title: Human immunodeficiency virus type-1 (HIV-1) infection increases the sensitivity of macrophages and THP-1 cells to cytotoxicity by cationic liposomes.
abstract: Cationic liposomes may be valuable for the delivery of anti-sense oligonucleotides, ribozymes, and therapeutic genes into human immunodeficiency virus type 1 (HIV-1)-infected and uninfected cells. We evaluated the toxicity of three cationic liposomal preparations, Lipofectamine, Lipofectin, and 1, 2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide (DMRIE) reagent, to HIV-infected and uninfected cells. Monocyte/macrophages were infected with HIV-1BaL and treated with liposomes in medium containing 20% fetal bovine serum (FBS) for 4 h or 24 h at 37 degree C. Uninfected monocytic THP-1 cells and chronically infected THP-1/HIV-1IIIB cells were treated with phorbol 12-myristate 13-acetate (PMA) and exposed to liposomes in the presence of 10% FBS. Toxicity was evaluated by the Alamar Blue assay and viral p24 production. The toxic effect of cationic liposomes was very limited with uninfected cells, although concentrations of liposomes that were not toxic within a few days of treatment could cause toxicity at later times. In HIV-1BaL-infected macrophages, Lipofectamine (up to 8 microM) and Lipofectin (up to 40 microM) were not toxic after a 4-h treatment, while DMRIE reagent at 40 microM was toxic. While a 4-h treatment of THP-1/HIV-1IIIB cells with the cationic liposomes was not toxic, even up to 14 days post-treatment, all three cationic liposomes were toxic to cells at the highest concentration tested after a 24-h treatment. Similar results were obtained with the Alamar Blue assay, Trypan Blue exclusion and a method that enumerates nuclei. Infected cells with relatively high overall viability could be impaired in their ability to produce virions, indicating that virus production appears to be more sensitive to treatment with the cationic liposomes than cell viability. Our results indicate that HIV-infected cells are more susceptible than uninfected cells to killing by cationic liposomes. The molecular basis of this differential effect is unknown; it is proposed that alterations in cellular membranes during virus budding cause enhanced interactions between cationic liposomes and cellular membranes.
authors.affiliation: Department of Microbiology, University of the Pacific School of Dentistry, San Francisco, CA 94115, USA.
authors.forename: K
authors.initials: K
authors.lastname: Konopka
authors.forename: E
authors.initials: E
authors.lastname: Pretzer
authors.forename: P L
authors.initials: PL
authors.lastname: Felgner
authors.forename: N
authors.initials: N
authors.lastname: Düzgüneş
mesh_terms: D000818:Animals; D002411:Cation Exchange Resins / Q000633:toxicity*; D002417:Cattle; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003470:Culture Media; D018023:HIV Seronegativity; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008055:Lipids / Q000633:toxicity*; D008081:Liposomes / Q000633:toxicity*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000821:virology*; D009000:Monocytes / Q000821:virology*; D010714:Phosphatidylethanolamines / Q000633:toxicity*; D000644:Quaternary Ammonium Compounds / Q000633:toxicity*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014771:Virion / Q000187:drug effects / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D002411:Cation Exchange Resins; D003470:Culture Media; D008055:Lipids; C086724:Lipofectamine; D008081:Liposomes; D010714:Phosphatidylethanolamines; D000644:Quaternary Ammonium Compounds; C087276:(3-dimyristyloxypropyl)(dimethyl)(hydroxyethyl)ammonium; C020888:1,2-dielaidoylphosphatidylethanolamine; D013755:Tetradecanoylphorbol Acetate