1 Medical Research Service, The
immediate-early (IE) genes of human cytomegalovirus
(CMV) can be expressed in monocytic cells and
are known to regulate viral and cellular genes. Reactivation of human
immunodeficiency virus (HIV-1) may be stimulated by a variety of
factors including other viruses and inflammatory cytokines. These
studies examine the role of hyperthermia and CMV in the regulation of
HIV-1 and tumor necrosis factor (TNF)-
THP-1 cells; endotoxin; tumor necrosis factor- HUMAN IMMUNODEFICIENCY VIRUS (HIV-1) infection is
characterized by a prolonged period of clinical latency. The
development of acquired immune deficiency syndrome (AIDS) occurs
through the reactivation of viral expression (3, 15, 23, 25). A variety of factors appear to upregulate the viral expression in HIV-1-infected cells (3, 15, 23, 25, 31-33). Cytomegalovirus (CMV) has been
implicated as an important cofactor in the disease progression of AIDS.
Experimental and clinical studies (1, 4-6, 11, 21, 22, 34)
demonstrated that the interaction between CMV and HIV-1 furthers
disease progression and leads to increased HIV-1 replication. CMV
immediate-early (IE) proteins can affect cellular function and enhance
inflammatory cytokine production (9, 12, 13). Heat shock proteins
(HSPs) from virally infected cells and cancer cells can stimulate an
immune response and also stimulate tumor necrosis factor (TNF)- Reagents. Lipopolysaccharide (LPS;
Escherichia coli 026:B6), silica TLC
plates, and ethyl acetate were obtained from Sigma (St. Louis, MO).
Acetyl-CoA and DEAE were obtained from Amersham (Arlington Heights,
IL). FAST CAT was obtained from
Molecular Probes (Eugene, OR). Merifluor CMV-immunofluorescent CMV
identification reagent was obtained from Meridian Diagnostics
(Cincinnati, OH).
Tissue culture. THP-1 cells, a
monocytic leukemia cell line, was obtained from American Type Culture
Collection (Manassas, VA) (30). The cells were maintained in RPMI 1640 medium (ICN, Gaithersburg, MD) with 4 mM
L-glutamine and 10% fetal
bovine serum (HyClone, Logan, UT).
Plasmids. Plasmid pJN201 contains the
CMV IE promoter upstream from the human CMV IE1, -2, and -3 genes (8). The plasmids were purified twice over cesium chloride
gradients. The Limulus amebocyte
lysate assay QCL-1000 was obtained from BioWhittaker (Walkersville,
MD). Endotoxin assays were performed as suggested by the manufacturer.
TNF- Transfection. Transient transfections
of THP-1 cells were performed with the DEAE-dextran transfection method
(26). Cells (10 × 106) were exposed
to plasmid DNA in 10 ml of a solution containing DEAE-dextran (7.5 µg/ml) for 40 min, washed once in RPMI 1640 medium containing 1.5 U/ml of heparin, and then washed in the same medium without heparin.
Transfected cells were cultured in 100-mm tissue culture dishes at a
concentration of 1 × 106
cells/ml in RPMI 1640 medium with 10% fetal bovine serum. The cells
were harvested for CAT assays. Transfection efficiency was monitored
with a fluorescently labeled antibody to CMV IE1 protein.
Immunofluorescent detection of CMV.
The cells were monitored for transfection efficiency by fluorescent
staining with an antibody to CMV IE1 protein 24 h after stimulation.
The cells were cytospun onto slides, fixed in methanol for 20 min,
stained with Merifluor CMV identification reagent (Meridian
Diagnostics) for 20 min, rinsed in PBS, and mounted with fluorescent
antibody mounting medium. Cells were counted under
ultraviolet (UV) spectroscopy.
CAT assay. CAT assays were performed
24 h after stimulation as described by Gorman et al. (10). The
acetylated derivatives were separated from nonacetylated
chloramphenicol by ascending chromatography with chloroform-methanol
(85:15). FAST CAT is a modified chloramphenicol with only one
acetylation site attached to fluorochrome and provides a linear range
of acetylation over a three-magnitude range. All experiments were run
within the linear range of this assay. TLC plates were read and
quantified with a Molecular Dynamics (Sunnyvale, CA) scanner.
Statistics. CAT assays were calculated
as the multiple of increase over the control value and
compared by t-tests. A
P value < 0.05 was used as the
cutoff for significance.
