NOVEL GUANOSINE QUARTET STRUCTURE BINDS TO THE HIV ENVELOPE AND INHIBITS ENVELOPE MEDIATED CELL-FUSION

We have identified a phosphorothioate oligonucleotide T(2)G(4)T(2), which is a potent inhibitor of HIV infection in vitro. The compound was identified by combinatorial screening of a library of all possible octanucleotide sequences. The oligonucleotide forms a parallel-stranded, tetrameric guanosine-quartet (G-quartet) structure which specifically binds to the HIV envelope glycoprotein (gp120) and inhibits both cell-to-cell and virus-to-cell infection at submicromolar concentrations. In the current study we demonstrate that the tetramer inhibits the infection of laboratory-derived isolate of HIV-1 and HIV-2 in a variety of phenotypically 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-resistant virus isolates tested. In combination with AZT, ISIS 5320 exhibits additive to slightly synergistic anti-HIV activity. Cell-based mechanism of action studies demonstrate that the compound inhibits the binding of infectious virus and virus-infected cells to uninfected target cells by binding to the cationic V3 loop of the envelope glycoprotein. The G-quartet structure is a potential candidate for use in anti-HIV chemotherapy.