Document 3243
 DOCN  M94A3243
 TI    Analysis of the cellular transduction pathways regulating HIV genome
       transcription as potential targets for antiviral therapy. European
       Communities Concerted Action.
 DT    9412
 AU    Virelizier JL; Arenzana F; Alcami J; Hay RT; Moscat J; Institut Pasteur,
       Paris, France.
 SO    Int Conf AIDS. 1994 Aug 7-12;10(1):120 (abstract no. PA0101). Unique
       Identifier : AIDSLINE ICA10/94369332
 AB    Presently available anti-HIV chemotherapies are mostly aimed at blocking
       HIV reverse transcriptase (RT) activity. However, as soon as the HIV
       genome is integrated into host cell DNA, such mechanism of action cannot
       suppress virus replication. Blocking transcription of integrated HIV
       provirus would be expected to synergise with anti-RT drugs, provided
       that the cellular mechanism(s) targeted would be sufficiently narrow to
       permit anti-viral, but not (or acceptable) anti-cellular effects. The
       European research network set up to tackle this problem (the ROCIO
       project, BIOMED programme) has shown that p21 ras-dependent transduction
       pathways reactivate HIV transcription through activation of
       phosphatidylcholine hydrolysis (PC-PLC-dependent) and a peculiar isoform
       of protein kinase C (zeta-PKC). PKC zeta blockade by pseudo-substrate
       peptides in Xenopus Oocytes, or by transdominant negative vectors in
       mammal cells blocked TNF-induced NF-kappa B and HIV enhancer activation.
       Further regulation occurs in the nucleus, where reduction of a disulfide
       bound in the p50 subunit enhances NF-kappa B binding activity by
       Thioredoxin to the HIV enhancer. In addition, I kappa B alpha opposes
       the transactivating effects of NF-kappa B on the HIV enhancer. Specific
       blockade of the activity of one or more molecules involved in this
       transduction pathway is expected to be an efficient way to block HIV
       reactivation in infected, resting CD4 lymphocytes, where we found that
       NF-kappa B activity is sine qua non for both transcription initiation
       and HIV Tat amplification of HIV LTR activation.
 DE    Animal  *Antiviral Agents  Drug Design  Enhancer Elements (Genetics)
       Female  *Gene Expression Regulation, Viral  Gene Products,
       tat/BIOSYNTHESIS  Genome, Viral  Human  HIV/*GENETICS/*METABOLISM  HIV
       Long Terminal Repeat  Isoenzymes/METABOLISM  NF-kappa B/BIOSYNTHESIS
       Oocytes/PHYSIOLOGY  Phosphatidylcholines/METABOLISM  Phospholipase
       C/METABOLISM  Protein Kinase C/METABOLISM  Proto-Oncogene Protein
       p21(ras)/METABOLISM  *Signal Transduction  *Transcription, Genetic
       Xenopus  MEETING ABSTRACT

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