AJOENE BLOCKADE OF INTEGRIN-DEPENDENT PRO CESSES IN THE HIV-INFECTED CELL SYSTEMS

Ajoene, (E,Z)-4,5,9-trithiadodeca-1,6,11-triene-9-oxide, isolated from extracts of garlic (Allium sativum) has been previously shown to inhi bit platelet aggregation by inactivating allosterically the platelet i ntegrin, GP IIb/IIIa. The structural and functional similarity of inte grins led the authors to suggest that ajoene may also inhibit adhesive interactions and fusion of leukocytes. Synthetic stereoisomers of ajo ene synthesized by the authors exhibited equal antiaggregatory activit ies (IC100 is similar to 50muM for platelets; IC100 is similar to 10 m uM for fMLP-stimulated neutrophils). Racemic ajoene inhibited the fusi on of H9 cells with HIV-infected H9:RF cells (IC50-45 muM; 16 h of inc ubation) and also exhibited a degree of antiviral activity (IC50 is si milar to 5 muM as assessed by inhibition of HIV-1/CEM/Lav 1 Bru replic ation in CEM13 cells; m. o. i. 0.1; 72 h). A considerabte increase in the latter became evident when the compound was administered in aliquo ts of 50 muM per 12 h of incubation (inhibition by 30%; total concentr ation 0,25 muM; 72 h). It is concluded that: (a) integrin-inactivating properties of abjoene are not restricted to inhibition of GP IIb/III- mediated processes in platelets, since the compound ''mimics'' the eff ects of anti-integrin mAbs in 3 distinct cell types, including HIV-inf ected T lymphoblasts; (b) inhibition of HIV-mediated syncytla formatio n by ajoene lends further support to the concept of critical involveme nt of integrins in cell fusion; (c) antiviral activity of ajoene may p oint to the existence of an alternative mechanism of HIV entry (integr in-mediated, CD4-independent pathway); (d) administration of ajoene (p ossibly in combination with conventional anti-HIV drugs) might become a promising approach to the treatment of AIDS.