AJOENE BLOCKADE OF INTEGRIN-DEPENDENT PROCESSES 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 inhibit platelet aggregation by inactivating allosterically the platelet integrin, GP IIb/IIIa. The structural and functional similarity of integrins led the authors to suggest that ajoene may also inhibit adhesive interactions and fusion of leukocytes. Synthetic stereoisomers of ajoene synthesized by the authors exhibited equal antiaggregatory activities (IC100 is similar to 50muM for platelets; IC100 is similar to 10 muM for fMLP-stimulated neutrophils). Racemic ajoene inhibited the fusion of H9 cells with HIV-infected H9:RF cells (IC50-45 muM; 16 h of incubation) and also exhibited a degree of antiviral activity (IC50 is similar to 5 muM as assessed by inhibition of HIV-1/CEM/Lav 1 Bru replication in CEM13 cells; m. o. i. 0.1; 72 h). A considerabte increase in the latter became evident when the compound was administered in aliquots of 50 muM per 12 h of incubation (inhibition by 30%; total concentration 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 effects of anti-integrin mAbs in 3 distinct cell types, including HIV-infected T lymphoblasts; (b) inhibition of HIV-mediated syncytla formation by ajoene lends further support to the concept of critical involvement of integrins in cell fusion; (c) antiviral activity of ajoene may point to the existence of an alternative mechanism of HIV entry (integrin-mediated, CD4-independent pathway); (d) administration of ajoene (possibly in combination with conventional anti-HIV drugs) might become a promising approach to the treatment of AIDS.