Stacking the odds: multiple sites for HSV-1 latency
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA937697 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23588327.fastq.gz | Fastqsanger.gz | |||
| SRR23588328.fastq.gz | Fastqsanger.gz | |||
| SRR23588329.fastq.gz | Fastqsanger.gz | |||
| SRR23588330.fastq.gz | Fastqsanger.gz | |||
| SRR23588331.fastq.gz | Fastqsanger.gz |
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Project description:investigated the possible contribution of various cells (i.e., B cells, DCs, fibroblasts, glial cells, ILCs, macrophages, microglia, monocytes, NK cells, neurons, neutrophils, and T cells) isolated from TG of latently infected mice to HSV-1 latency
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Project description:HSV-2 coinfection is associated with increased HIV-1 viral loads and expanded tissue reservoirs, but the mechanisms are not well-defined. HSV-2 recurrences result in an influx of activated CD4+ T cells to sites of viral replication and an increase in activated CD4+ T cells in peripheral blood. We hypothesized that HSV-2 induces changes in these cells that facilitate HIV-1 reactivation and replication and tested this hypothesis in human CD4+ T cells and 2D10 cells, a model of HIV-1 latency. HSV-2 promoted latency reversal in HSV-2 infected and bystander 2D10 cells. Bulk and single-cell RNA sequencing studies of activated primary human CD4+ T cells identified decreased expression of HIV-1 restriction factors and increased expression of transcripts including MALAT1 that could drive HIV replication in both the HSV-2-infected and bystander cells. Transfection of 2D10 cells with VP16, an HSV-2 protein that regulates transcription, significantly upregulated MALAT1 expression, decreased trimethylation of lysine 27 on histone H3 protein, and triggered HIV latency reversal. Knockout of MALAT1 from 2D10 cells abrogated the response to VP16 and reduced the response to HSV-2 infection. These results demonstrate that HSV-2 contributes to HIV-1 reactivation through diverse mechanisms including upregulation of MALAT1 to release epigenetic silencing.
2023-05-07 | GSE229391 | GEO
Project description:HSV-2 coinfection is associated with increased HIV-1 viral loads and expanded tissue reservoirs, but the mechanisms are not well-defined. HSV-2 recurrences result in an influx of activated CD4+ T cells to sites of viral replication and an increase in activated CD4+ T cells in peripheral blood. We hypothesized that HSV-2 induces changes in these cells that facilitate HIV-1 reactivation and replication and tested this hypothesis in human CD4+ T cells and 2D10 cells, a model of HIV-1 latency. HSV-2 promoted latency reversal in HSV-2 infected and bystander 2D10 cells. Bulk and single-cell RNA sequencing studies of activated primary human CD4+ T cells identified decreased expression of HIV-1 restriction factors and increased expression of transcripts including MALAT1 that could drive HIV replication in both the HSV-2-infected and bystander cells. Transfection of 2D10 cells with VP16, an HSV-2 protein that regulates transcription, significantly upregulated MALAT1 expression, decreased trimethylation of lysine 27 on histone H3 protein, and triggered HIV latency reversal. Knockout of MALAT1 from 2D10 cells abrogated the response to VP16 and reduced the response to HSV-2 infection. These results demonstrate that HSV-2 contributes to HIV-1 reactivation through diverse mechanisms including upregulation of MALAT1 to release epigenetic silencing.
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Project description:The cellular insulator CCCTC-binding factor (CTCF) plays a role in HSV-1 latency through the establishment of chromatin boundaries. We previously found that the CTRL2 regulatory element downstream from the LAT enhancer is bound by CTCF during latency and undergoes CTCF eviction at early times post-reactivation in mice latent with 17Syn+ . It has been previously shown that the CTRL2 binding domain is a functional insulator with both enhancer-blocking and silencing capabilities. Considering these findings, we hypothesized that the CTRL2 site plays a key role in regulating latent HSV-1 gene expression. To test this, we used a mutant virus with a 135 bp deletion spanning only the core CTRL2 domain (DCTRL2) in the 17Syn+ background. Following ocular infection of mice, we found significant differences between DCTRL2 and wild-type virus during the acute infection and latency. Notably, mouse mortalities were significantly higher in the DCTRL2 virus compared to the 17Syn+, while lower viral genomes were found after latency indicating that deletion of CTRL2 site disrupted latency establishment. This fact, coupled with increased LAT intron and VP16 expression indicated that the establishment of latency was disrupted in the DCTRL2 mutant. These data provide evidence that chromatin domains of the latent HSV-1 genome are in part maintained by the CTRL2 binding.
