ANTISENSE OLIGODEOXYNUCLEOTIDE PHOSPHOROTHIOATE COMPLEMENTARY TO GAG MESSENGER-RNA BLOCKS REPLICATION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 IN HUMAN PERIPHERAL-BLOOD CELLS

Gene-expression modulator 91 (GEM91) is a 25-nt antisense oligodeoxynu cleotide phosphorothioate complementary to the Gag mRNA of human immun odeficiency virus type 1 (HIV-1). Cellular uptake and intracellular di stribution of GEM91 within cells suggest that this oligomer is readily available for antisense activity. GEM91 inhibited HIV-1 replication i n a dose-dependent and sequence-specific manner. In a comparative stud y, 2 mu M GEM91 was as effective as 5 mu M 3'-azido-3'-deoxythymidine in blocking virus replication during the 28-day treatment of an HIV-1- infected T-cell line. GEM91 also completely inhibited (> 99%) the grow th of three different HIV-1 isolates in primary lymphocytes and preven ted the cytopathic effect of the virus in primary CD4(+) T cells. Simi larly, treatment with GEM91 for 3 weeks of HIV-1/BaL-infected primary macrophages blocked virus replication. Based on GEM91 anti-HIV-activit y, safety, and pharmacokinetic profile in animals, a clinical trial wa s started using this compound as an antisense oligonucleotide drug for the treatment of the acquired immunodeficiency syndrome.