POTENT AND SPECIFIC-INHIBITION OF HIV ENVELOPE-MEDIATED CELL-FUSION AND VIRUS BINDING BY G-QUARTET-FORMING OLIGONUCLEOTIDE (ISIS-5320)

We have previously reported identification of a phosphorothioate oligo nucleotide TTGGGGTT (ISIS 5320) as a potent inhibitor of HIV infection in vitro. The oligonucleotide forms a parallel-stranded, tetrameric g uanosine quartet (G-quartet) structure that specifically binds to the HIV envelope glycoprotein (gp120) and inhibits both cell-to-cell and v irus-to-cell infection at submicromolar concentrations. In the current study we demonstrate that the tetramer inhibits the infection of labo ratory-derived isolates of HIV-1 and HIV-2 in a variety of phenotypica lly distinct, established human cell lines and a panel of biologically diverse clinical isolates in fresh human peripheral blood lymphocytes and macrophages. The compound was also active against all drug-resist ant virus isolates tested. In combination with AZT, ISIS 5320 exhibits additive to slightly synergistic anti-HIV activity. Cell-based mechan ism of action studies demonstrate that the compound inhibits the bindi ng of infectious virus and virus-infected cells to uninfected target c ells by binding to the cationic V3 loop of the envelope glycoprotein. The G-quartet structure is a potential candidate for use in anti-HIV c hemotherapy.