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Project description:Herpes simplex virus type 1 (HSV-1) is a 152 Kb double stranded DNA alpha-herpesvirus, which establishes long life latent infection in sensory neurons. Most of our knowledge regarding HSV-1 latency comes from in vivo studies using small animal models, mainly rodents and rabbits, which are not naturally infected by HSV-1. Furthermore, these animal models do not fully recapitulate the species specific effects of human HSV-1 infection. Human cellular models utilize trigeminal ganglia removed from cadavers or, alternatively, neuron-like cells derived from cancerous cell lines that do not fully reflect effects on normal human neurons. This limitation poses the need to develop an in vitro model to investigate molecular details of the mechanisms underlying latency and reactivation in human neurons. Induced pluripotent stem (iPS) cell technologies offer an unprecedented opportunity to generate unlimited supplies of neurons and the facility to manipulate such cells in vitro. In this study, we developed an in vitro HSV-1 infection model in human iPS-derived neural progenitor cells (NPCs) and neurons, which displays the main hallmarks of latency defined in animal models and in humans. Induced pluripotent stem (iPS) cells were generated from human skin biopsy samples
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Project description:Herpes simplex virus type 1 (HSV-1) is a 152 Kb double stranded DNA alpha-herpesvirus, which establishes long life latent infection in sensory neurons. Most of our knowledge regarding HSV-1 latency comes from in vivo studies using small animal models, mainly rodents and rabbits, which are not naturally infected by HSV-1. Furthermore, these animal models do not fully recapitulate the species specific effects of human HSV-1 infection. Human cellular models utilize trigeminal ganglia removed from cadavers or, alternatively, neuron-like cells derived from cancerous cell lines that do not fully reflect effects on normal human neurons. This limitation poses the need to develop an in vitromodel to investigate molecular details of the mechanisms underlying quiescence and reactivation in human neurons. Induced pluripotent stem (iPS) celltechnologies offer an unprecedented opportunity to generate unlimited supplies of neurons and the facility to manipulate such cells in vitro. In this study, we developed an in vitro HSV-1 infection model in human iPS-derived neurons, which displays the main hallmarks of latency defined in animal models and in humans. Our results show for the first time that: i) persistent infection cannot be established in neural progenitor cells (NPCs); ii) the ability of HSV-1 to establish persistent infection is extended to glutamatergic neurons, and not limited to sensory neurons; iii) in neuronal cultures persistently infected with HSV-1, viral genome is localized at the nuclear periphery; iv) HSV-1 acute infection reduces RNA editing at the GluRB site. These results highlight the importance of iPS-based platforms to elucidate unknown aspects of HSV-1 quiescence in human neurons. NPCs were 70-80% confluence
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Project description:In cellular genomes, CTCF insulators impact transcription over small distances in a one-dimensional manner and over much longer distances in a three-dimensional manner by maintaining chromatin loops. We have previously shown that the latent HSV-1 genome contains CTCF insulators that function to regulate lytic transcription of adjacent genes in a one-dimensional manner. Here, we test the hypothesis that HSV-1 CTCF insulators nucleate chromatin loops to regulate the expression of distance separated gene regions through three-dimensional organization of viral genomes. We used 4C-seq methods to identify multiple long-range cis interactions in HSV-1 genomes that generate viral chromatin domains, including those nucleated by the viral CTCF insulator CTRL2. Deletion of the CTRL2 insulator disrupted these viral chromatin domains. Loop-nucleating interactions were quantitated with a novel approach (UMI-4C-seq) that utilizes unique molecular identifiers to label and count chromatin interactions associated with specific viewpoint primers. Cis-interaction peaks across four different viewpoints were quantified. Viral genomes lacking CTRL2 displayed more cis-interaction peaks and wider ranges of interaction lengths compared to wt virus, suggesting altered chromatin organization. Furthermore, differential looping analysis showed viral genomes lacking CTRL2 displayed a more transcriptionally permissive chromatin environment. Thus, the CTRL2 insulator functions as a critical regulator of long-range chromatin interactions and its deletion reshapes the viral chromatin landscape, leading to a more accessible and dynamic regulatory environment that may influence HSV-1 transcriptional programs and latency-associated chromatin states.
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