{"doi":"10.3390/v14102288","title":"Host Cell Redox Alterations Promote Latent HIV-1 Reactivation through Atypical Transcription Factor Cooperativity","abstract":"Immune cell state alterations rewire HIV-1 gene expression, thereby influencing viral latency and reactivation, but the mechanisms are still unfolding. Here, using a screen approach on CD4+ T cell models of HIV-1 latency, we revealed Small Molecule Reactivators (SMOREs) with unique chemistries altering the CD4+ T cell state and consequently promoting latent HIV-1 transcription and reactivation through an unprecedented mechanism of action. SMOREs triggered rapid oxidative stress and activated a redox-responsive program composed of cell-signaling kinases (MEK-ERK axis) and atypical transcription factor (AP-1 and HIF-1α) cooperativity. SMOREs induced an unusual AP-1 phosphorylation signature to promote AP-1/HIF-1α binding to the latent HIV-1 proviral genome for its activation. Consistently, latent HIV-1 reactivation was compromised with pharmacologic inhibition of oxidative stress sensing or of cell-signaling kinases, and transcription factor’s loss of expression, thus functionally linking the host redox-responsive program to viral transcriptional rewiring. Notably, SMOREs induced the redox program in primary CD4+ T cells and reactivated latent HIV-1 in aviremic patient samples alone and in combination with known latency-reversing agents, thus providing physiological relevance. Our findings suggest that manipulation of redox-sensitive pathways could be exploited to alter the course of HIV-1 latency, thus rendering host cells responsive to help achieve a sterilizing cure.","journal":"Viruses","year":2022,"id":287771,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9531,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":926094,"name":"Nora-Guadalupe P. Ramirez","orcid":"0000-0002-7992-1683","position":1,"is_corresponding":false},{"id":12401,"name":"Jeon Lee","orcid":"0000-0002-9071-7157","position":2,"is_corresponding":false},{"id":968197,"name":"Sonali Pandhe","orcid":null,"position":3,"is_corresponding":false},{"id":494260,"name":"Lei Wang","orcid":"0000-0001-6915-2713","position":4,"is_corresponding":false},{"id":968198,"name":"Juan Hernandez-Doria","orcid":null,"position":5,"is_corresponding":false},{"id":263027,"name":"Adam M. Spivak","orcid":"0000-0003-1815-7893","position":6,"is_corresponding":false},{"id":263028,"name":"Vicente Planelles","orcid":"0000-0002-5318-2982","position":7,"is_corresponding":false},{"id":968199,"name":"Tianna Petersen","orcid":null,"position":8,"is_corresponding":false},{"id":104967,"name":"Mamta K. Jain","orcid":"0000-0003-2292-6544","position":9,"is_corresponding":false},{"id":446148,"name":"Elisabeth D. Martínez","orcid":"0000-0003-1131-3689","position":10,"is_corresponding":false},{"id":314068,"name":"Iván D’Orso","orcid":"0000-0002-1409-2351","position":11,"is_corresponding":false},{"id":968196,"name":"Emily Cruz-Lorenzo","orcid":null,"position":0,"is_corresponding":true}],"reference_count":94,"raw_metadata":null,"created_at":"2026-07-19T00:30:01.051685Z","pmid":"36298843","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":[]}