Histone chaperone CAF‐1 promotes HIV‐1 latency by leading the formation of phase‐separated suppressive nuclear bodies

Ma, Xiancai; Chen, Tao; Peng, Zhilin; Wang, Ziwen; Li, Jun; Yang, Tao; Wu, Liyang; Liu, Guangyan; Zhou, Mo; Tong, Muye; Guan, Yuanjun; Zhang, Xu; Lin, Yingtong; Tang, Xiaoping; Li, Linghua; Tang, Zhonghui; Pan, Ting; Zhang, Hui

doi:10.15252/embj.2020106632

Cited by 34 publications

(33 citation statements)

References 106 publications

(134 reference statements)

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“…Although CHAF1A/B first became prominent for its nucleosome assembly activity ( 25 ), the discovery of various interaction partners indicated broader functions, including roles in DNA replication, DNA repair and, of relevance here, maintenance of heterochromatin ( 21 , 30 ). Of particular interest among its partners is the silencing factor HP1 (heterochromatin protein 1), a key player in heterochromatin formation ( 32 – 34 ). HP1 has a high binding affinity for H3K9me3 and genome-wide profiles revealed H3K9me3 enrichment at transcriptionally inactive endogenous retroviruses ( 35 – 37 ).…”

Section: Resultsmentioning

confidence: 99%

“…A full understanding of the silencing machinery of early HIV-1 events may suggest new methods of control of viral transmission through enhancing the efficiency of viral suppression and may offer implications for other steps of the HIV-1 life cycle. The CAF-1 complex became of particular interest for the HIV-1 field very recently, since it has been published that CAF-1 is enriched on HIV-1 LTRs and shown to promote maintenance of HIV-1 latency, a major hurdle to cure AIDS ( 34 ). Enhancing its activities might promote long-term silencing, while inhibition might promote reactivation and allow for ultimate virus clearance.…”

Section: Discussionmentioning

confidence: 99%

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CHAF1A/B mediate silencing of unintegrated HIV-1 DNAs early in infection

Geis

Sabo

Chen

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Early events of the retroviral life cycle are the targets of many host restriction factors that have evolved to prevent establishment of infection. Incoming retroviral DNAs are transcriptionally silenced before integration in most cell types, and efficient viral gene expression occurs only after formation of the provirus. The molecular machinery for silencing unintegrated retroviral DNAs of HIV-1 remains poorly characterized. Here, we identified the histone chaperones CHAF1A and CHAF1B as essential factors for silencing of unintegrated HIV-1 DNAs. Using RNAi-mediated knockdown (KD) of multiple histone chaperones, we found that KD of CHAF1A or CHAF1B resulted in a pronounced increase in expression of incoming viral DNAs. The function of these two proteins in silencing was independent of their interaction partner RBBP4. Viral DNA levels accumulated to significantly higher levels in CHAF1A KD cells over controls, suggesting enhanced stabilization of actively transcribed DNAs. Chromatin immunoprecipitation assays revealed no major changes in histone loading onto viral DNAs in the absence of CHAF1A, but levels of the H3K9 trimethylation silencing mark were reduced. KD of the H3K9me3-binding protein HP1γ accelerated the expression of unintegrated HIV-1 DNAs. While CHAF1A was critical for silencing HIV-1 DNAs, it showed no role in silencing of unintegrated retroviral DNAs of mouse leukemia virus. Our study identifies CHAF1A and CHAF1B as factors involved specifically in silencing of HIV-1 DNAs early in infection. The results suggest that these factors act by noncanonical pathways, distinct from their histone loading activities, to mediate silencing of newly synthesized HIV-1 DNAs.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CHAF1A/B mediate silencing of unintegrated HIV-1 DNAs early in infection

