Repression of tax-mediated human t-lymphotropic virus type 1 transcription by inducible cAMP early repressor (ICER) protein in peripheral blood mononuclear Cells

Abstract

Human T-lymphotropic virus type 1 (HTLV-1) infection causes adult T-cell leukemia and is characterized by long periods of clinical latency with low levels of viral production. Transcription of HTLV-1 is controlled through sequences in the promoter and enhancer regions of the long terminal repeat of the integrated provirus. Important among these sequences are three 21 bp imperfect repeats responsive to the viral oncogenic protein Tax (TRE). Members of the CREB/ATF-1/CREM family of transcription factors bind to TRE-1 and are critical for HTLV-1 transcription. Other less studied family members include the inducible cAMP early repressor (ICER) proteins. ICER proteins lack phosphorylation and activation domains and are potent inhibitors of transcription. The ability of ICER to bind TRE-1 and its effects on HTLV-1 Tax mediated transcription have not been studied in the natural cell targets of the virus, peripheral blood mononuclear cells (PBMC). We show that ICER mRNA levels are low in quiescent PBMC, but rise and remain elevated for up to 18 hr after mitogenic stimulation of these cells. Electrophoretic mobility shift assays using recombinant Tax and ICER demonstrate that ICER binds TRE-1 and that binding is increased in the presence of Tax. Furthermore, over expression of ICER IIgamma suppressed Tax-mediated transcription whereas an anti-sense ICER II plasmid designed to block endogenous ICER enhanced Tax-mediated transcription in activated PBMC. Together our data indicate that ICER inhibits Tax-mediated transcription in activated PBMC and suggest a role for ICER in maintenance of HTLV-1 persistence.