{"doi":"10.3389/fimmu.2023.1213455","title":"Viral dissemination and immune activation modulate antiretroviral drug levels in lymph nodes of SIV-infected rhesus macaques","abstract":"Introduction and methods: To understand the relationship between immunovirological factors and antiretroviral (ARV) drug levels in lymph nodes (LN) in HIV therapy, we analyzed drug levels in twenty-one SIV-infected rhesus macaques subcutaneously treated with daily tenofovir (TFV) and emtricitabine (FTC) for three months. Results: The intracellular active drug-metabolite (IADM) levels (TFV-dp and FTC-tp) in lymph node mononuclear cells (LNMC) were significantly lower than in peripheral blood mononuclear cells (PBMC) (P≤0.005). Between Month 1 and Month 3, IADM levels increased in both LNMC (P≤0.001) and PBMC (P≤0.01), with a steeper increase in LNMC (P≤0.01). The viral dissemination in plasma, LN, and rectal tissue at ART initiation correlated negatively with IADM levels at Month 1. Physiologically-based pharmacokinetic model simulations suggest that, following subcutaneous ARV administration, ART-induced reduction of immune activation improves the formation of active drug-metabolites through modulation of kinase activity and/or through improved parent drug accessibility to LN cellular compartments. Conclusion: These observations have broad implications for drugs that need to phosphorylate to exert their pharmacological activity, especially in the settings of the pre-/post-exposure prophylaxis and efficacy of antiviral therapies targeting pathogenic viruses such as HIV or SARS-CoV-2 replicating in highly inflammatory anatomic compartments.","journal":"Frontiers in Immunology","year":2023,"id":388823,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9439,"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":794993,"name":"Paula DeGrange","orcid":"0000-0002-7705-9831","position":1,"is_corresponding":false},{"id":401850,"name":"Simone Perazzolo","orcid":"0000-0003-4498-7823","position":2,"is_corresponding":false},{"id":795527,"name":"Andrew Bonvillain","orcid":null,"position":3,"is_corresponding":false},{"id":1158681,"name":"Amanda Tobery","orcid":null,"position":4,"is_corresponding":false},{"id":617991,"name":"Jacob Kaplan","orcid":"0000-0001-8770-485X","position":5,"is_corresponding":false},{"id":945708,"name":"Hyukjin Jang","orcid":null,"position":6,"is_corresponding":false},{"id":1011200,"name":"Refika Turnier","orcid":null,"position":7,"is_corresponding":false},{"id":1158295,"name":"Michael L. Davies","orcid":"0000-0003-4431-6448","position":8,"is_corresponding":false},{"id":370688,"name":"Mackenzie L. Cottrell","orcid":"0000-0002-0291-5111","position":9,"is_corresponding":false},{"id":401853,"name":"Rodney J. Y. Ho","orcid":"0000-0001-5960-4288","position":10,"is_corresponding":false},{"id":794994,"name":"Michele Di Mascio","orcid":"0000-0001-6609-9689","position":11,"is_corresponding":false},{"id":794992,"name":"Sharat Srinivasula","orcid":"0000-0003-1867-5762","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T01:18:18.214733Z","pmid":"37790938","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":[]}