{"doi":"10.2147/ijn.s401304","title":"Nanodepots Encapsulating a Latency Reversing Agent and Broadly Neutralizing Antibody Enhance Natural Killer Cell Cytotoxicity Against an in vitro Model of Latent HIV","abstract":"Purpose: Current antiretroviral therapies (ART) for human immunodeficiency virus (HIV) are not curative, as the virus persists in latent reservoirs, requiring lifelong adherence to ART and increasing the risk of co-morbidities. \"Shock and kill\" approaches to reactivate HIV from latent reservoirs followed by administration of anti-HIV drugs represent a promising strategy for eradicating latent HIV. To achieve effective shock and kill, we describe a strategy to eradicate the HIV reservoir that combines latency reversing agents (LRAs), broadly neutralizing antibodies (bnAbs), and natural killer (NK) cells. This strategy utilizes a polymer nanodepot (ND) that co-encapsulates the LRA and bnAb to reactivate latent infection and elicit enhanced cytotoxicity from co-administered NK cells. Methods: Poly(lactic-co-glycolic acid) (PLGA) NDs were synthesized using the nanoprecipitation method to co-encapsulate an LRA (TNF-α) and a bnAb (3BNC117) (TNF-α-3BNC117-NDs). ACH-2 cells were used as a cellular model of latent HIV infection. An NK92 subline, genetically modified to constitutively express the Fc receptor CD16, was administered to ACH-2 cells in combination with TNF-α-3BNC117-NDs. ACH-2 cell death and extracellular p24 were measured via flow cytometry and ELISA, respectively. Results: Stable PLGA NDs co-encapsulated TNF-α and 3BNC117 with high efficiencies and released these agents in physiological conditions. NK92 phenotype remained similar in the presence of TNF-α-3BNC117-NDs. TNF-α released from NDs efficiently reactivated HIV in ACH-2 cells, as measured by a 3.0-fold increase in the frequency of intracellular p24 positive cells. Released 3BNC117 neutralized and bound reactivated virus, targeting 57.5% of total ACH-2 cells. Critically, TNF-α-3BNC117-NDs significantly enhanced NK92 cell-mediated killing of ACH-2 cells (1.9-fold) and reduced extracellular levels of p24 to baseline. Conclusion: These findings suggest the therapeutic potential of our novel ND-based tripartite strategy to reactivate HIV from latently infected cells, generate an HIV-specific site for bnAb binding, and enhance the killing of reactivated HIV-infected target cells by NK92 cells.","journal":"International Journal of Nanomedicine","year":2023,"id":377279,"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":0.9571,"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":462732,"name":"Allan Bowen","orcid":null,"position":1,"is_corresponding":false},{"id":636394,"name":"Jie Chen","orcid":"0000-0002-5847-4888","position":2,"is_corresponding":false},{"id":727515,"name":"Preethi B. Balakrishnan","orcid":"0000-0001-5576-7530","position":3,"is_corresponding":false},{"id":409941,"name":"Allison B. Powell","orcid":"0009-0009-8076-0563","position":4,"is_corresponding":false},{"id":1140686,"name":"Kondareddy Cherukula","orcid":"0000-0003-4205-1634","position":5,"is_corresponding":false},{"id":263320,"name":"Carolina Colli Cruz","orcid":"0000-0001-7065-3769","position":6,"is_corresponding":false},{"id":95313,"name":"R. Brad Jones","orcid":"0000-0003-4470-1231","position":7,"is_corresponding":false},{"id":409945,"name":"Rebecca M. Lynch","orcid":"0000-0002-7188-8073","position":8,"is_corresponding":false},{"id":462733,"name":"Elizabeth E. Sweeney","orcid":null,"position":9,"is_corresponding":false},{"id":311595,"name":"Rohan Fernandes","orcid":"0000-0001-9439-4626","position":10,"is_corresponding":false},{"id":1025335,"name":"Joshua Ghofrani","orcid":"0000-0002-5956-9096","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-19T01:16:36.370283Z","pmid":"37520301","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":[]}