Ontology highlight
ABSTRACT:
PROVIDER: PRJNA318913 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3403080.fastq.gz | Fastqsanger.gz | |||
| SRR3403090.fastq.gz | Fastqsanger.gz | |||
| SRR3403100.fastq.gz | Fastqsanger.gz | |||
| SRR3403081.fastq.gz | Fastqsanger.gz | |||
| SRR3403091.fastq.gz | Fastqsanger.gz |
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Project description:Identifying cellular mechanisms maintaining HIV-1 latency in the viral reservoir is crucial for devising effective cure strategies. Here we developed a flow cytometry-fluorescent in situ hybridization (flow-FISH) approach using a combination of probes that detects abortive and elongated HIV-1 transcripts for ex vivo isolation and characterization of viral reservoir cells in peripheral blood from people with HIV-1. Following the isolation of three distinct cell populations from CD4+ T cells (i.e. cells harboring transcriptionally latent HIV-1, cells harboring transcriptionally active HIV-1, or uninfected cells), we determined their transcriptomic profile by RNA sequencing (RNAseq). Supervised gene expression analysis identified several differentially expressed mitochondrial genes in infected cell populations compared to uninfected cells, but also in latently infected compared to productively infected CD4+ T cells. Our transcriptomic profiling data shows an association between diminished mitochondrial functioning and the transcriptional activity of the viral reservoir. These findings underline the relevance of metabolic regulation in HIV-1 infection, and support the development of strategies modulating immunometabolism to target viral latency.
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Project description:Surface expression of the viral Envelope protein (Env) was used to enrich reactivated latent T cells producing HIV-RNA, and single cell RNASeq was performed to study gene expression differences between latent cells and controls.
2018-03-02 | GSE104490 | GEO
Project description:Introduction of antiretroviral therapy has limited the spread of HIV and improved clinical outcomes. Yet, a complete cure for infection remains out of reach, as in the face of therapy, a transcriptionally silent but replication-competent provirus persists in a long-lived cell reservoir. Towards identifying new host proteins that regulate HIV gene transcription and latency, we performed a genome-wide CRISPR knockout screen in human CD4+ T cells. We identified the Activating Transcription Factor as a regulator of HIV gene transcription. ATF1 is recruited to the HIV promoter and activates viral gene expression. Gain and loss of function experiments demonstrate that depletion of ATF1 expression decreases HIV gene expression and promotes latency in primary CD4+ infected T cells. Interestingly, ATF1 regulates CCR5 expression and indirectly affects R5-tropic HIV infection. Mechanistically, ATF1 depletion impairs occupancy of RNA Polymerase II on the HIV promoter, and this is accompanied with elevated levels of H3K9me3 repression histone mark around the viral promoter. Genome wide analysis of ATF1 shows that it occupies cellular gene promoters including HIV, thereby controls gene targets that indirectly affect HIV infection. We conclude that ATF1 is an activator of gene transcription that dictates HIV gene expression via both direct and indirect mechanisms.
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Project description:The epigenetic mechanisms established by histone modifications may affect the transcriptional silencing of HIV-1 and viral latency. A systematic epigenome profiling could be applicable to develop new epigenetic diagnostic markers for detecting HIV-1 latency. In this study, histone modification profiles of HIV-1 latency cell lines were compared with those of uninfected CD4+ T cell line. The HIV-1 latency gave rise to differential histone modification regions. The differential enrichment patterns helped us to define potential effector genes leading to the viral latency. The histone H3K4me3 and H3K9ac profiles were obtained from the HIV-1 latency cell lines (NCHA1, NCHA2, and ACH2) and control CD4+ T cell line (A3.01)
2014-06-06 | E-GEOD-58247 | biostudies-arrayexpress
Project description:To replicate in the host, HIV-1 must produce RNA and protein, and this depends cellular factors that also control gene expression. Recently, it has been shown that novel components of this machinery post-transcriptionally modify mRNAs with direct consequences for their structure and stability. The most common among these modifications is the addition of a methyl group to the N6 position of adenosine, termed m6A methylation. Here we are interested the interface of HIV-1 with this posttranscriptional mRNA modification pathway. We show that viral transcripts harbor a number of discrete methylation sites and are bound at those sites by these YTHDF proteins. These sites are conserved among distinct HIV-1 isolates and are observed during viral replication in numerous cell types. With reporter assays we also show that these sites stabilize mRNAs when compared to similar sequences mutated to be incapable of methylation. We further show that overexpression of these reader proteins boosts viral protein expression.
