Transcriptional Circuit Fragility Influences HIV Proviral Fate

Morton, Emily L.; Forst, Christian V.; Zheng, Yue; Paula-Silva, A.B. De; Ramirez, Nora-Guadalupe P.; Planelles, Vicente; D’Orso, Iván

doi:10.1101/504969

Cited by 7 publications

(8 citation statements)

References 94 publications

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“…KRAB recruits the cofactor KAP1 (also known as TRIM 28 and TIF1b) to promote durable heritable epigenetic chromatin modifications, and has been proposed to maintain heterochromatin and repress transcription of endogenous retroelements [ 38 , 39 , 40 , 41 , 42 , 58 , 59 ]. It should be noted that KAP1 activity may be context-dependent, and has been suggested to be an activator as well as a repressor for HIV-1 transcription [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Targeted Chromatinization and Repression of HIV-1 Provirus Transcription with Repurposed CRISPR/Cas9

Olson

Basukala

Lee

et al. 2020

Viruses

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The major barrier to HIV-1 cure is the persistence of latent provirus, which is not eradicated by antiretroviral therapy. The “shock and kill” approach entails stimulating viral production with latency-reversing agents followed by the killing of cells actively producing the virus by immune clearance. However, this approach does not induce all intact proviruses, leaving a residual reservoir. CRISPR/Cas9 has been utilized to excise integrated Human Immunodeficiency Virus (HIV) DNA from infected cells in an RNA-guided, sequence-specific manner. Here, we seek to epigenetically silence the proviral DNA by introducing nuclease-deficient disabled Cas9 (dCas9) coupled with a transcriptional repressor domain derived from Kruppel-associated box (KRAB). We show that specific guide RNAs (gRNAs) and dCas9-KRAB repress HIV-1 transcription and reactivation of latent HIV-1 provirus. This repression is correlated with chromatin changes, including decreased H3 histone acetylation and increased histone H3 lysine 9 trimethylation, histone marks that are associated with transcriptional repression. dCas9-KRAB-mediated inhibition of HIV-1 transcription suggests that CRISPR can be engineered as a tool for block-and-lock strategies.

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Section: Discussionmentioning

confidence: 99%

Targeted Chromatinization and Repression of HIV-1 Provirus Transcription with Repurposed CRISPR/Cas9

Olson

Basukala

Lee

et al. 2020

Viruses

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“…Cells were cultured in complete medium supplemented with 30 IU/mL IL-2. At day 7, cells were infected with VSV-G pseudotyped NL4.3-deltaEnv-nLuc-2ANef viruses using spinoculation (Morton et al, 2019). At day 17, CD4+ cells were isolated using the Dynabeads TM CD4 Positive Isolation Kit (ThermoFisher).…”

Section: Experimental Model and Subject Detailsmentioning

confidence: 99%

IFI16 Targets the Transcription Factor Sp1 to Suppress HIV-1 Transcription and Latency Reactivation

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Bosso

Jønsson

et al. 2019

Cell Host & Microbe

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“…Over the past two decades, great efforts have been made for elucidating how HIV integrates into the human genome and how HIV proviral transcription normally operates (Ott et al 2011;Mbonye and Karn 2014;Hughes and Coffin 2016;Mbonye and Karn 2017;Michieletto et al 2019;Morton et al 2019). Interestingly, in CD4 + T cells of patient samples and in ex vivo studies, HIV preferentially integrates into chromatin-accessible sites located near the nuclear pore and within or near transcriptionally active regions (Schroder et al 2002;Cohn et al 2015;Marini et al 2015;Lucic et al 2019).…”

Section: Introductionmentioning

confidence: 99%

An integrated genomics approach towards deciphering human genome codes shaping HIV-1 proviral transcription and fate

Ruess

Guzmán

et al. 2020

Preprint

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A large body of work has revealed fundamental principles of HIV-1 integration into the human genome.However, the effect of the integration site to proviral transcription activity has so far remained elusive.Here we combine open-source, large-scale datasets including epigenetics, transcriptome, and 3D genome architecture to interrogate the chromatin states, transcription activity landscape, and nuclear sub-compartments around HIV-1 integration sites in CD4 + T cells to decipher human genome codes shaping the transcription of proviral classes defined based on their position and orientation in the genome. Using a Hidden Markov Model, we describe the importance of specific chromatin states and genome architecture in the control of HIV-1 transcription activity. Additionally, implementation of a machine-learning logistic regression model reveals upstream chromatin accessibility, transcription activity, and categorical nuclear sub-compartments as optimal features predicting HIV-1 transcriptional outcomes. We finally demonstrate clinical relevance by interrogating the positions of intact proviruses persisting in patients under suppressive therapy and provide a compass compatible with clinical decision-making.

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Transcriptional Circuit Fragility Influences HIV Proviral Fate

Cited by 7 publications

References 94 publications

Targeted Chromatinization and Repression of HIV-1 Provirus Transcription with Repurposed CRISPR/Cas9

Targeted Chromatinization and Repression of HIV-1 Provirus Transcription with Repurposed CRISPR/Cas9

IFI16 Targets the Transcription Factor Sp1 to Suppress HIV-1 Transcription and Latency Reactivation

An integrated genomics approach towards deciphering human genome codes shaping HIV-1 proviral transcription and fate

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