we have investigated whether Tat might alter p53 acetylation and tumor suppressor-responsive transcription. Here, we demonstrate that both Tat and p53 co-localize with p300/CREB-binding protein-associated factor and p300 in nuclei of IMR-32 human neuroblastoma cells and in PC-12 pheochromocytoma cells. Further, p53 trans-activation of the 14-3-3varsigma promoter was markedly repressed by Tat-histone acetyltransferase interactions, and p53 acetylation by p300/CREB-binding protein-associated factor on residue Lys(320) was diminished as a result of Tat-histone acetyltransferase binding in vivo and in vitro. Tat also inhibited p53 acetylation by p300 in a dosage-dependent manner in vitro. Finally, HIV-1-infected Molt-4 cells displayed reduced p53 acetylation on lysines 320 and 373 in response to UV irradiation. Our results allude to a mechanism whereby the human immunodeficiency virus type-1 trans-activator might impair tumor suppressor functions in immune/neuronal-derived cells, thus favoring the establishment of neoplasia during AIDS.