NF-kappaB-repressing factor inhibits elongation of human immunodeficiency virus type 1 transcription by DRB sensitivity-inducing factor

Authors:
Dreikhausen U, Hiebenthal-Millow K, Bartels M, Resch K and Nourbakhsh M
In:
Source: Mol Cell Biol
Publication Date: (2005)
Issue: 25(17): 7473-7483
Research Area:
Immunotherapy / Hematology
Cells used in publication:
Jurkat
Species: human
Tissue Origin: blood
Platform:
Nucleofector® I/II/2b
Experiment
To measure effect of NRF binding site in regulation of HIV LTR-1 transcriptional activity, cells were transfected with constructs expressing firefly luciferase under control of either wild-type HIV-1 LTR or a HIV-1 LTR lacking a functional NRF binding site (10 µg) and a construct expressing renilla luciferase (2.5 µg). Luciferase was examined in both PMA/ionomycin stimulated and non-stimulated samples. Firefly luciferase activities was normalised to Renilla luciferase activities. Binding of transcription factors to HIV-1 LTR was examined by chromatin immunoprecipitation (ChIP) analysis of cells transfected with the same HIV-1 LTR luciferase reporter constructs.
Abstract
Human immunodeficiency virus type 1 (HIV-1) is able to establish a latent infection during which the integrated provirus remains transcriptionally silent. In response to specific stimuli, the HIV-1 long terminal repeat (LTR) is highly activated, enhancing both transcriptional initiation and elongation. Here, we have identified a specific binding sequence of the nuclear NF-kappaB-repressing factor (NRF) within the HIV-1 LTR. The aim of this work was to define the role of NRF in regulating the LTR. Our data show that the endogenous NRF is required for transcriptional activation of the HIV-1 LTR in stimulated cells. In unstimulated cells, however, NRF inhibits HIV-1 LTR activity at the level of transcription elongation. Binding of NRF to the LTR in unstimulated cells prevents recruitment of elongation factor DRB sensitivity-inducing factor and formation of processive elongation complexes by hyperphosphorylated RNA polymerase II. Our data suggest that NRF interrupts the regulatory coupling of LTR binding factors and transcription elongation events. This inhibitory mechanism might contribute to transcriptional quiescence of integrated HIV-1 provirus.