INHIBITION OF HIV-1 REPLICATION BY HYDROXYCHLOROQUINE - MECHANISM OF ACTION AND COMPARISON WITH ZIDOVUDINE

We have previously described the inhibition of human immunodeficiency virus serotype 1 (HIV-1) using the antimalarial hydroxychloroquine (HC C), a weak base that inhibits the posttranslational modification of gl ycoprotein 120 (gp120) in T cells and monocytes. The mechanism of inhi bition of gp120 production was presumed to be the ability of HCQ to in crease endosomal pH and therefore alter enzymes required for gp120 pro duction. To further clarify this action, we have determined the effect of HCQ and its enantiomers on endosomal pH. Pretreatment of cells wit h HCQ and the levo- and dextro-enantiomers at concentrations demonstra ted to suppress anti-HIV-1 activity increased endosomal pH to levels s imilar to increases seen with chloroquine and ammonium chloride, two o ther weak bases, and decreased gp120 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-infe cted T-cell and monocytic cell lines (63 and 63(HIV)). HCQ suppressed HIV-1 replication in a dose-dependent manner in both recently and chro nically infected T-cell and monocytic cell lines, In contrast, ZDV pre treatment had potent anti-HIV-1 activity in the newly infected T and m onocytic cells but, not in chronically infected cells. An additive eff ect of HCQ with ZDV was observed in the newly infected T and monocytic cells but not in the chronically infected cells. Although the anti-HI V-1 effect of HCQ was less than that of ZDV, HCQ may still be potentia lly useful either as an alternative HIV-1 treatment or in combination with other anti-HIV-1 agents, especially in patients who have rheumati c manifestations of HIV-1 infection.