THE MULTIPLE INHIBITORY MECHANISMS OF GEM 91(R), A GAG ANTISENSE PHOSPHOROTHIOATE OLIGONUCLEOTIDE, FOR HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1

GEM 91 (gene expression modulator) is a 25-mer oligonucleotide phospho rothioate complementary to the gag initiation site of HIV-1. GEM 91 ha s been studied in various in vitro cell culture models to examine inhi bitory effects on different stages of HIV-1 replication. Experiments w ere focused on the binding of virions to the cell surface, inhibition of virus entry, reverse transcription (HIV DNA production), inhibition of steady state viral mRNA levels, inhibition of virus production fro m chronically infected cells, and inhibition of HIV genome packaging w ithin virions. Experiments were also performed in vitro in an attempt to generate strains of HIV with reduced sensitivity to GEM 91, We obse rved sequence-dependent inhibition of virus entry/reverse transcriptio n and a reduction in steady state viral RNA levels, We also observed s equence-independent inhibition of virion binding to cells and inhibiti on of virus production by chronically infected cells, Using in vitro m ethods that were successful in generating HIV strains with reduced sen sitivity to AZT, we were unable to generate strains with reduced sensi tivity to GEM 91.