INHIBITION OF HIV-1 REPLICATION BY COMBINATION OF A NOVEL INHIBITOR OF TNF-ALPHA WITH AZT

The small molecule S9a was derived from an established tumor necrosis factor-alpha (TNF-alpha) inhibitor (Canventol) by replacement of the i sopropylidine group with a phenyl ring. S9a at 10 to 100 nM inhibited HIV production as potently as 3'-azido-3'-deoxythymidine (AZT), an inh ibitor of viral reverse transcriptase. Further more, S9a and AZT in co mbination, at noncytoxic concentrations strongly inhibited HIV-1 repli cation that was more than additive and substantially prolonged the app earance of virus both in acutely infected CD4(+) lymphocytes (SupT) in culture and in peripheral blood mononuclear cells (PBMCs) infected wi th a primary HIV-I isolate. S9a inhibited TNF-alpha promoter-driven re porter gene activity. It was proposed that the mechanism of antiviral action of S9a war; on the host cell, by blocking TNF-alpha transcripti on via a Tat-induced tar-independent loop, which decreases downstream NF-kappa B activation of HIV-1 long terminal repeat (LTR), S9a was sup erior to the first generation compound Canventol, which was superior t o the natural compound sarcophytol A, demonstrating that further struc ture-based enhancement of potency of these compounds is feasible. This study suggests a therapeutic approach against AIDS by application of tyro drugs, one against a cellular and the other a viral target, which may provide an approach to the problem of frequent emergence of resis tant variants to combinations of drugs that target only HIV-genes.