A REV-INDUCIBLE MUTANT GAG GENE STABLY TRANSFERRED INTO T-LYMPHOCYTES- AN APPROACH TO GENE-THERAPY AGAINST HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 INFECTION

One strategy for somatic gene therapy for human immunodeficiency virus type 1 (HIV-1) infection is based on the regulated expression of domi nant negative mutants of the HIV-1 gag gene. To limit expression of th e mutant Gag polypeptide to HIV-1-infected cells, we have constructed a replication-defective retroviral vector that contains a Rev-responsi ve element. By using this construct we have obviated problems that can be associated with constitutive expression of an exogenous gene, an i mportant step toward developing a human therapy. In uncloned T lymphoc ytes infected (transduced) with this retroviral construct, HIV-1 repli cation was inhibited by 94% with a concomitant decrease in the cytopat hic effects of the virus. In addition, simian immunodeficiency virus ( SIV) replication was also shown to be significantly inhibited, suggest ing that this mutant Gag protein may have antiviral efficacy against a broad range of primate lentiviruses and that an SIV/macaque model can be used for further in vivo studies. These results have important imp lications in assessing the potential of somatic gene therapy in the tr eatment of HIV-1 infection.