The chromatin landscape at the HIV-1 provirus integration site determines viral expression

0559755 - ÚMG 2023 RIV GB eng J - Journal Article
Vansant, G. - Chen, H.C. - Zorita, E. - Trejbalová, Kateřina - Miklík, Dalibor - Filion, G. - Debyser, Z.
The chromatin landscape at the HIV-1 provirus integration site determines viral expression.
Nucleic Acids Research. Roč. 48, č. 14 (2020), s. 7801-7817. ISSN 0305-1048. E-ISSN 1362-4962
Institutional support: RVO:68378050
Keywords : retrovirus integration * HIV latency * chromatin a LEDGF/p75
OECD category: Biochemistry and molecular biology
Impact factor: 16.971, year: 2020
Method of publishing: Open access
https://academic.oup.com/nar/article/48/14/7801/5864711?login=true

HIV-1 persists lifelong in memory cells of the immune system as latent provirus that rebounds upon treatment interruption. Therefore, the latent reservoir is the main target for an HIV cure. Here, we studied the direct link between integration site and transcription using LEDGINs and Barcoded HIV-ensembles (B-HIVE). LEDGINs are antivirals that inhibit the interaction between HIV-1 integrase and the chromatin tethering factor LEDGF/p75. They were used as a tool to retarget integration, while the effect on HIV expression was measured with B-HIVE. B-HIVE tracks insert-specific HIV expression by tagging a unique barcode in the HIV genome. We confirmed that LEDGINs retarget integration out of gene-dense and actively transcribed regions. The distance to H3K36me3, the marker recognized by LEDGF/p75, clearly increased. LEDGIN treatment reduced viral RNA expression and increased the proportion of silent provirus. Finally, silent proviruses obtained after LEDGIN treatment were located further away from epigenetic marks associated with active transcription. Interestingly, proximity to enhancers stimulated transcription irrespective of LEDGIN treatment, while the distance to H3K36me3 only changed after treatment with LEDGINs. The fact that proximity to these markers are associated with RNA expression support the direct link between provirus integration site and viral expression.
Permanent Link: https://hdl.handle.net/11104/0332958