Ontology highlight
ABSTRACT:
PROVIDER: PRJNA797956 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17642756_1.fastq.gz | Fastqsanger.gz | |||
| SRR17642756_2.fastq.gz | Fastqsanger.gz | |||
| SRR17642757_1.fastq.gz | Fastqsanger.gz | |||
| SRR17642757_2.fastq.gz | Fastqsanger.gz |
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Project description:Molecular mechanisms of HIV-1 latency have been studied extensively to achieve a functional cure for the acquired immunodeficiency syndrome (AIDS). To develop more promising latency-reversing agents (LRAs) to efficiently reactivate the latent reservoir which is subsequently eliminated by immune surveillance, new therapeutic targets need to be evaluated. Here, we found that the Polycomb group (PcG) protein CBX4 contributes to HIV-1 latency in many latency models and primary CD4+ T cells. CBX4 forms nuclear bodies with liquid–liquid phase separation (LLPS) properties on the HIV-1 long terminal repeat (LTR). Further proteomics analysis revealed that CBX4 recruits EZH2 to CBX4 bodies and SUMOylates EZH2 utilizing its SUMO E3 ligase activity, which enhances the H3K27 methyltransferase activity of EZH2. Our results indicated that CBX4 bridges the Polycomb repressive complex 1 (PRC1) and PRC2, resulting in synergistically maintaining HIV-1 latency. Dissolution of phase-separated CBX4 bodies could be a potential intervention to reactivate latent HIV-1.
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Project description:HIV-1 latency is a major obstacle to achieve a functional cure for AIDS. To eradicate the viral reservoir, one of the strategies is to specifically reactivate HIV-1-infected cells and followed by elimination with potent immune surveillance. However, present latency-reversing agents (LRAs) are quite dissatisfactory because of their high toxicity and low efficiency. New targets need to be identified to develop more promising LRAs. Here, we found that histone chaperone chromatin assembly factor 1 (CAF-1) promotes HIV-1 latency by forming versatile suppressive nuclear bodies. CAF-1 plays a leading role for the formation of bodies recruiting multi-layer suppressive epigenetic modifiers and maintainers, and is of the characteristic of liquid-liquid phase separation (LLPS). Three distinct disordered regions of CHAF1A subunit coalesce CAF-1 body components by forming LLPS and play a key in maintaining HIV-1 latency. Therefore, disruptive induction of phase-separated CAF-1 body could be an important strategy to reactivate latent HIV-1.
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Project description:CAF-1 promotes HIV-1 latency by leading the formation of phase-separated suppressive nuclear bodies.
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Project description:Metabolic alterations, such as oxidative stress, are hallmarks of HIV-1 infection. However, their influenceon the development of viral latency, and thus on HIV-1 persistence during antiretroviral therapy (ART),have just begun to be explored. We analyzed omics profiles ofin-vitroandin-vivomodels of infection byHIV-1 and its simian homolog SIVmac. We found that cells survive retroviral replication by upregulatingantioxidant pathways and intertwined iron import pathways. These changes are associated withremodeling of the redox sensitive promyelocytic leukemia protein nuclear bodies (PML NBs), an importantconstituent of nuclear architecture and a marker of HIV-1 latency. We found that PML is depleted inproductively infected cells and restored by ART. Moreover, we identified intracellular iron as a key linkbetween oxidative stress and PML depletion, thus supporting iron metabolism modulators aspharmacological tools to impair latency establishment.
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Project description:HIV-1 latency results from a combination of tightly regulated molecular processes that act at distinct steps of HIV-1 gene expression. In an effort to elucidate the molecular players that govern viral latency, we previously performed a dCas9 chromatin immunoprecipitation coupled with mass spectrometry (Catchet-MS) and identified proteins bound differentially to the latent LTR that putatively promote HIV-1 latency. Here we characterize the Catchet-MS identified PCI domain-containing 2 (PCID2) protein to play a dual role in promoting HIV-1 latency by enforcing both HIV-1 transcription repression as well as post-transcriptional blocks. PCID2 bound the latent HIV-1 LTR and repressed transcription initiation during latency. Depletion of PCID2 remodeled the chromatin landscape at the HIV-1 promoter and resulted in transcriptional activation and reversal of latency. Immunoprecipitation coupled to Mass Spectrometry identified the PCID2 interacting proteins to include members of the spliceosome and other splicing regulators, including negative regulators of viral RNA alternative splicing. PCID2 depletion resulted in over-splicing of intron-containing HIV-1 RNA and mis-regulated expression of vRNA splice variants. Finally, consistent with its role in NXF1-mediated nascent RNA nucleocytoplasmic export as part of the TREX2 complex, PCID2 modulates export of completely spliced vRNA. In summary, we demonstrate that PCID2 is a previously unidentified factor involved in HIV-1 latency regulation which plays a dual role in blocking HIV-1 gene expression by acting on transcription initiation as well as viral RNA processing.
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