Molecular architecture of the HIV-1 long-terminal repeat. The viral promoter, the long-terminal repeat (LTR), can be divided into the U3, R, and U5 regions. Upon integration, the LTR presents stretches of DNase I hypersensitivity sites (shown as HS2, HS3, and HS4) as a result of the well-defined, conversed positioning of the two nucleosomes; nuc-0 and nuc-1. This architecture results in exposure of stretches of DNA extremely rich in transcription factor-binding sites that include different regulatory proteins in the process of HIV-1 transcription. These factors respond to various extracellular and intracellular stimuli, resulting in upregulation/downregulation of specific downstream transcription factors that act via binding to their respective binding sites in the LTR. Also, positioning of nuc-1 is crucial because it is present immediately downstream of the start site (+1); this nucleosome needs to be remodeled for active processive transcription to ensue from the LTR. Moreover, modifications like acetylation, phosphorylation, and methylation of histone tails regulate LTR-directed transcription. The HIV-1 Tat protein regulates the chromatin environment via interactions with several components including methyltransferases, acetyltransferases, and a number of transcription factors in addition to binding to the TAR element in nascent HIV-1 RNA.
