Tat controls transcriptional persistence of unintegrated HIV genome in primary human macrophages

Highlights: • Unintegrated HIV DNA (uDNA) accumulates in infected macrophages where it can persistenly transcribe early viral genes. • Tat is produced from unintegrated HIV genome early in HIV infection (uTat, uDNA-derived Tat). • In the absence of uTat, uDNA is assembled into repressive episomal minichromatin. • uTat antagonizes uDNA minichromatin repression to maintain persistent viral transcription in macrophages. • uTat-mediated viral persistence may establish a viral reservoir in macrophages. In HIV infected macrophages, a large population of viral genomes persists as the unintegrated form (uDNA) that is transcriptionally active. However, how this transcriptional activity is controlled remains unclear. In this report, we investigated whether Tat, the viral transactivator of transcription, is involved in uDNA transcription. We demonstrate that de novo Tat activity is generated from uDNA, and this uDNA-derived Tat (uTat) transactivates the uDNA LTR. In addition, uTat is required for the transcriptional persistence of uDNA that is assembled into repressive episomal minichromatin. In the absence of uTat, uDNA minichromatin is gradually silenced, but remains highly inducible by HDAC inhibitors (HDACi). Therefore, functionally, uTat antagonizes uDNA minichromatin repression to maintain persistent viral transcription in macrophages. uTat-mediated viral persistence may establish a viral reservoir in macrophages where uDNA were found to persist.