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1994-10-25
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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).