Proviral location affects cognate peptide-induced virus production and immune recognition of 2 HIV-1-infected T cell clones
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PROVIDER: PRJNA992489 | ENA |
REPOSITORIES: ENA
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Project description:In this study, we determined the effect of proviral inducibility on CD8+ T cell recognition of HIV-infected clones. We showed that a T cell clone containing a provirus integrated in relatively transcriptionally inactive site was much less recognized by CD8+ T cells than a T cell clone containing a provirus that was integrated into a trancriptionally active site.
2023-07-14 | GSE236837 | GEO
Project description:BACKGROUNDHIV-1-infected CD4+ T cells contribute to latent reservoir persistence by proliferating while avoiding immune recognition. Integration features of intact proviruses in elite controllers (ECs) and people on long-term therapy suggest that proviruses in specific chromosomal locations can evade immune surveillance. However, direct evidence of this mechanism is missing.METHODSIn this case report, we characterized integration sites and full genome sequences of expanded T cell clones in an EC before and after chemoradiation. We identified the cognate peptide of infected clones to investigate cell proliferation and virus production induced by T cell activation, and susceptibility to autologous CD8+ T cells.RESULTSThe proviral landscape was dominated by 2 large clones with replication-competent proviruses integrated into zinc finger (ZNF) genes (ZNF470 and ZNF721) in locations previously associated with deeper latency. A third nearly intact provirus, with a stop codon in Pol, was integrated into an intergenic site. Upon stimulation with cognate Gag peptides, infected clones proliferated extensively and produced virus, but the provirus in ZNF721 was 200-fold less inducible. While autologous CD8+ T cells decreased the proliferation of cells carrying the intergenic provirus, they had no effect on cells with the provirus in the ZNF721 gene.CONCLUSIONSWe provide direct evidence that upon activation of infected clones by cognate antigen, the lower inducibility of intact proviruses in ZNF genes can result in immune evasion and persistence.FUNDINGOffice of the NIH Director and National Institute of Dental & Craniofacial Research; NIAID, NIH; Johns Hopkins University Center for AIDS Research.
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Project description:Clonal expansion of HIV infected CD4+ T cells is a barrier to HIV eradication. We previously described a marked reduction in the frequency of the most clonally expanded infected CD4+ T cells in an individual with elite control (ES24) after initiating chemoradiation for metastatic lung cancer with a regimen that included paclitaxel and carboplatin. We tested the hypothesis that this phenomenon was due to a higher susceptibility to the chemotherapeutic drugs of CD4+ T cell clones that were sustained by active proliferation. We studied a CD4+ T cell clone with replication-competent provirus integrated into the ZNF721/ABCA11P genes, termed ZNF721i. We stimulated the clone with its cognate peptide and then exposed the cells to paclitaxel and/or carboplatin or the antiproliferative drug, mycophenolate mofetil. While treatment of cells with the cognate peptide alone led to a marked expansion of the ZNF721i clone, treatment with the cognate peptide followed by culture with either paclitaxel or mycophenolate mofetil abrogated this process. The drugs did not affect the proliferation of other CD4+ T cell clones that were not specific for the cognate peptide. This strategy of antigen-specific stimulation followed by treatment with an antiproliferative agent may lead to the selective elimination of clonally expanded HIV-infected cells.
2025-08-25 | GSE305896 | GEO
Project description:Regulatory CD4 T cells (Treg) confer non-overlapping functions in intestinal immune tolerance, tissue maintenance, repair, and regeneration. Cytokines and T cell receptor (TCR) signals, in combination with environmental cues, direct Treg proliferation and differentiation. However, how intestinal antigens shape intestinal Treg populations, their specialization and stability remain unknown. Here we show that only Treg bearing specific TCRs expand in the colon, resulting in highly oligoclonal Treg populations. Treg TCR repertoires are private, but crucially, when the same repertoire of polyclonal Treg was transferred into different recipients, the same clones expanded in each recipient, suggesting that cognate TCR-antigen interactions drive colonic Treg accumulation. Expanded Treg clones were correlated with Treg stability and individual transcriptional states that were maintained in different recipients irrespective of the presence or absence of intestinal inflammation. Our data suggest a role for antigen recognition in the selection and functional specialization of intestinal Treg. We speculate that the therapeutic use of Treg must take into account TCR context-mediated properties to optimise Treg stability and function in vivo.