Hyperthermia augments HIV-1
transcription. The ability to stimulate HIV-1
transcription and replication in the absence of HIV-1 tat
protein may play an important role in stimulating HIV-1 replication in latently infected cells. HIV-1 replication is induced by
a wide range of stimuli including cytokines, viruses, UV light, heat,
and endotoxin. We first examined the ability of hyperthermia and
CMV IE genes to modulate HIV-1 transcription in monocytic cells. In these studies, HIV-1 transcription was measured with an
HIV-1-CAT promoter construct. THP-1 cells were either transfected with
HIV-1-CAT (0.05 µg/ml) or cotransfected with HIV-1-CAT (0.05 µg/ml)
and the CMV IE gene (pJN201; 0.05 µg/ml). The cells were either left unstimulated or stimulated with LPS (1.0 µg/ml) 4 h after
heat for 2 h at 42°C. The cells were harvested 24 h after LPS
stimulation, and CAT assays were performed (Fig.
1). Compared with that in
control transfected unstimulated cells, HIV-1-CAT activity increased
4.1 ± 0.3-fold in control transfected LPS-stimulated cells, 0.9 ± 0.2-fold in CMV IE transfected unstimulated cells, and 30.2 ± 13.0-fold in CMV IE transfected LPS-stimulated cells. After
heat exposure, HIV-1-CAT activity increased 1.1 ± 0.3-fold in
unstimulated cells, 8.5 ± 1.5-fold in LPS-stimulated cells, 51.3 ± 20.5-fold in CMV IE transfected unstimulated cells, and 129.7± 43.7-fold in CMV IE transfected LPS-stimulated cells.
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
. THP-1 cells were transfected
with the CMV IE genes. HIV-1 and TNF-
transcription were
assessed with chloramphenicol acetyltransferase promoter constructs.
Hyperthermia sufficient to stimulate production of heat shock proteins
was used to stimulate the cells. Hyperthermia significantly enhances the effect of CMV IE gene products on the expression of
HIV-1 and TNF-
. The increases in HIV-1 transcription appear to be in part due to increases in TNF-
. Heat shock proteins induced by hyperthermia may play an important role in the viral regulation of
monocytic function by CMV.
; heat shock
proteins; human immunodeficiency virus
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
production (2, 24, 28, 29). Viral proteins complexed with HSPs may play
an important role in the generation of the immune and inflammatory
responses seen in many viral infections. We hypothesized that
hyperthermia sufficient to induce HSP accumulation acts in concert with
CMV IE proteins to increase HIV-1 transcription and inflammatory
cytokine transcription. We further examined the effect of hyperthermia as a stimulus of HIV-1 transcription and TNF-
transcription alone and in combination with CMV IE proteins.
METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
-chloramphenicol acetyltransferase (CAT) constructs were kindly
provided by Dr. Lois Geist (University of Iowa, Iowa City) (9). The
TNF-
constructs contained from
650 to +1 bp of the TNF-
promoter. Endotoxin levels were <0.1 endotoxin unit/ml (1 pg/ml) in
all solutions and plasmid preparations used during transfection.
HIV-1-CAT contains the HIV-1 long-terminal repeat upstream from the CAT
gene (18).
RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
View larger version (82K):
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Fig. 1.
Effect of cytomegalovirus (CMV) intermediate-early (IE) proteins and
hyperthermia on human immunodeficiency (HIV)-1 chloramphenicol (CM)
acetyltransferase (CAT; CM-AC) activity.
A: representative CAT assay with
HIV-1-CAT. LPS, lipopolysaccharide; unst, unstimulated.
B: results of 3 experiments. HIV-1-CAT
activity increased 4.1 ± 0.3-fold in control transfected
LPS-stimulated cells, 0.9 ± 0.2-fold in CMV IE transfected
unstimulated cells, and 30.2± 13.0-fold in CMV IE transfected
LPS-stimulated cells compared with that in control transfected
unstimulated cells. In heat-exposed cells, HIV-1-CAT activity increased
1.1 ± 0.3-fold in unstimulated cells, 8.5 ± 1.5-fold
in LPS-stimulated cells, 51.3 ± 20.5-fold in CMV IE transfected
unstimulated cells, and 129.7± 43.7-fold in CMV IE
transfected LPS-stimulated cells. Hyperthermia-treated CMV IE
transfected cells with (P = 0.047) or
without (P = 0.03) LPS stimulation
were significantly increased (*) over CMV IE transfected cells that
were not exposed to hyperthermia.