Geis

Sabo

Chen

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Following TNF-alpha induction, there is a statistically significant (p<0.05) 3-fold reduction in CPM value of Exon 7 to 9 splice junction, which is highly concordant with the decrease of isoform lacking Exon 8 observed via ONT long-read sequencing. Re-analyzed data from Ma et al 2021 (31)…”

Section: Supplementary Figures and Tablesmentioning

confidence: 99%

Selective Ablation of 3’ RNA ends and Processive RTs Facilitate Direct cDNA Sequencing of Full-length Host Cell and Viral Transcripts

Gallardo

Nguyen

Routh

et al. 2022

Preprint

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Alternative splicing (AS) is necessary for viral proliferation in host cells and a critical regulatory component of viral gene expression. Conventional RNA-seq approaches provide incomplete coverage of AS due to their short read-lengths and are susceptible to biases and artifacts introduced in prevailing library preparation methodologies. Moreover, viral splicing studies are often conducted separately from host cell transcriptome analysis, precluding an assessment of the viral manipulation of host splicing machinery. To address current limitations, we developed a quantitative full-length direct cDNA sequencing strategy to simultaneously profile viral and host cell transcripts. This nanopore-based approach couples processive reverse transcriptases with a novel one-step chemical ablation of 3' RNA ends (termed CASPR) which decreases ribosomal RNA reads and enriches for poly-adenylated coding sequences. We extensively validate our approach using synthetic reference transcripts and show CASPR doubles the breadth of coverage per transcript and increases detection of long transcripts (>4kb), while being functionally equivalent to PolyA+ selection for transcript quantification. We used our approach to interrogate host cell and HIV-1 transcript dynamics during viral reactivation and identified novel putative HIV-1 host factors containing exon skipping or novel intron retentions and delineated the HIV-1 transcriptional state associated with these differentially regulated host factors.

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“…Recently the histone chaperone CAF-1 was found to engage at the longterminal repeat (LTR) of the HIV-1 provirus. In addition to recruiting chromatin modifiers, CAF-1 may contribute to HIV-1 latency by forming phase-separated nuclear bodies (Ma et al, 2021).…”

Section: Proviral Latency Is Induced By De Novo Silencingmentioning

confidence: 99%

Targeting Epigenetics to Cure HIV-1: Lessons From (and for) Cancer Treatment

Svensson

2021

Front. Cell. Infect. Microbiol.

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The Human Immunodeficiency Virus type 1 (HIV-1) integrates in the host genome as a provirus resulting in a long-lived reservoir of infected CD4 cells. As a provirus, HIV-1 has several aspects in common with an oncogene. Both the HIV-1 provirus and oncogenes only cause disease when expressed. A successful cure of both cancer and HIV-1 includes elimination of all cells with potential to regenerate the disease. For over two decades, epigenetic drugs developed against cancer have been used in the HIV-1 field to modulate the state of the proviral chromatin. Cells with an intact HIV-1 provirus exist in three states of infection: productive, inducible latent, and non-inducible latent. Here focus is on HIV-1, transcription control and chromatin structure; how the inducible proviruses are maintained in a chromatin structure that allows reactivation of transcription; and how transcription switches between different stages to allow for an abundance of different transcripts from a single promoter. Recently it was shown that a functional cure of HIV can be achieved by encapsulating all intact HIV-1 proviruses in heterochromatin, giving hope that epigenetic interventions may be used to end the HIV-1 epidemic.

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Histone chaperone CAF‐1 promotes HIV‐1 latency by leading the formation of phase‐separated suppressive nuclear bodies

Cited by 34 publications

References 106 publications

CHAF1A/B mediate silencing of unintegrated HIV-1 DNAs early in infection

CHAF1A/B mediate silencing of unintegrated HIV-1 DNAs early in infection

Selective Ablation of 3’ RNA ends and Processive RTs Facilitate Direct cDNA Sequencing of Full-length Host Cell and Viral Transcripts

Targeting Epigenetics to Cure HIV-1: Lessons From (and for) Cancer Treatment

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