Parallel analysis of transcription, integration, and sequence of single HIV-1 proviruses
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ABSTRACT:
PROVIDER: PRJNA706953 | ENA |
REPOSITORIES: ENA
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Project description:HIV-1-infected cells that persist despite antiretroviral therapy (ART) are frequently considered ‘‘transcriptionally silent,’’ but active viral gene expression may occur in some cells, challenging the concept of viral latency. Applying an assay for profiling the transcriptional activity and the chromosomal locations of individual proviruses, we describe a global genomic and epigenetic map of transcriptionally active and silent proviral species and evaluate their longitudinal evolution in persons receiving suppressive ART. Using genome-wide epigenetic reference data, we show that proviral transcriptional activity is associated with activating epigenetic chromatin features in linear proximity of integration sites and in their inter- and intrachromosomal contact regions. Transcriptionally active proviruses were actively selected against during prolonged ART; however, this pattern was violated by large clones of virally infected cells that may outcompete negative selection forces through elevated intrinsic proliferative activity. Our results suggest that transcriptionally active proviruses are dynamically evolving under selection pressure by host factors.
2022-01-12 | GSE168337 | GEO
Project description:The study examined proviral and neighboring gene transcription at sites of intact latent HIV-1 integration in cultured T cells obtained directly from people living with HIV, as well as engineered primary T cells and cell lines and showed that the site of integration has a dominant effect on the transcriptional activity of intact HIV-1 proviruses in the latent reservoir
2024-06-25 | GSE267987 | GEO
Project description:The study examined proviral and neighboring gene transcription at sites of intact latent HIV-1 integration in cultured T cells obtained directly from people living with HIV, as well as engineered primary T cells and cell lines and showed that the site of integration has a dominant effect on the transcriptional activity of intact HIV-1 proviruses in the latent reservoir
2024-06-25 | GSE267988 | GEO
Project description:HIV-1-infected cells that persist despite antiretroviral therapy (ART) are frequently considered "transcriptionally silent," but active viral gene expression may occur in some cells, challenging the concept of viral latency. Applying an assay for profiling the transcriptional activity and the chromosomal locations of individual proviruses, we describe a global genomic and epigenetic map of transcriptionally active and silent proviral species and evaluate their longitudinal evolution in persons receiving suppressive ART. Using genome-wide epigenetic reference data, we show that proviral transcriptional activity is associated with activating epigenetic chromatin features in linear proximity of integration sites and in their inter- and intrachromosomal contact regions. Transcriptionally active proviruses were actively selected against during prolonged ART; however, this pattern was violated by large clones of virally infected cells that may outcompete negative selection forces through elevated intrinsic proliferative activity. Our results suggest that transcriptionally active proviruses are dynamically evolving under selection pressure by host factors.
| S-EPMC8809251 | biostudies-literature
Project description:CD4 T cells with latent HIV-1 infection persist despite treatment with currently available antiretroviral agents and represent the main barrier to a cure of HIV-1 infection. Pharmacological disruption of viral latency may increase the immunological vulnerability of HIV-1-infected cells, but the clinical efficacy of latency-reversing agents for reducing HIV-1 persistence remains to be proven. Here, we show in a randomized, controlled human clinical trial that the histone deacetylase inhibitor panobinostat, when administered in combination with pegylated interferon-a2a, induces a structural transformation of the HIV-1 reservoir cell pool, characterized by a disproportionate overrepresentation of HIV-1 proviruses integrated in ZNF genes and in chromatin regions with reduced H3K27ac marks, the molecular target site for panobinostat. In contrast, proviruses near H3K27ac marks appeared to be actively selected against, likely due to increased susceptibility to panobinostat. These data suggest that latency-reversing treatment with panobinostat can accelerate immune selection of HIV-1 proviruses.
2024-02-29 | GSE234623 | GEO
Project description:CD4 T cells with latent HIV-1 infection persist despite treatment with currently available antiretroviral agents and represent the main barrier to a cure of HIV-1 infection. Pharmacological disruption of viral latency may increase the immunological vulnerability of HIV-1-infected cells, but the clinical efficacy of latency-reversing agents for reducing HIV-1 persistence remains to be proven. Here, we show in a randomized, controlled human clinical trial that the histone deacetylase inhibitor panobinostat, when administered in combination with pegylated interferon-a2a, induces a structural transformation of the HIV-1 reservoir cell pool, characterized by a disproportionate overrepresentation of HIV-1 proviruses integrated in ZNF genes and in chromatin regions with reduced H3K27ac marks, the molecular target site for panobinostat. In contrast, proviruses near H3K27ac marks appeared to be actively selected against, likely due to increased susceptibility to panobinostat. These data suggest that latency-reversing treatment with panobinostat can accelerate immune selection of HIV-1 proviruses.
