title: Inhibition of human immunodeficiency virus type-1 replication in macrophages and H9 cells by free or liposome-encapsulated L-689,502, an inhibitor of the viral protease.
abstract: Macrophages are recognized as a major reservoir of HIV-1 in infected individuals. We examined the effect of an inhibitor of the viral protease, L-689,502, on virus production by monocyte-derived macrophages infected with HIV-1BaL. Continuous treatment with L-689,502 drastically inhibited virus production in a dose-dependent manner in the range of 10-200 nM, in some cases by more than 1000-fold, compared to untreated cells. Since liposomes can be targeted to macrophages in vivo, we examined whether the inhibitor was effective following delivery in liposomes. The inhibitor encapsulated in multilamellar liposomes was more effective than the free drug in inhibiting virus production in macrophages, throughout the concentration range studied. The EC90 of the liposomal inhibitor was 2.9- to 4.5-fold lower than that of the free compound. L-689,502 encapsulated in sterically stabilized liposomes with prolonged circulation time inhibited virus production at a level comparable to the free inhibitor. When macrophages were infected and treated for only a limited time, L-689,502 in multilamellar liposomes was the most effective of the three treatments. In chronically infected H9 cells treated continuously, the free inhibitor was more effective than the liposome-encapsulated drug, but virus production was reduced only to 40-60% of controls. In contrast, treatment of acutely infected H9 cells with either free or encapsulated L-689,502 inhibited virus production by up to three orders of magnitude. Our results indicate that liposomes may be useful for the delivery of HIV protease inhibitors with low aqueous solubility and low oral bio-availability, and for the targeting of these drugs to lymph nodes.
authors.affiliation: Department of Microbiology, School of Dentistry, University of the Pacific, San Francisco, CA 94115, USA.
authors.forename: E
authors.initials: E
authors.lastname: Pretzer
authors.forename: D
authors.initials: D
authors.lastname: Flasher
authors.forename: N
authors.initials: N
authors.lastname: Düzgüneş
mesh_terms: D002460:Cell Line; D004337:Drug Carriers; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008081:Liposomes; D008264:Macrophages / Q000821:virology*; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D015203:Reproducibility of Results; D013601:T-Lymphocytes / Q000821:virology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D004337:Drug Carriers; D017320:HIV Protease Inhibitors; D008081:Liposomes; D009025:Morpholines; D010455:Peptides; C072111:L 689502