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Dioxin: a potential AIDS co-factor
Thanks to my colleague Pat Costner, we have this information on
dioxin and AIDS:
Four years ago, a relationship between AIDS and dioxin exposure
was postulated in the following paper:
Source: C. Pokrovsky, A. Cherykh, O.N. Yastrebova, and I.B.
Tsyrlov. 2,3,7,8-Tetrachlorodibenzo-p-dioxin as a Possible
Activator of HIV Infection. Biochemical and Biophysical Research
Communications, Vol. 179, No. 1, August 30, 1991, pp. 46-51
The primary observation made in this study is as follows:
"Furthermore, in MT-4 cell culture infected by HIV-1 virus an
increase of virus production after a treatment of cells with
2,3,7,8-TCDD has been revealed.
During the same year, Arnold Schecter published the following
study, in which he reported elevated levels of dioxins and
dibenzofurans, known immunosuppressants, in clinically
symptomatic AIDS patients as compared with asymptomatic but
human immunodeficiency virus (HIV)-infected patients who had
below-average dioxin levels:
Source: Schecter, A.J., Poiesz, B.J., Brandt-Rauf, P.W., Papke,
O., and Ball, M. Dioxin levels in blood of AIDS patients and
controls. Med. Sci. Res. 19:273-275 (1991).
Last year, the following article appeared in Science News:
Source: Raloff, J. AIDS progression fostered by dioxin?
Science News 147 (14):214. 1995
Smokers infested with HIV-1 tend to develop AIDS more quickly
than nonsmokers. Some scientists have also observed that
dioxinlike compounds foster the proliferation of this AIDS
virus in cultured cells. New research offers one possible
explanation for both findings.
It shows that HIV-1 possesses a hitherto unrecognized docking
site for a cellular protein to which dioxins and many other
toxic compounds bind. When this protein binds with a
pollutant and the resulting complex links with the virus, it
activates HIV's genes.
TCDD, the most toxic dioxin, and a number of related compounds
all bind to this protein, known as the Ah (aryl hydrocarbon)
receptor, which resides in the liquid interior of cells. The
binding of a pollutant to this receptor initiates a
transformation that suddenly renders the duo capable of
entering a cell's nucleus, where they can inappropriately turn
genes on or off.
In the April "Environmental Health Perspectives," researchers
at the University of Cincinnati Medical Center report finding
a binding site for the Ah receptor in the portion of HIV's
genetic material where regulatory proteins bind to activate
viral genes -- an area called the long-terminal repeat.
To gauge the receptor's importance, they inserted a bacterial
gene known as CAT into that long-terminal repeat as a genetic
flag. They then infected mouse liver cells with the modified
HIV and monitored the extent to which the virus turned CAT on
when the cells were exposed to a range of toxicants.
Benzo(a)pyrene,a carcinogen present in cigarette smoke, and
aflatoxin B1, a fungal poison, both quintupled CAT activity
over the level seen in unstimulated cells or cells exposed to
the solvent used to deliver the pollutants. TCDD and three
combustion by-products doubled or tripled CAT activity.
But none of the compounds affected the activity of CAT in a
mutant form of HIV lacking the Ah receptor binding site or in
cells protected against reactive, biologically molecular
fragments known as free radicals (for their free, or unpaired,
Those follow-up experiments confirm that both the receptor
binding site and free radicals must be present in the cell for
the activation of HIV by these types of pollutants, explains
Alvaro Puga, who led the studies.
How important are these compounds to AIDS? That will depend
on which cells host the virus, Puga says -- specifically,
whether they have Ah receptors and can foster the free radicals
needed to cause damage.
