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

Vansant, Greet; Chen, Heng‐Chang; Zorita, Eduard; Trejbalová, Kateřina; Miklík, Dalibor; Filion, Guillaume J.; Debyser, Zeger

doi:10.1093/nar/gkaa536

Cited by 49 publications

(100 citation statements)

References 111 publications

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“…An important determinant of proviral chromatin state and expression that cannot be determined from our ATAC-seq data is the influence of the viral integration site. Specifically, the transcription state of neighboring genes and the activity of nearby enhancers will likely modulate the chromatin state and expression of the provirus [ 57 ]. HIV frequently integrates near clusters of endogenous enhancer elements [ 58 ], and studies in Jurkat cells have shown a clear influence of local endogenous enhancers on HIV expression [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Epigenomic characterization of latent HIV infection identifies latency regulating transcription factors

et al. 2021

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Transcriptional silencing of HIV in CD4 T cells generates a reservoir of latently infected cells that can reseed infection after interruption of therapy. As such, these cells represent the principal barrier to curing HIV infection, but little is known about their characteristics. To further our understanding of the molecular mechanisms of latency, we characterized a primary cell model of HIV latency in which infected cells adopt heterogeneous transcriptional fates. In this model, we observed that latency is a stable, heritable state that is transmitted through cell division. Using Assay of Transposon-Accessible Chromatin sequencing (ATACseq) we found that latently infected cells exhibit greatly reduced proviral accessibility, indicating the presence of chromatin-based structural barriers to viral gene expression. By quantifying the activity of host cell transcription factors, we observe elevated activity of Forkhead and Kruppel-like factor transcription factors (TFs), and reduced activity of AP-1, RUNX and GATA TFs in latently infected cells. Interestingly, latency reversing agents with different mechanisms of action caused distinct patterns of chromatin reopening across the provirus. We observe that binding sites for the chromatin insulator CTCF are highly enriched in the differentially open chromatin of infected CD4 T cells. Furthermore, depletion of CTCF inhibited HIV latency, identifying this factor as playing a key role in the initiation or enforcement of latency. These data indicate that HIV latency develops preferentially in cells with a distinct pattern of TF activity that promotes a closed proviral structure and inhibits viral gene expression. Furthermore, these findings identify CTCF as a novel regulator of HIV latency.

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Section: Discussionmentioning

confidence: 99%

Epigenomic characterization of latent HIV infection identifies latency regulating transcription factors

et al. 2021

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“…Finally, like other assays based on reactivation of proviruses with a latency reversal agent (LRA), STIP-Seq probably does not pick up all translation-competent proviruses, as reactivation is a stochastic process 36,58 . In this regard, it has been suggested that the IS can have an influence on the reactivation of the provirus 33,50,74 , and that different LRAs might induce reactivation of distinct proviral species 75,76 . As such, future studies with STIP-Seq investigating the relationship between different classes of LRA and the IS of the reactivated proviruses, would be of great interest.…”

Section: Discussionmentioning

confidence: 99%

In-depth single-cell analysis of translation-competent HIV-1 reservoirs identifies cellular sources of plasma viremia

Cole

Lambrechts

Gantner

et al. 2021

Preprint

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Clonal expansion of HIV-infected cells contributes to the long-term persistence of the HIV reservoir in ART-suppressed individuals. However, the contribution to plasma viremia from cell clones that harbor inducible proviruses is poorly understood. Here, we describe a single-cell approach to simultaneously sequence the TCR, integration sites and proviral genomes from translation-competent reservoir cells, called STIP-Seq. By applying this approach to blood samples from eight participants, we showed that the translation-competent reservoir mainly consists of proviruses with short deletions at the 5-prime-end of the genome, often involving the major splice donor site. TCR and integration site sequencing revealed that antigen-responsive cells can harbor inducible proviruses integrated into cancer-related genes. Furthermore, we found several matches between proviruses retrieved with STIP-Seq and plasma viruses obtained during ART and upon treatment interruption, showing that STIP-Seq can capture clones that are responsible for low-level viremia or viral rebound.

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“…From the perspective of a cure, one of the most pressing questions is the relationship between integration site and proviral transcription. Although chromatin landscape around HIV-1 integration sites can influence viral gene expression ( 206 , 211 ), how this relates to latency and cellular persistence/clonal expansion in patients is not explicitly known. Additional research on understanding the reasons why particular integration sites are enriched in clonally expanded and persistent cells in vivo is surely warranted.…”

Section: Resultsmentioning

confidence: 99%

“…These observations are consistent with the notion that suppression of viral transcription is a key component of HIV-1 latency. The use of barcoded viruses to track individual integration sites has accordingly indicated that latent proviruses are more distal from activating epigenetic marks than are expressed viruses ( 206 , 211 ). Recently, proviruses from elite controllers, which represent a minority of patients that control their infection in the absence of ART, were shown to adopt a state of ‘deep latency’ due to integration into heterochromatic regions such as centromeric satellite DNA and Krüppel-associated box domain-containing zinc finger genes ( 212 ).…”

Section: Introductionmentioning

confidence: 99%

Factors that mold the nuclear landscape of HIV-1 integration

Bedwell

Engelman

2020

Nucleic Acids Research

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The integration of retroviral reverse transcripts into the chromatin of the cells that they infect is required for virus replication. Retroviral integration has far-reaching consequences, from perpetuating deadly human diseases to molding metazoan evolution. The lentivirus human immunodeficiency virus 1 (HIV-1), which is the causative agent of the AIDS pandemic, efficiently infects interphase cells due to the active nuclear import of its preintegration complex (PIC). To enable integration, the PIC must navigate the densely-packed nuclear environment where the genome is organized into different chromatin states of varying accessibility in accordance with cellular needs. The HIV-1 capsid protein interacts with specific host factors to facilitate PIC nuclear import, while additional interactions of viral integrase, the enzyme responsible for viral DNA integration, with cellular nuclear proteins and nucleobases guide integration to specific chromosomal sites. HIV-1 integration favors transcriptionally active chromatin such as speckle-associated domains and disfavors heterochromatin including lamina-associated domains. In this review, we describe virus-host interactions that facilitate HIV-1 PIC nuclear import and integration site targeting, highlighting commonalities among factors that participate in both of these steps. We moreover discuss how the nuclear landscape influences HIV-1 integration site selection as well as the establishment of active versus latent virus infection.

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

Cited by 49 publications

References 111 publications

Epigenomic characterization of latent HIV infection identifies latency regulating transcription factors

Epigenomic characterization of latent HIV infection identifies latency regulating transcription factors

In-depth single-cell analysis of translation-competent HIV-1 reservoirs identifies cellular sources of plasma viremia

Factors that mold the nuclear landscape of HIV-1 integration

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