title: Inhibition of HIV-1 replication by hydroxychloroquine: mechanism of action and comparison with zidovudine.
abstract: We have previously described the inhibition of human immunodeficiency virus serotype 1 (HIV-1) using the antimalarial hydroxychloroquine (HCQ), a weak base that inhibits the posttranslational modification of glycoprotein 120 (gp 120) in T cells and monocytes. The mechanism of inhibition of gp 120 production was presumed to be the ability of HCQ to increase endosomal pH and therefore alter enzymes required for gp120 production. To further clarify this action, we have determined the effect of HCQ and its enantiomers on endosomal pH. Pretreatment of cells with HCQ and the levo- and dextro-enantiomers at concentrations demonstrated to suppress anti-HIV-1 activity increased endosomal pH to levels similar to increases seen with chloroquine and ammonium chloride, two other weak bases, and decreased gp 120 production. The dextro- and levo-enantiomers suppressed HIV-1 replication to a similar extent and were no more toxic than racemic HCQ. We next compared the anti-HIV-1 effect of HCQ with zidovudine (ZDV) in both newly and chronically HIV-1-infected T-cell and monocytic cell lines (63 and 63HIV). HCQ suppressed HIV-1 replication in a dose-dependent manner in both recently and chronically infected T-cell and monocytic cell lines. In contrast, ZDV pretreatment had potent anti-HIV-1 activity in the newly infected T and monocytic cells but not in chronically infected cells. An additive effect of HCQ with ZDV was observed in the newly infected T and monocytic cells but not in the chronically infected cells. Although the anti-HIV-1 effect of HCQ was less than that of ZDV, HCQ may still be potentially useful either as an alternative HIV-1 treatment or in combination with other anti-HIV-1 agents, especially in patients who have rheumatic manifestations of HIV-1 infection.
authors.affiliation: Division of Clinical Immunology.
authors.forename: G
authors.initials: G
authors.lastname: Chiang
authors.forename: M
authors.initials: M
authors.lastname: Sassaroli
authors.forename: M
authors.initials: M
authors.lastname: Louie
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: V J
authors.initials: VJ
authors.lastname: Stecher
authors.forename: K
authors.initials: K
authors.lastname: Sperber
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology*; D002455:Cell Division; D002460:Cell Line; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000096:biosynthesis / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006886:Hydroxychloroquine / Q000494:pharmacology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000473:pathology / Q000821:virology; D009000:Monocytes / Q000187:drug effects / Q000473:pathology / Q000821:virology; D011233:Precipitin Tests; D012367:RNA, Viral / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology / Q000821:virology; D014779:Virus Replication / Q000187:drug effects* / Q000502:physiology; D015215:Zidovudine / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D000962:Antimalarials; D015699:HIV Envelope Protein gp120; D012367:RNA, Viral; D015215:Zidovudine; D006886:Hydroxychloroquine; D054303:HIV Reverse Transcriptase