INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 TRANSCRIPTION AND REPLICATION BY DNA SEQUENCE-SELECTIVE PLANT LIGNANS

A plant lignan, 3'-O-methyl nordihydroguaiaretic acid (3'-O-methyl NDG A, denoted Malachi 4:5-6 or Mal.4; molecular weight 316), was isolated from Larrea tridentata and found to be able to inhibit human immunode ficiency virus (HIV) Tat-regulated transactivation in vivo, induce pro tection of lymphoblastoid CEM-SS cells from HIV (strain IIIB) killing, and suppress the replication of five HIV-1 strains (WM, MN, VS, JR-CS F, and IlI(B)) in mitogen-stimulated peripheral blood mononuclear cell s, all in a dose-dependent manner. Mal.4 inhibits both basal transcrip tion and Tat-regulated transactivation in vitro. The target of Mal.4 h as been localized to nucleotides -87 to -40 of the HIV long terminal r epeat, Mal.4 directly and specifically interferes with the binding of Spl to Spl sites in the HIV long terminal repeat, By inhibiting provir al expression, Mal.4 may be able to interrupt the life cycles of both wild-type and reverse transcriptase or protease mutant viruses in HIV- infected patients.