Portions of the original journal article appear below:
Yao, Y., Hoffer, A., Chang, C., and Puga, A. Dioxin Activates
HIV-1 Gene Expression by an Oxidative Stress Pathway Requiring a
Functional Cytochrome P450 CYP1A1 Enzyme. Environ. Health
Perspect. 103(4): 366-371, 1995
We have studied the effect of several environmental chemicals
on the transient expression of a chloramphenicol
acetyltransferase (cat) reporter gene linked to the promoter
sequences in the long terminal repeat (LTR) of the human
immunodeficiency virus type 1 (HIV-1). Aflatoxin b1, 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD; dioxin) and benzo[a]pyrene
cause a significant increases in CAT expression in mouse
hepatoma Hepa-1 cells. The induction of CAT after TCDD
treatment is abolished by administration N-acetyl-L-cysteine
or 2-mercaptoethanol and does not take place in a mutant cell
line that lacks CYP1A1 enzymatic activity. Linker-scanning
mutational analysis of transcription factor binding sites in
the promoter revealed that both the NFkB and an adjacent
aromatic hydrocarbon response element (AhRE) are required for
TCDD-dependent CAT expression. In addition, mutation of the
NFAT/AP-1 binding sites in the negative regulatory region of
the promoter increases the magnitude of the TCDD effect. We
conclude that induction of a functional CYP1A1 monooxygenase
by TCDD stimulates a pathway that generates thiol-sensitive
reactive oxygen intermediates which, in turn, are responsible
for the TCDD-dependent activation of genes linked to the LTR.
These data might provide an explanation for findings that TCDD
increases infectious HIV-1 titers in experimental systems and
for epidemiologic reports suggesting that exposure to aromatic
hydrocarbons, such as found in cigarette smoke, is associated
with an acceleration in AIDS progression.
Halogenated aromatic hydrocarbons such as 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD; dioxin) cause a profusion
of apparently unrelated toxic effects in which the single
common denominator is the aromatic hydrocarbon receptor-
mediated transcriptional activation of the cytochrome P450
CYP1A1 gene (1-6). In humans, exposure to dioxin and various
other chlorinated phenolic agents causes chloracne, a long-
lasting skin disease characterized by the hyperkeratinization
of follicular sebocytes (7,8). In addition, recent long-term
epidemiological studies have established a link between
exposure to high dose of TCDD and certain types of cancers
(9,10). Dioxin is one of the strongest tumor promoters ever
tested in animal model systems; it causes an elevated
incidence of hepatic carcinoma and pulmonary and skin tumors
(11-13) and promotes tumor formation at one-hundredth the dose
of the classical tumor promoter 12-)-tetradecanoylphorbol-13-
acetate (TPA) in the skin of hairless mice (14-16). During
rodent embyogenesis, TCDD administration also causes
craniofacial abanormalities such as cleft palate and
hydronephrosis (17-20). Characteristic events of secondary
palate formation, such as osteoblast differentiaion and
synthesis and mineralization of extracellular matrix, are
inhbited by TCDD (21). Unlike in whole animal studies, TCDD
has no toxic effect in tissue culture cells,although it causes
an elevation of intracellular calcium, which induced decreased
[ eta]-adrenergic responsiveness in cardiac myocytes (22,23),
and causes apoptosis of immature thymocytes (224,25). In this
regard, the developing immune sytem is a particularly
sensitive target for TCDD, with thymic atrophy being the most
common pathological consequence of exposure (26).
The results that we present in this article indicate that
TCDD, aflatoxin B1, and several polycyclic aromatic
hydrocarbons (PAHs) can significantly activate the expression
of genes linked to the LTR sequences of HIV-1. ... In the
case of TCDD, stimulated values are significantly higher than
control values, although they do not usually exceed them by
more than 2.5- to 3-fold. This stimulation is in agreement
with observations by others that TCDD can cause an increase of
infectious HIV-1 titers in experimental systems (43,44). As
for PAHs, the highest levels of CAT activation that we
observed were a result of BaP treatment, a finding that may
provide a possible molecular explanation for the observation
that cigarette smoking accelerates the progression of AIDS
(45-48). It is, of course, likely that the effect of cigarett
smoke on AIDS progressionr esults from a hwich gene activation by BaP is
Surprisingly, DBA had no effect on CAT expression, a finding
that we cannot explain at present.