Hyperthermia significantly increased HIV-1 transcription in CMV IE transfected cells, with an increase from 0.9- to 51.3-fold over the control value in unstimulated cells (P = 0.03) and from 30.2- to 129.7-fold over the control value in LPS-stimulated cells (P = 0.047). Heat alone increased HIV-1 transcription in LPS-stimulated cells twofold. Hyperthermia significantly enhanced HIV-1 transcription in CMV IE transfected cells. In previous studies (9, 12, 13) with the CMV IE genes under the control of the CMV IE promoter, stimuli such as LPS increased expression of the CMV IE proteins in THP-1 cells. To evaluate whether hyperthermia increased CMV IE protein expression, we used a fluorescent-labeled antibody against CMV IE1 protein and counted cells by fluorescent microscopy. THP-1 cells transfected with the CMV IE genes demonstrated 3-5% of the cells expressing CMV IE1 protein; with the addition of LPS, 17-20% of the cells expressed CMV IE1 protein. Hyperthermia did not change CMV IE1 protein expression in either the CMV IE transfected cells or the CMV IE transfected cells stimulated with LPS. These experiments examined the percentage of cells expressing CMV IE1 protein but did not quantitate the level of expression of CMV IE1 protein per cell. The increases in HIV-1 transcription may be due to CMV IE and hyperthermia stimulation of inflammatory cytokines.
Hyperthermia augments CMV IE gene-associated TNF-
promoter activity. We next examined the ability of
hyperthermia and CMV IE gene products to increase cytokine
transcription. We evaluated TNF-
because of its ability to stimulate
HIV-1 transcription. To evaluate the effect of the CMV IE
genes on the TNF-
promoter, cotransfection experiments were
performed with a TNF-
construct containing the region from
650 to +1 bp of the TNF-
promoter upstream from
the CAT gene. THP-1 cells were either transfected with TNF-
-CAT (0.5 µg/ml) or cotransfected with TNF-
-CAT (0.5 µg/ml) plus the
CMV IE gene (pJN201; 0.05 µg/ml). The cells were either
left unstimulated or stimulated with LPS (1 mg/ml) 4 h after heat for 2 h at 42°C. The cells were harvested 24 h after LPS stimulation, and
CAT assays were performed (Fig. 2).
Compared with that in control transfected unstimulated cells,
TNF-
-CAT activity increased 1.4 ± 0.5-fold in control
transfected LPS-stimulated cells, 1.5 ± 0.2-fold in CMV IE
transfected unstimulated cells, and 17.3 ± 13.1-fold in CMV IE
transfected LPS-stimulated cells. After heat exposure, TNF-
-CAT
activity increased 2.4 ± 0.4-fold in unstimulated cells, 7.2 ± 4.4-fold in LPS-stimulated cells, 116.8 ± 74.8-fold in CMV IE
transfected unstimulated cells, and 343.2 ± 62.3-fold in CMV IE
transfected LPS-stimulated cells.
|
These studies demonstrate a significant increase in TNF- with CMV IE
transfected cells, increasing from 17.3-fold in LPS-stimulated cells to
343.2-fold in heated LPS-stimulated cells
(P = 0.03). The increases in TNF-
transcription were not due to changes in CMV IE gene
expression induced by hyperthermia. These studies suggest that
hyperthermia induces changes that either enhance the ability of
CMV IE gene products to act as transcription factors or
induce other factors that work in concert with CMV IE gene products to enhance TNF-
transcription.
Hyperthermia induces 70-kDa HSP
production. To evaluate the effect of hyperthermia on
the cells, we examined changes in HSP production by measuring HSP70
production by Western blot analysis. We evaluated 70-kDa HSP (HSP70)
production in THP-1 cells exposed to heat at 42°C for 2 h. HSP70
increased over time, with a peak in HSP70 protein production as
measured by Western blot 8 h after heat exposure (Fig.
3). HSP70 protein production persisted
up to 48 h. We also examined HSP70 production in our system. No HSP70 was seen in transfected cells, LPS-stimulated cells, or cells transfected with the CMV IE gene unless they were also
exposed to heat (data not shown). The increases in HSP70 production
parallel the increases in TNF- transcription.
|
Hyperthermia augments TNF- promoter activity at
later time points. Hyperthermia induces a translational
block with no protein synthesis for several hours. HSPs such as HSP70
are the first proteins produced after resolution of the translational
block. We examined whether there were continued increases in TNF-
transcription at later time points. Experiments were repeated with a
delay of 24 h between heat shock and LPS stimulation. THP-1 cells were either transfected with TNF-
-CAT (0.5 µg/ml) or cotransfected with
TNF-
-CAT (0.5 µg/ml) plus the CMV IE gene (pJN201; 0.05 µg/ml). Cells were either left unstimulated or stimulated with LPS (1 µg/ml) 24 h after heat for 2 h at 42°C. The cells were harvested
24 h after LPS stimulation, and CAT assays were performed (Fig.
