       Document 0535
 DOCN  M9630535
 TI    A Tat-induced auto-up-regulatory loop for superactivation of the human
       immunodeficiency virus type 1 promoter.
 DT    9603
 AU    Biswas DK; Salas TR; Wang F; Ahlers CM; Dezube BJ; Pardee AB; Division
       of Cell Growth and Regulation, Dana-Farber Cancer; Institute, Boston,
       Massachusetts 02115, USA.
 SO    J Virol. 1995 Dec;69(12):7437-44. Unique Identifier : AIDSLINE
       MED/96078986
 AB    The virus-encoded Tat protein strongly activates transcription of human
       immunodeficiency virus (HIV). A well-recognized mechanism involves
       interaction of Tat with the nascent RNA transcript of the viral tar
       gene; mutation of tar greatly decreases activation by Tat. However, Tat
       still provides a low level of activation, demonstrating that it also has
       a tar-independent mode of action. We propose that this tar-independent
       mode of Tat action is through activation of gene transcription to
       produce tumor necrosis factor alpha. This cytokine and other compounds
       that activate NF-kappa B up-regulate the HIV promoter at a low level,
       similarly to the second Tat action. Through this mechanism, they also
       activate promoters of tumor necrosis factor alpha and other cytokines
       and thereby establish an auto-up-regulatory loop. Activated NF-kappa B
       motifs in the HIV promoter synergize with Tat/tar. Mutations of these
       motifs decrease activation by Tat to a few percent of the wild-type
       value. In cooperation, the two modes of activation by Tat (tar dependent
       and cytokine based) set up positive up-regulatory loops which greatly
       superactivate transcription of HIV. Agents that block these synergistic
       pathways at three different steps and are more inhibitory in combination
       than is any one alone have been found. Thereby, multidrug modalities for
       transcription of HIV are proposed for virus suppression.
 DE    Base Sequence  Cell Line  Cytokines/*BIOSYNTHESIS/METABOLISM  Gene
       Expression  *Gene Expression Regulation, Viral  Gene Products,
       tat/*METABOLISM  Human  *HIV Long Terminal Repeat  HIV-1/*GENETICS
       Interleukin-1/BIOSYNTHESIS  Interleukin-6/BIOSYNTHESIS  Kinetics
       Molecular Sequence Data  Mutagenesis  NF-kappa B/METABOLISM
       Oligodeoxyribonucleotides  *Promoter Regions (Genetics)  RNA,
       Viral/BIOSYNTHESIS/METABOLISM  Support, Non-U.S. Gov't  Transcription,
       Genetic  Transfection  Tumor Cells, Cultured  Tumor Necrosis
       Factor/BIOSYNTHESIS  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

