The chromatin landscape at the HIV-1 provirus integration site determines viral expression
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ABSTRACT:
PROVIDER: PRJNA558259 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11783957.fastq.gz | Fastqsanger.gz | |||
| SRR11783958.fastq.gz | Fastqsanger.gz | |||
| SRR11783959.fastq.gz | Fastqsanger.gz | |||
| SRR11783960.fastq.gz | Fastqsanger.gz | |||
| SRR11783961.fastq.gz | Fastqsanger.gz |
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Project description:We investigated the link between HIV-1 integration by using B-HIVE and LEDGINs. B-HIVE tracks insert-specific HIV expression by tagging a unique barcode in the HIV genome. LEDGINs are antivirals that inhibit the interaction between HIV-IN and its chromatin tethering cofactor LEDGF/p75. They are known to retarget HIV-1 integration sites. Here, we confirmed that LEDGIN treatment retargets integration out of transcriptionally active regions and reduce HIV expression. Silent provirus was located at increased distance to H3K36me3, the recognition marker of LEDGF/p75, after treatment with LEDGINs. Viral RNA expression was also influenced by the proximity of enhancers, regardless of the presence of LEDGINs.
2020-07-03 | GSE135295 | GEO
Project description:HIV-1 persists as an integrated DNA provirus in infected cells. Antiretroviral therapy (ART) does not inhibit HIV-1 promoter activity. It is often assumed that HIV-1 reactivation versus latency passively follows host gene activation and repression near the HIV-1 integration site. HIV-1 proviruses integrated into active genes are then transcriptionally active, typically resulting in immune clearance of infected cells. HIV-1 proviruses integrated into repressive chromatin conversely escape immune surveillance. To understand how host gene activity affects HIV-1 transcription, we examined how CRISPR-mediated activation and inhibition of host genes affected HIV-1 nearby chromatin accessibility and RNA transcription using qPCR, ATAC-seq, and strand-specific RNA-seq, in seven Jurkat T cell clones having known HIV-1 integration site. We further examined host CRISPR-mediated HIV-1 activation and inhibition effects on host chromatin accessibility and RNA transcription. We found that host gene activation at the integration site decreased HIV-1 transcription, while host gene inhibition frequently increased HIV-1 transcription. Changes to transcription occurred in both HIV-1 orientations relative to the host gene. Particularly at same-orientation integration sites, reductions in HIV-1 transcription were accompanied by reduced chromatin accessibility at the HIV-1 promoter. However, when HIV-1 integrated in close proximity to host transcription start site, host gene activation increased HIV-1 transcription. When HIV-1 integrated into a non-genic region, we found that HIV-1 increased host chromatin accessibility, remained transcriptionally active, and drove high level of aberrant host RNA transcription. Overall, we found that instead of passively following host gene activity, HIV-1 shapes host chromatin accessibility while an interplay of host factors and transcriptional interference modulate its expression.
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Project description:Human immunodeficiency virus (HIV) infection is a chronic condition, where viral DNA integrates into the genome. The fate of the provirus determines the infection course. Latently infected cells form a persistent, heterogeneous reservoir. The reservoir that reinstates an active infection comprises cells with intact provirus that can be reactivated. We confirmed that latent cells from patients exhibited active transcription throughout the provirus. To find transcriptional determinants, we characterized the establishment and maintenance of latency during proviral chromatin maturation in primary CD4+ T-cells for four months after HIV infection. As heterochromatin (marked with H3K9me3 or H3K27me3) gradually stabilized, the provirus became less accessible and lost activation potential. In a subset of infected cells, active marks (i.e., H3K27ac) remained detectable, even after prolonged proviral silencing. After T-cell activation, the proviral activation occurred uniquely in cells with H3K27ac-marked proviruses. Our observations suggested that, after transient proviral activation, cells were actively returned to latency.
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Project description: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.
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Project description:The study examined proviral and neighboring gene transcription at sites of intact latent HIV-1 integration in cultured T cells obtained directly from people living with HIV, as well as engineered primary T cells and cell lines and showed that the site of integration has a dominant effect on the transcriptional activity of intact HIV-1 proviruses in the latent reservoir
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