ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ACTIVITY OF AN OLIGOCATIONICCOMPOUND MEDIATED VIA GP120 V3 INTERACTIONS

An oligocationic peptide compound (ALX40-4C) was developed for conside ration in the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This compound was designed to mimic the basic domain of th e HIV-1 transactivation protein, Tat, and will competitively,inhibit T at binding to its specific RNA hairpin target (TAR [transactivation re gion]), found at the 5' end of all HIV-1 transcripts. Blocking Tat-TAR interactions can abrogate HIV-1 replication. ALX40-4C was shown to in hibit replication of HIV-1(NL4-3) in a range of cell types, including primary cells and transformed cell lines, by as much as 10(4)-fold. In some experiments, virus rescue was not possible even after removal of ALX40-4C from the cultures. Strain-dependent resistance has been demo nstrated for all antiretroviral agents tested; therefore, we tested fo r variable sensitivity to ALX40-4C. The cloned primary strains, HIV-1( JR-CSF) and HIV-1(JR-FL,) ALX40-4C inhibition. Unexpectedly, determina nts for efficient ALX40-4C inhibition were mapped by using recombinant virus strains to the V3 region of gp120 and were shown to act at earl y events in viral replication, which include viral entry. If entry and reverse transcription are bypassed by transfection, a more modest, vi rus strain-independent inhibition is shown; this inhibition is likely due to blocking of Tat-TAR interaction.'Thus, the highly basic oligoca tionic Tat inhibitor ALX40-4C appears to interfere with initial virus- target cell interactions which involve HIV-1 gp120 V3 determinants, mo st efficiently for T-cell line-adapted strains.