In conclusion, our data are consistent with a signal
transduction mechanism that includes at least two different
TCDD-dependent pathways. On one hand, activation of the Ah
receptor triggers expression mediated by the AhRE site present
in the LTR. On the other hand, TCDD induction of a funcitonal
CYP1A1 monooxygenase stimulates generation of thiol-sensitive
reactive oxygen species, which in turn activate transcription
factors operative in LTR-direct expression. We find that, in
addition to TCDD, several other toxic environmental chemicals
can activate expression of the HIV-1 promoter-enhancer
sequences, underscoring the important that exposure to these
compounds might have in the progression of AIDS.
Source: Tsyrlov, I.B., and Pokrovsky, A. Stimulatory effect of
the CYP1A1 inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin on the
reproduction of HIV-1 in human lymphoid cell culture.
Xenobiotica 23 (4):457-467, 1993
1. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was an inducer
of microsomal benzo[a]pyrene hydroxylase (AHH) and 7-
ethoxyresorulin O-diethylase (EROD) in MT-4 human lymphoid
2. The monoclonal antibody (Mab), 1-7-1, and the
immunodepleted polyclonal antibody (Pab), anti-CYP1A1(-A2),
inhibit AHH and EROD activities pre-induced by 10 nM TCDD in
MT-4 cells. Hence, the specific monoxygenase isoform induced
in the lymphoid cells by TCDD appears to by CYP1A1 the
expression of which is mediated by the Ah receptor.
3. Incubation of MT-4 cells with TCDD at 10, 50 and 150 nM
for 1-5 and 48 h followed by infection of the cells with ht8)n
immunodeficiency virus 1 (HIV-1) was accompanied by a 3 6 fold
increase in the activity of viral RNA-dependent DNA-
polymerase. The most marked effect on reverse transcriptase
activity occurred with 10 nM TCDD 5-9 days after HIV-1
4. In the same period there was accumulation of vital
protein, determined by ELISA, with a 4 8-fold increase in
production of viral protein. The above effects of TCDD have
been observed even when MT-4 cells were washed 1-5 h after
beginning incubation with TCDD.
During the past three decades, chlorinated aromatic
hydrocarbons have generated a marked concern for safety,
because of their widespread occurrence in the environment and
their potential toxicity. The prototypical agent, TCDD,
produces in experimental animals and man diverse set of
biological responses, including modulation of the microsomal
monooxygenases and changes in the immunological response
(Whitlock 1987, Silbergeld and Gasiewicz 1989, Tsyrlov 1990).
The mechanism of the immunomodulatory action of TCDD is
The development of immunodeficiency in the acquired
immunodeficiency syndrome (AIDS) has been associated wit8).
... This confirms the results of others who have shown that
TCDD was a much more potent inducer of CYP1A1 than any other
polycyclic aromatic hydrocarbon (Poland and Glover 1974,
Durrin et al. 1987).
The results obtained indicate that TCDD had a marked
stimulatory effect on HIV-1 production in primary HIV-infected
cells. This was in agreement with the results of Schecter et
al. (1991) who found higher levels of polychlorinated dibenzo-
p-dioxins and dibenzofurans in the blood of AIDS patients with
opportunistic infections than found in HIV-positive patients
with no clinical manifestation.
It is noteworthy that, in spite of the greatly increased
expression of the viral proteins and reverse transcriptase
activity, the percentage of viable cells in the TCDD-treated
culture was unaltered compared with untreated control,
remaining as high as 60%.
Activation of HIV infection may be effected by chemicals
(Bohan et al. 1987), and proteins and viruses (Rando et al.
1987, Nabel 1988, Seto et al. 1988, Zack et al. 1988).
The activation effect of TCDD on HIV-1 production might be
explained by the binding of TCDD to the Ah receptor in MT-4
cells, because the removal of free TCDD did not interfere with
the activation effect observed (figures 3-5).
One possibility is that the effect of TCDD could be associated
with the influence of products of the expression of a gene (or
genes) on the regulatory proteins of HIV-1, namely tat, art or
trs determining the level of the virus reproduction
(Hammarskjold and Rekosh 1989). Another possibility, not to
be excluded, is that the activation of viral production may be
a result of combined action on translation, namely processing,
RNA stability, translation or protein stability.