A Two-Color Haploid Genetic Screen Identifies Novel Host Factors Involved in HIV-1 Latency

Röling, Michael D.; Sisakht, Mahsa Mollapour; Ne, Enrico; Moulos, Panagiotis; Crespo, Raquel; Stoszko, Mateusz; Crignis, Elisa De; Bodmer, Helen; Kan, Tsung Wai; Akbarzadeh, Maryam; Harokopos, Vaggelis; Hatzis, Pantelis; Palstra, Robert-Jan; Mahmoudi, Tokameh

doi:10.1128/mbio.02980-21

Cited by 6 publications

(13 citation statements)

References 104 publications

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“…In a different methodological approach, by using a prey-bait yeast system Pedro et al also identified novel HIV-1 LTR interactors. In other studies, such as CRISPR KO based screens ( 85 , 86 ), gene-trap mutagenesis ( 87 ) or (single cell)RNA-seq analysis on sorted latent vs active infected cells ( 88 , 89 ) the screen results identified putative targets that regulate HIV-1 latency and latency reactivation not only via direct binding to the LTR but also via putative indirect molecular mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Beyond the differences in methodological approach and latency models, we found common hits identified by Catchet-MS and those in previously published studies. These include the helicase DDX5 ( 89 ), members of the TREX1 ( 90 ) and TREX2 complex ( 87 ), transcriptional regulators such as GON4L ( 86 ) and CBX3 ( 88 ), members of the proteasome complex ( 86 ), SP-related factors ( 91 ) and interferon related factors such as IRF2BP2 ( 87 , 91 ) and ISG15 ( 88 ). The identification of previously identified and characterized interactors serve as positive controls and justify the validity of our approach.…”

Section: Discussionmentioning

confidence: 99%

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Catchet-MS identifies IKZF1-targeting thalidomide analogues as novel HIV-1 latency reversal agents

Crespo

Izquierdo-Lara

et al. 2022

Nucleic Acids Research

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A major pharmacological strategy toward HIV cure aims to reverse latency in infected cells as a first step leading to their elimination. While the unbiased identification of molecular targets physically associated with the latent HIV-1 provirus would be highly valuable to unravel the molecular determinants of HIV-1 transcriptional repression and latency reversal, due to technical limitations, this has been challenging. Here we use a dCas9 targeted chromatin and histone enrichment strategy coupled to mass spectrometry (Catchet-MS) to probe the differential protein composition of the latent and activated HIV-1 5′LTR. Catchet-MS identified known and novel latent 5′LTR-associated host factors. Among these, IKZF1 is a novel HIV-1 transcriptional repressor, required for Polycomb Repressive Complex 2 recruitment to the LTR. We find the clinically advanced thalidomide analogue iberdomide, and the FDA approved analogues lenalidomide and pomalidomide, to be novel LRAs. We demonstrate that, by targeting IKZF1 for degradation, these compounds reverse HIV-1 latency in CD4+ T-cells isolated from virally suppressed people living with HIV-1 and that they are able to synergize with other known LRAs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Catchet-MS identifies IKZF1-targeting thalidomide analogues as novel HIV-1 latency reversal agents

Crespo

Izquierdo-Lara

et al. 2022

Nucleic Acids Research

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“…In our own work, we have recently shown in two independent unbiased omics studies that proteins involved in RNA metabolism are prominent regulators of HIV-1 latency ( Röling et al., 2021 ). Using a haploid genetic screen we identified close to 70 host genes that are putatively involved in promoting or maintaining HIV-1 latency.…”

Section: What’s Rna Got To Do With It? the Contribution Of Rna-bindin...mentioning

confidence: 99%

HibeRNAtion: HIV-1 RNA Metabolism and Viral Latency

Crespo

Rao

Mahmoudi

2022

Front. Cell. Infect. Microbiol.

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HIV-1 infection remains non-curative due to the latent reservoir, primarily a small pool of resting memory CD4+ T cells bearing replication-competent provirus. Pharmacological reversal of HIV-1 latency followed by intrinsic or extrinsic cell killing has been proposed as a promising strategy to target and eliminate HIV-1 viral reservoirs. Latency reversing agents have been extensively studied for their role in reactivating HIV-1 transcription in vivo, although no permanent reduction of the viral reservoir has been observed thus far. This is partly due to the complex nature of latency, which involves strict intrinsic regulation at multiple levels at transcription and RNA processing. Still, the molecular mechanisms that control HIV-1 latency establishment and maintenance have been almost exclusively studied in the context of chromatin remodeling, transcription initiation and elongation and most known LRAs target LTR-driven transcription by manipulating these. RNA metabolism is a largely understudies but critical mechanistic step in HIV-1 gene expression and latency. In this review we provide an update on current knowledge on the role of RNA processing mechanisms in viral gene expression and latency and speculate on the possible manipulation of these pathways as a therapeutic target for future cure studies.

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“…The discovery of chromatin modulators involved in HIV transcription has gained significant attention. Recently, the chromodomain helicase DNA-binding protein (CHD9) was shown to promote HIV-1 latency via direct association with the 5′-LTR [68 ▪▪ ]. Knock-down of CHD9 with shRNAs in J-Lat A2 and J-Lat 11.1 cells resulted in significant reversal from latency [68 ▪▪ ].…”

Section: Hiv-1 Transcription and Latency Regulationmentioning

confidence: 99%

HIV-1 transcriptional modulation: novel host factors and prospective therapeutic strategies

Gibaut

Mori

Valente

2023

Current Opinion in HIV and AIDS

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Purpose of review This review highlights advances in HIV transcription and epigenetic latency mechanisms and outlines current therapeutic approaches to eliminate or block the HIV-1 latent reservoir. Recent findings Novel host factors have been reported to modulate HIV-1 transcription and latency. Chromatin affinity purification strategies followed by mass spectrometry (ChAP-MS) identified the chaperone protein p32 to play an important role in HIV-1 transcriptional regulation via interactions with the viral transcriptional activator Tat. Similarly, an shRNA screen identified the methyltransferase SMYD5 contributing to HIV-1 transcriptional activation also by modulating Tat activity. These new factors, among others, represent potential druggable targets that could be explored in the ‘block-and-lock’ or ‘shock-and-kill’ approaches. Summary The HIV-1 latent reservoir is established early after infection, persists during antiretroviral therapy, and is the source of viral rebound after treatment interruption. An HIV cure requires either eliminating this reservoir or blocking latent proviral reactivation in the absence of antiretroviral therapy (ART). Understanding the mechanisms and key-players modulating HIV transcriptional and reactivation may facilitate therapeutic advancements. Here we summarize, the latest findings on host factors’ roles in HIV transcriptional regulation.

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A Two-Color Haploid Genetic Screen Identifies Novel Host Factors Involved in HIV-1 Latency

Cited by 6 publications

References 104 publications

Catchet-MS identifies IKZF1-targeting thalidomide analogues as novel HIV-1 latency reversal agents

Catchet-MS identifies IKZF1-targeting thalidomide analogues as novel HIV-1 latency reversal agents

HibeRNAtion: HIV-1 RNA Metabolism and Viral Latency

HIV-1 transcriptional modulation: novel host factors and prospective therapeutic strategies

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