{"doi":"10.1101/2023.05.26.23290576","title":"HIV-1 latency reversal agent boosting is not limited by opioid use","abstract":"Abstract The opioid epidemic may impact the HIV-1 reservoir and its reversal from latency in virally suppressed people with HIV (PWH). We studied forty-seven PWH and observed that lowering the concentration of HIV-1 latency reversal agents (LRA), used in combination with small molecules that do not reverse latency, synergistically increases the magnitude of HIV-1 re-activation ex vivo , regardless of opioid use. This LRA boosting, which combines a Smac mimetic or low-dose protein kinase C agonist with histone deacetylase inhibitors, can generate significantly more unspliced HIV-1 transcription than phorbol 12-myristate 13-acetate (PMA) with ionomycin (PMAi), the maximal known HIV-1 reactivator. LRA boosting associated with greater histone acetylation in CD4 + T cells and modulated T cell activation-induced markers and intracellular cytokine production; Smac mimetic-based boosting was less likely to induce immune activation. We found that HIV-1 reservoirs in PWH contain unspliced and polyadenylated (polyA) virus mRNA, the ratios of which are greater in resting than total CD4 + T cells and can correct to 1:1 with PMAi exposure. Latency reversal results in greater fold-change increases to HIV-1 poly(A) mRNA than unspliced message. Multiply spliced HIV-1 transcripts and virion production did not consistently increase with LRA boosting, suggesting the presence of a persistent post-transcriptional block. LRA boosting can be leveraged to probe the mechanisms of an effective cellular HIV-1 latency reversal program.","journal":"medRxiv","year":2023,"id":408100,"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":0.9594,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1187384,"name":"Jennifer Bouzy","orcid":null,"position":1,"is_corresponding":false},{"id":446832,"name":"Archana Asundi","orcid":"0000-0003-3910-909X","position":2,"is_corresponding":false},{"id":270171,"name":"Jessica L. Taylor","orcid":"0000-0001-5256-0796","position":3,"is_corresponding":false},{"id":81778,"name":"Samantha Roche","orcid":null,"position":4,"is_corresponding":false},{"id":296035,"name":"Alex Olson","orcid":"0000-0002-3371-3213","position":5,"is_corresponding":false},{"id":218317,"name":"Kendyll Coxen","orcid":null,"position":6,"is_corresponding":false},{"id":218318,"name":"Heather Corry","orcid":"0009-0006-4902-5702","position":7,"is_corresponding":false},{"id":218344,"name":"Hannah Jordan","orcid":"0000-0003-3705-9551","position":8,"is_corresponding":false},{"id":108255,"name":"Kiera Clayton","orcid":"0009-0006-9398-0651","position":9,"is_corresponding":false},{"id":312539,"name":"Nina Lin","orcid":"0000-0002-4913-0442","position":10,"is_corresponding":false},{"id":218329,"name":"Athe Tsibris","orcid":"0000-0002-2681-3216","position":11,"is_corresponding":false},{"id":1187383,"name":"Tyler J. Lilie","orcid":null,"position":0,"is_corresponding":true}],"reference_count":92,"raw_metadata":null,"created_at":"2026-07-19T01:21:14.562812Z","pmid":"37398278","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":[]}