2024-02-29 | GSE234624 | GEO
Project description:Antiretroviral therapy controls but does not cure HIV-1 infection due to a reservoir of rare CD4 + T cells harboring latent proviruses. Little is known about the transcriptional program of latent cells. Here we report a novel strategy to enrich clones of latent cells carrying intact, replication-competent HIV-1 proviruses from blood based on their expression of unique T cell receptors. Latent cell enrichment enabled single cell transcriptomic analysis of 1,050 CD4 + T cells belonging to expanded clones harboring intact HIV-1 proviruses from 6 different individuals. The analysis revealed that most of these cells are T effector memory cells that are enriched for expression of HLA-DR, HLA-DP, CD74, CCL5, Granzymes A and K, cystatin F, LYAR and DUSP2. We conclude that expanded clones of latent cells carrying intact HIV-1 proviruses persist preferentially in a distinct CD4 + T cell population opening new possibilities for eradication.
2022-06-03 | GSE204756 | GEO
Project description:Using novel methods for mapping U/A base pairs in HIV DNA, we find that HIV proviruses within infected monocytes and macrophages contain high levels of U/A base pairs arising from the high levels of dUTP present during reverse transcription in these cells. Although U/A pairs retain the coding information of T/A pairs, they are the substrate for the nuclear uracil base excision repair (UBER) machinery that effectively degrades most of the uracilated viral DNA at the pre-integration stage of infection. Uracilated proviruses that successfully integrate either retain the uracils, undergo U/A T/A repair, or experience catastrophic mutagenesis induced by cytokine stimulated error-prone repair. Uracil is abundant in proviruses isolated from genomic DNA of short-lived blood monocytes, but not T cells, of HIV infected blood donors who show complete drug suppression plasma virus. This suggests that monocytes are recently infected by coming into contact with persistent virus producing cells in one or more tissue reservoirs. Data for HIV lockdown of Illumina libraries of MDM cells post viral infection with and without UDG treatment as compared to HT29-ugi cells treated with RTX.
2016-01-19 | E-GEOD-76091 | biostudies-arrayexpress
Project description:Co-transfected samples of IFI27 and HIV-1 proviruses in HEK293T cell were analyzed using label-free quantitative proteomics technology
2024-02-23 | PXD050120 |
Project description:The restructuring of chromatin architecture following lentiviral integration is not well elucidated. We jointly interrogate (HIV-distal & -local) chromatin organization (via Hi-C & ATAC-seq) and the RNA landscape around defined sites of proviral integration using HIV-inducible cellular models. We report chromatin interaction networks and nuclear ultrastructure around integrated HIV-1 are predominantly preserved, suggesting HIV integration does not induce large scale remodeling of cellular chromatin. Instead, we find that induction of proviral transcription leads to stark local changes in nucleosome organization with chromatin accessibility increasing at the intergenic junction between the HIV-1 3’ LTR and flanking cellular genome. This result suggests subtle changes in chromatin structure may be mediating proviral activation. Using long-read Nanopore RNA-seq, we interrogate the local host & HIV transcriptomes, observing a small fraction of HIV-1 transcripts are chimeric read-through products, where transcription initiates at the HIV-1 5’ LTR promoter and continues extensively into the flanking cellular genome. Despite provirus-driven read-through, HIV-1 appears to have only a modest effect on the local transcriptional environment. The changes in chromatin accessibility and read-through at activated proviruses closely resembles lytic Herpes simplex virus type 1 (HSV-1) induced cellular chromatin reprogramming. We propose chromatin “opening” at the 3’ LTR HIV-host junction is important for sustained proviral activity, and overall, HIV proviruses do not significantly alter local host transcription and chromatin structure. Our studies provide the first in-depth integrative investigation of 3D chromatin organization, nucleosome density, and HIV-host transcriptomes at HIV-host genic boundaries.
2021-10-26 | GSE184345 | GEO