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M94A3216.TXT
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Document 3216
DOCN M94A3216
TI Activating effects of dioxin on HIV-1 in human CD4+ lymphoid cells.
DT 9412
AU Tsyrlov IB; Pokrovsky AG; NCI/NIH, Bethesda, MD 20892.
SO Int Conf AIDS. 1994 Aug 7-12;10(1):127 (abstract no. PA0126). Unique
Identifier : AIDSLINE ICA10/94369359
AB 2,3,7,8-TCDD (dioxin) and dioxin-like compounds are widely known because
of their potential toxicity, including immunological disturbance the
mechanism of which is still unknown. Here, effects of dioxin were
assessed in regard to a marker enzyme CYP1A1 and HIV-1 genes. Dioxin and
HIV-1 both affect the same target cells, i.e. human CD4+ lymphocytes.
Induction with 1.0 nM dioxin of CYP1A1 activity was demonstrated. It was
also shown that 1.0 nM dioxin was a potent activator of HIV-1 reverse
transcriptase in CD4+ cells, i.e. there was 3- to 6-fold increase of
enzyme activity. As for viral protein, its content estimated by ELISA in
dioxin-treated CD4+ cells was 4-8-fold greater than in control group. In
this study we found also that several polycyclic hydrocarbons stimulated
in CD4+ cells the CYP1A1 activity and HIV-1 production. The decisive
problem of AIDS desease is what are the factors responsible for
transformation of HIV-positive patients to clinical manifestation, and
the mechanisms participating in this transformation. The results
obtained here indicate that even 1.0 nM dioxin had a marked stimulatory
effect on HIV-1 production in primary HIV-infected CD4+ cells. As the
same concentration of dioxin caused the Ah receptor-mediated induction
of CYP1A1, it allowed to suggest that intracellular receptor-ligand
complex is also involved in trans-activation of HIV-1 gene. In most
cases known, a trans-activation of the HIV-1 gene is a decisive step in
the regulation of its reproduction. The Ah receptor is a regulatory
protein participating in trans-activation of Cyp1a1 gene expression.
Although requiring experimental verification, a suggestion seems logical
on a similar mechanism involved in activation of HIV-1 gene by dioxin.
If this is the case, an effective competitor with dioxin (or
benzo[a]pyrene in tabacco smoke) for the Ah-receptor could be checked.
Using the model described, we have tested some natural flavonoids, which
are shown to compete with dioxin for the Ah-receptor, as potential
anti-HIV drugs.
DE Comparative Study Cytochrome P-450/BIOSYNTHESIS Dioxins/*PHARMACOLOGY
Enzyme Activation Enzyme-Linked Immunosorbent Assay Gene Expression
Regulation, Viral/DRUG EFFECTS Genes, Viral Human HIV-1/DRUG
EFFECTS/*GROWTH & DEVELOPMENT/METABOLISM Reverse
Transcriptase/METABOLISM Trans-Activation (Genetics) T4
Lymphocytes/*MICROBIOLOGY/PHYSIOLOGY Viral
Proteins/ANALYSIS/BIOSYNTHESIS Virus Activation/*DRUG EFFECTS MEETING
ABSTRACT
SOURCE: National Library of Medicine. NOTICE: This material may be
protected by Copyright Law (Title 17, U.S.Code).