INHIBITION OF HIV-1 REPLICATION BY A TAT RNA-BINDING DOMAIN PEPTIDE ANALOG

The peptidic compound, rg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Cys(biotin)- NH2 (Tat10-biotin), contains-the 9-amino acid sequence from the basic domain or the Tat protein responsible for specific interaction with TA R RNA. The cysteine residue provides an attachment site for biotin, wh ich acts as a cellular uptake enhancer. Tat10-biotin binds a fragment of TAR RNA (Delta TAR) avidly and specifically, as measured in an elec trophoretic gel shift assay. Tat10-biotin inhibited tar gene-induced e xpression of a stably transfected chloramphenicol acetyl transferase ( CAT) reporter gene linked to the HIV-1 long terminal repeat (LTR) in a model cell assay, but did riot inhibit phorbol ester-induced expressi on of CAT, thereby demonstrating a Tat-dependent mechanism of inhibiti on, Inhibition of HIV-I replication after acute infection of MT2 cells was demonstrated by absence of HN-induced syncytium formation and cyt otoxicity, as well as by suppression of reverse transcriptase producti on. These results suggest that a peptide or peptide mimetic capable of competing with the TAR RNA-binding domain of Tar protein might be use ful as a therapeutic agent for AIDS.