ANTIVIRAL AND BIOLOGICAL PROPERTIES OF DIMETHOXYTRITYL-LINKED GUANINE-RICH OLIGODEOXYNUCLEOTIDES THAT INHIBIT REPLICATION BY PRIMARY CLINICAL HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ISOLATES

We have investigated the biological and antiviral properties of a dime thoxytrityl (DmTr)-linked guanine (G)-rich oligodeoxynucleotide (ODN) with a phosphodiester linkage, SA-1042 (5' DmTr-TGGGAGGTGGGTCTG 3'), t hat has been shown to exhibit potent inhibition of human immunodeficie ncy virus type 1 (HIV-l)-induced cytopathic effect. In a study of the modification of the sequences of SA-1042, it was revealed that the inh ibitory effect is exhibited in a highly sequence-specific manner, at t he G-rich core sequence (5' TGGG 3'), especially near the 5' end. In a study of the gel mobility-antiviral activity relationship, DmTr modif ication and the G-rich core sequence of DmTr-ODNs were indispensable f or the Formation of a hyperstructure and for their antiviral activity. HIV-induced syncytium formation in co-cultures of MOLT-4 cells and ch ronically infected MOLT-4/HIV-1(IIIB) cells was blocked by SA-1042 at a 50% inhibitory concentration (IC50) of 6.5 mu g ml(-1). Time-of-addi tion studies revealed that SA-1042 blocked virus attachment to cells. The susceptibility of 10 fresh HIV-1 clinical isolates [nine with sync ytium-inducing (SI) phenotypes and one with a non-SI phenotype], and f ive laboratory strains with both phenotypes to SA-1042 was assessed by a focus reduction assay using CD4(+) Hela cells or by p24 antigen qua ntitative assay using human peripheral blood mononuclear cells. SA-104 2 was active in both assays. These results suggest that SA-1042, which inhibits the adsorption and fusion steps of HIV-1 replication through its hyperstructure formation and the G-rich core sequence, exhibits p otent activity against primary clinical isolates.