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Project description:Selective targeting of HIV infected clones by cognate peptide stimulation and antiproliferative drugs
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Project description:Infections by Human T cell Leukaemia Virus type 1 (HTLV-1) persist for the lifetime of the host by integrating into the genome of CD4+ T cells. Proviral gene expression is core to proviral survival and the maintenance of the proviral load, through the pro-proliferative changes it induces in infected cells. Despite their role in HTLV-1 infection and a persistent cytotoxic T lymphocyte response raised against them, proviral transcripts from the sense-strand are rarely detected in fresh cells extracted from the peripheral blood, and have recently been found to be expressed intermittently by a small subset of cells at a given time. Ex vivo culture of infected cells prompts synchronised proviral expression in infected cells from peripheral blood, allowing the study of factors involved in reactivation in primary cells. Here, we used bulk RNA-seq to examine the host transcriptome over six days in vitro, following proviral reactivation in primary peripheral CD4+ T cells isolated from subjects with non-malignant HTLV-1 infection. Infected cells displayed a conserved response to reactivation, characterised by discrete stages of gene expression, cell division and subsequently horizontal transmission of the virus. We observed widespread changes in Polycomb gene expression following reactivation, including an increase in PRC2 transcript levels and diverse changes in the expression of PRC1 components. We hypothesize that these transcriptional changes constitute a negative feedback loop that maintains proviral latency by re-deposition of H2AK119ub1 following the end of proviral expression. Using RNAi, we found that certain deubiquitinases, BAP1, USP14 and OTUD5 each promote proviral transcription. These data demonstrate the detailed trajectory of HTLV-1 proviral reactivation in primary HTLV-1-carrier lymphocytes and the impact on the host cell.
2023-07-24 | GSE234450 | GEO
Project description: Not available
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Project description:HIV integrates semi-randomly into the genome of immune cells and thus proviruses that persist in patients under long-term, highly active suppressive therapy can be detected in various positions (inside and outside) and orientations (same, convergent and divergent) respective to genes, promoters, and enhancers. Thus, this integration landscape heterogeneity can influence HIV transcription activity thereby dictating proviral fate (active vs latent). However, the effect of the integration site to proviral transcription activity has so far remained elusive. Here we integrate open-source, large-scale datasets including epigenetics, transcriptome, and 3D genome architecture to interrogate the chromatin states, transcription activity landscape, nuclear sub-compartments, and topological associated domains around HIV integration sites in CD4+ T cell-based models to decipher ‘codes’ in the human genome shaping proviral transcription. As part of this integrated approach, here we collect nucleosome occupancy profiles in Jurkat CD4+ T cells.
2021-05-05 | GSE144753 | GEO
Project description:The reservoir of latently HIV-1 infected cells is heterogeneous. To achieve an HIV-1 cure the reservoir of activatable proviruses should be removed, whereas permanently silenced proviruses may be tolerated. We have developed a method to assess the proviral nuclear microenvironment in single cells. Latently HIV-1 infected cells were transduced with a zinc finger protein specifically binding to the HIV-1 promoter, producing a fluorescent signal as the viral transactivator Tat is recruited to the HIV-1 promoter. In these cells we assessed the proviral chromatin composition simultaneously with the proviral activation. By linking the Tat promoter recruitment to viral activation, we dissected the mechanisms of HIV-1 reactivation and the consequences of HIV-1 production. A pulse of promoter-associated Tat was identified that contrasts to the continuous production of viral proteins. As expected, promoter H3K4me3 led to massive expression of the provirus following T cell stimulation. However, the activation induced cell cycle arrest and death resulted in an expanded surviving cell fraction with proviruses encapsulated in repressive chromatin. Further, this model can be used to reveal mechanisms of action of small molecules. In a proof-of-concept study we determine the effect of CBP/P300-inhibitor GNE049. We found that only active enhancers, associated with H3K4me1 and H3K27ac, efficiently recruit Tat, as GNE049 that specifically inhibits enhancer H3K27ac also depletes promoter Tat. Despite the absence of Tat, HIV-1 latency reversal still occurred. Single cell assessment of the chromatin composition of the latent HIV-1 proviruses revealed how T cell stimulation modulates the proviral activity and the subsequent fate of the infected cell.
2021-10-04 | GSE183275 | GEO