Selective targeting of HIV infected clones by cognate peptide stimulation and antiproliferative drugs
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PROVIDER: PRJNA1308140 | ENA |
REPOSITORIES: ENA
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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:Proviral location affects cognate peptide-induced virus production and immune recognition of 2 HIV-1-infected T cell clones
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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
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2023-04-01 | GSE227409 | 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.
2024-03-13 | GSE260965 | 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:New approaches that generate long-lasting therapeutic responses in therapy-resistant metastatic cancer patients are urgently needed. To address this challenge, we developed SpotNeoMet, a novel data-driven pipeline that systematically identifies recurrently presented neopeptides in treatment-resistant patients. We identified seven therapy resistance mutations predicted to produce neo-peptides presented by common HLAs. Using HLA-immunopeptidomics, we discovered three novel neopeptides derived from Androgen Receptor (AR) H875Y, a common metastatic castration-resistant prostate cancer (mCRPC) mutation. We validated these neoantigens as highly immunogenic and then isolated and characterized cognate T-cell receptors (TCRs) from healthy donor peripheral blood mononuclear cells. We demonstrated that AR H875Y specific TCRs are highly specific and kill prostate cancer cells presenting AR neo-peptides in vitro and in vivo. Our new pipeline identifies novel immunotherapy targets and potential treatment options for mCRPC patients. Moreover, SpotNeoMet offers a systematic route to identify 'HLA-peptide' pairs and their cognate TCRs across treatment-resistant cancers.
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