Activation of the human immunodeficiency virus type I long terminal repeat by 1 alpha,25-dihydroxyvitamin D3.
Instituto de Investigaciones Biomédicas--Universidad Autónoma de Madrid, Madrid, Spain.
The genetic predisposition of the host and the virus is the most important determinant for prediction of the course of human immunodeficiency virus type I (HIV-1) viral infection and acquired immune deficiency syndrome (AIDS) progression. Transcription from the HIV-1 long terminal repeat (LTR) is a crucial step for viral replication. Here, we describe a stimulatory role of the vitamin D receptor (VDR) on HIV-1 LTR transactivation. Transient transfections reveal that VDR activates the LTR in HeLa, U937, and Cos-1 cells in a ligand-dependent manner. 1alpha,25-Dihydroxyvitamin D3 (vitD3) promotes activation of a minimal LTR construct (from nucleotides -35 to +89), lacking a previously described hormone response element that binds several nuclear receptors. NF-kappaB (nuclear factor-kappa B) and Sp1-binding sites, which are responsible for most basal LTR activity in HeLa cells, are also dispensable for vitD3-dependent HIV-1 transcription. Although the tat response element element is not required for VDR-mediated HIV-1 gene expression, the viral protein Tat acts in a synergistic manner with the receptor to stimulate LTR activity. Furthermore, our data also show cooperation of the receptor with various cellular coactivators for HIV-1 transactivation by vitD3. Paradoxically, mutations in the VDR ligand-dependent transcriptional activation function-2 that abrogate vitD3-dependent stimulation through classical vitamin D response elements, do not reduce vitD3-mediated LTR transactivation. Furthermore, point mutations in the DNA-binding domain that abolish receptor binding to consensus DNA sequences do not affect ligand-dependent HIV-1 stimulation. These results show that VDR activates the HIV-1 LTR through different mechanisms, including non-classical nuclear receptor transcriptional actions that may ensure viral transcription under different physiological scenarios.
PMID: 17556530 [PubMed - indexed for MEDLINE]