title: Selective endocytosis of fluorothymidine and azidothymidine coupled to LDL into HIV infected mononuclear cells.
abstract: Drug targeting via lipoproteins may be of benefit for use of cytotoxic drugs like fluorothymidine (FLT) or azidothymidine (AZT). Both drugs are potent inhibitors of the human immunodeficiency virus (HIV) reverse transcriptase and are used in the therapy of HIV infection. With regard to this project, the selective endocytosis in HIV infected human macrophages was studied after covalent coupling of AZT and LDL to low density lipoproteins (LDL). Cultured human macrophages and the lymphocytic Molt 4/8 cell line were infected with HIV-1 in vitro and subsequently treated with FLT-LDL or AZT-LDL. Viral replication was followed by determination of cell-released capsid antigen p24. Internalisation into HIV-1 infected human macrophages by the scavenger receptor pathway leads to a dose dependent inhibition of HIV replication. Otherwise, in HIV infected, but scavenger receptor missing lymphocytes (Molt 4/8 cells), neither endocytosis nor inhibition of HIV replication results. Thus, covalent coupling of drugs to LDL leads to a macrophage specific transport. This strategy could possibly avoid toxic side effects in the therapeutic use of antiretroviral drugs and thus may open a way for an earlier chemotherapy in HIV infection.
authors.affiliation: Institut für Biochemie, Fachbereich Chemie, Freie Universität Berlin, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Mankertz
authors.forename: E
authors.initials: E
authors.lastname: Matthes
authors.forename: K
authors.initials: K
authors.lastname: Rokos
authors.forename: H
authors.initials: H
authors.lastname: von Baeyer
authors.forename: G
authors.initials: G
authors.lastname: Pauli
authors.forename: E
authors.initials: E
authors.lastname: Riedel
mesh_terms: D002478:Cells, Cultured; D015224:Dideoxynucleosides / Q000008:administration & dosage* / Q000737:chemistry; D004705:Endocytosis; D015658:HIV Infections / Q000188:drug therapy*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000382:microbiology*; D008077:Lipoproteins, LDL / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D015224:Dideoxynucleosides; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D054303:HIV Reverse Transcriptase; C002854:alovudine