NATIVE OLIGODEOXYNUCLEOTIDES SPECIFICALLY ACTIVE AGAINST HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 IN-VITRO - A G-QUARTET-DRIVEN EFFECT

Among a series of unmodified phosphodiester (PO)-oligodeoxynucleotides (PO-ODNs) complementary to some of the human immunodeficiency virus t ype 1 (HIV-1) regulatory genes, several PO-ODN sequences complementary to the vpr gene (PO-ODNs-a-vpr, where a-vpr is the antisense vpr sequ ence) emerged as potent inhibitors (at concentrations of 0.8 to 3.3 mu M) of HIV-1 multiplication in de novo infected MT-4 cells, while they showed no cytotoxicity for uninfected cells at concentrations up to 1 00 mu M Unlike phosphorothioate counterparts, PO-ODN-a-vpr sequences w ere not inhibitory to HIV-2 multiplication in de novo infected C8166 c ells and neither prevented the fusion between chronically infected and bystander CD4(+) cells nor inhibited the activity of the HIV-1 revers e transcriptase in enzyme assays. Moreover, they were not inhibitory t o HIV-1 multiplication in chronically infected cells. Delayed addition experiments showed that PO-ODNs-a-vpr inhibit an event in the HIV-1 r eplication cycle following adsorption to the host cell, but preceding reverse transcription. Structure-activity relationship studies indicat ed that the antiviral activity of the test PO-ODN-a-vpr sequences is n ot related to an antisense mechanism but to the presence, within the a ctive sequences, of contiguous guanine residues. Physical characteriza tion of the test PO-ODNs suggested that the active structure is a tetr amer stabilized by G quartets (i.e., four G residues connected by eigh t hydrogen bonds).