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Project description:The implementation of antiretroviral therapy (ART) has effectively restricted the transmission of Human Immunodeficiency Virus (HIV) and improved overall clinical outcomes. However, a complete cure for HIV remains out of reach, as the virus persists in a stable pool of infected cell reservoir that is resistant to therapy and thus a main barrier towards complete elimination of viral infection. While the mechanisms by which host proteins govern viral gene expression and latency are well-studied, the emerging regulatory functions of non-coding RNAs (ncRNA) in the context of T cell activation, HIV gene expression and viral latency have not yet been thoroughly explored. Here, we report the identification of the Cytoskeleton Regulator (CYTOR) long non-coding RNA (lncRNA) as an activator of HIV gene expression that is upregulated following T cell stimulation. Functional studies show that CYTOR suppresses viral latency by directly binding to the HIV promoter and associating with the cellular positive transcription elongation factor (P-TEFb) to activate viral gene expression. CYTOR also plays a global role in regulating cellular gene expression, including those involved in controlling actin dynamics. Depletion of CYTOR expression reduces cytoplasmic actin polymerization in response to T cell activation. In addition, treating HIV-infected cells with pharmacological inhibitors of actin polymerization reduces HIV gene expression. We conclude that both direct and indirect effects of CYTOR regulate HIV gene expression.
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Project description:Chimeric Antigen Receptor (CAR) T cell therapy shows promise for various diseases. Our studies in humanized mice and non-human primates (NHPs) demonstrate that hematopoietic stem cell (HSCs) modified with anti-HIV CAR achieve lifelong engraftment, providing functional anti-viral CAR-T cells that reduce viral rebound after ART withdrawal. However, T cell exhaustion due to chronic immune activation remains a key obstacle for sustained CAR-T efficacy, necessitating additional measures to achieve functional cure. We recently showed that low dose rapamycin treatment reduced inflammation and improved anti-HIV T cell function in HIV-infected humanized mice. Here, we report that rapamycin improved CAR-T cell function both in vitro and in vivo. In vitro treatment with rapamycin enhanced CAR-T cell mitochondria respiration and cytotoxicity. In vivo treatment with low-dose rapamycin in HIV-infected, CAR-HSC mice decreased chronic inflammation, prevented exhaustion of CAR-T cells and improved CAR-T control of viral replication. RNAseq analysis of CAR-T cells from humanized mice showed that rapamycin downregulated multiple checkpoint inhibitors and the upregulated key survival genes. Mice treated with CAR-HSCs and rapamycin had delayed viral rebound post-ART and reduced HIV reservoir compared to CAR-HSCs alone. These findings suggest that HSCs-based anti-HIV CAR-T combined with rapamycin treatment is a promising approach for treating persistent inflammation and improving immune control of HIV replication.
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Project description:Retroviral integration is mediated by a unique enzymatic process shared by all retroviruses and retrotransposons. During integration, double-stranded linear viral DNA is inserted into the host genome in a process catalyzed by viral-encoded integrase. However, host cell defenses against HIV-1 integration are not clear. This study identifies -catenin-like protein 1 (CTNNBL1) as a potent inhibitor of HIV-1 integration via association with viral IN and its cofactor, lens epithelium-derived growth factor/p75. CTNNBL1 overexpression blocks HIV-1 integration and inhibits viral replication, whereas CTNNBL1 depletion significantly upregulates HIV-1 integration into the genome of various target cells. Further, CTNNBL1 expression is downregulated in CD4+ T cells by activation, and CTNNBL1 depletion also facilitates HIV-1 integration in resting CD4+ T cells. Thus, host cells may employ CTNNBL1 to inhibit HIV-1 integration into the genome. This finding suggests a strategy for the treatment of HIV infections.
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Project description:The epigenetic mechanisms established by histone modifications may affect the transcriptional silencing of HIV-1 and viral latency. A systematic epigenome profiling could be applicable to develop new epigenetic diagnostic markers for detecting HIV-1 latency. In this study, histone modification profiles of HIV-1 latency cell lines were compared with those of uninfected CD4+ T cell line. The HIV-1 latency gave rise to differential histone modification regions. The differential enrichment patterns helped us to define potential effector genes leading to the viral latency.
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Project description:Latency reversal and clearance strategies for HIV cure are beginning to employ IAP antagonists (IAPi) to induce unprecedented levels of latent reservoir expression without immunotoxicity during suppressive antiretroviral therapy (ART). However, full targeting of the reservoir may require combinatorial approaches. A Jurkat latency model screen for IAPi combination partners demonstrated synergistic latency reversal with Bromodomain and Extra-Terminal domain protein inhibitors (BETi). Mechanistic investigations using CRISPR-CAS9 and single cell-RNAseq informed comprehensive ex vivo evaluations of IAPi plus pan-BET, bromodomain (BD)-selective BET, or selective BET isoform targeting in CD4 T cells from ART-suppressed donors. IAPi+BETi treatment resulted in striking induction of cell-associated HIV gag RNA but lesser induction of fully elongated and tat-rev RNA, especially compared to T cell activation positive controls. IAPi/BETi resulted in HIV protein induction in bulk cultures of CD4 T cells using an ultrasensitive p24 assay, but did not translate to enhanced viral outgrowth frequency using a standard quantitative viral outgrowth assay. Overall, this study defines HIV transcriptional elongation and splicing as key barriers to latent HIV protein expression following latency reversal, delineates the roles of BET proteins and their bromodomains in HIV latency, and provides rationale for testing of IAPi+BETi in animal models of HIV latency.
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