{"doi":"10.1101/2025.08.06.668975","title":"Synergistic latency reversal by the IAP antagonist AZD5582 and BET inhibitor JQ1, combined with Nef ablation, facilitates immune-mediated elimination of latently HIV-1-infected T-cells","abstract":"ABSTRACT The ‘shock-and-kill’ strategy can reactivate latent HIV-1 in vivo but has failed to meaningfully reduce the reactivatable reservoir, suggesting insufficient immunological visibility of infected cells. To investigate latency reversal agent (LRA)-specific shortcomings, we developed a novel HIV-1 latency model - Jurkat E6.1 subclonal T-cell lines, each harbouring a single, full-length, NL4.3-based provirus with a GFP OPT reporter in the Env V5 loop - and quantified HIV-1 reactivation, Env surface presentation across LRAs and synergistically acting combinations. Bryostatin-1 induced GBP5-mediated restriction of surface Env and resistance to apoptosis. Bryostatin-1/JQ1 synergised for HIV-1 reactivation and boosted levels of cell-surface Env, but failed to reduce resistance to apoptosis. AZD5582/JQ1 boosted cell-surface Env levels, without co-induction of GBP5, T-cell activation or apoptotic resistance. HIV-1 Nef antagonised cytotoxic killing of HIV-1-reactivating T-cells - its knockout, combined with AZD5582/JQ1, achieved the highest immune-mediated elimination of latently infected T-cells, representing a promising HIV cure approach.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":571923,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9584,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1478214,"name":"CK Hui","orcid":null,"position":1,"is_corresponding":false},{"id":1005097,"name":"Bengisu Akbil","orcid":"0000-0002-1263-4313","position":2,"is_corresponding":false},{"id":567873,"name":"Jenny Jansen","orcid":null,"position":3,"is_corresponding":false},{"id":932610,"name":"Dominic Wooding","orcid":"0000-0002-9985-0413","position":4,"is_corresponding":false},{"id":1477907,"name":"Oya Cingöz","orcid":"0000-0002-0096-4948","position":5,"is_corresponding":false},{"id":57978,"name":"Christine Goffinet","orcid":"0000-0002-3959-004X","position":6,"is_corresponding":false},{"id":566946,"name":"Dylan Postmus","orcid":"0000-0002-9551-0411","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T02:57:19.669553Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}