4). Compared with that in control
transfected unstimulated cells, TNF-
-CAT activity increased 2.0 ± 0.6-fold in control transfected LPS-stimulated cells, 2.7 ± 0.7-fold in CMV IE transfected unstimulated cells, and 5.3 ± 1.5-fold in CMV IE transfected LPS-stimulated cells. After heat
exposure, TNF-
-CAT activity increased 5.9 ± 2.4-fold
in unstimulated cells, 12.8 ± 5.2-fold in LPS-stimulated cells,
139.8 ± 53.5-fold in CMV IE transfected unstimulated cells, and
103.1 ± 44.7-fold in CMV IE transfected LPS-stimulated cells. Hyperthermia-exposed CMV IE transfected cells with
(P = 0.03) or without
(P = 0.02) LPS stimulation were
significantly increased over the cells that were not exposed to
hyperthermia. Hyperthermia continued to stimulate TNF-
transcription
at later time points when there is also production of HSP70.
|
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DISCUSSION |
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The combination of CMV IE proteins and hyperthermia significantly
enhances HIV-1 (Fig. 1) and TNF- (Fig. 2) transcription. CMV is an
important cofactor in the pathogenesis of HIV-1 infection. One of the
most common coinfections found in HIV-1-infected subjects is CMV.
Coinfection with CMV and HIV-1 has been demonstrated in brain, lung,
and retinal tissues (7, 19, 20, 27). Experimental and clinical studies
(1, 4-6, 11, 21, 22, 34) suggested that the interaction between
CMV and HIV-1 leads to increased HIV-1 replication and disease
progression. CMV may affect HIV-1 infection by stimulating production
of inflammatory cytokines known to upregulate HIV-1 replication (9, 12,
13). CMV IE gene products may stimulate HIV-1 replication by
direct interaction with the HIV-1 promoter or through enhanced cytokine
production, which then stimulates HIV-1 replication. In these studies,
the increase in TNF-
transcription suggests that increased
inflammatory cytokine production could contribute to the increased
HIV-1 transcription. These studies did not demonstrate increased
TNF-
protein production.
CMV IE proteins have been shown to increase interleukin-1,
interleukin-6, and TNF- production in LPS-stimulated cells. In previous studies (9, 12, 13), LPS has been needed as a cofactor with
CMV IE proteins to increase inflammatory cytokine production. One
mechanism by which LPS enhanced the effect of CMV IE gene
products on inflammatory cytokine production in monocytic cells was by
increasing expression of the CMV IE gene products. Hyperthermia, however, did not increase CMV IE gene
expression in our experiments. The present studies demonstrate an
increase in TNF-
transcription by hyperthermia and CMV IE proteins
in the absence of LPS. A possible cofactor in enhancing the effect of
CMV IE gene products on TNF-
and HIV-1 transcription may
be HSPs.
Hyperthermia alone can enhance HIV-1 expression approximately twofold
as seen in a study by Kretz-Remy and Arrigo (14) and in
our experiments. The increases seen with the addition of the CMV IE gene products are significantly higher than the
changes due to hyperthermia or CMV IE gene products alone.
Our studies demonstrated a significant increase in TNF-
transcription with the presence of CMV IE proteins and hyperthermia.
The increased transcription due to the addition of CMV IE
gene products occurs at time periods of 24-48 h after exposure to
heat when there was also an increase in HSP70.
Hyperthermia induces mitochondrial uncoupling, generation of oxygen
radicals, a translational block, and generation of HSP accumulation.
Increased inflammatory cytokine production has been demonstrated when
cells are exposed to bacterial HSPs, and HSPs from virally infected
cells and cancer cells can induce an immune response and stimulate
TNF- production (2, 24, 28, 29). Although hyperthermia sufficient to
cause cellular HSP accumulation was used as a stimulus, it is tempting
to consider that the HSPs are responsible, in part, for our findings.
HSPs are a family of proteins central to the heat shock response (16,
17, 35). They are an acidic group of proteins (isoelectric
point 5.0-6.5) and vary in size from 27 to 110 kDa.
Accumulation of HSPs is associated with a tolerance to a variety of
stresses including heat, UV irradiation, ischemia, and
cytotoxic cytokines such as TNF-
. HSPs are ubiquitous intracellular
transports or chaperones. Management of proteins and protein fragments
is a common function of all HSPs. Mechanisms by which HSPs may
enhance the effect of CMV IE proteins include protection of the CMV IE
proteins from degradation, which increases the length of time the
proteins are present in the cell, and facilitation of transport of the
CMV IE proteins to other cells, or they may act as chaperones enhancing
CMV IE protein transport into the nucleus.
The data taken as a whole support the model that CMV coinfection drives
an inflammatory response that stimulates HIV-1 replication. The
inflammatory response induced by hyperthermia and CMV IE proteins increases both HIV-1 and TNF- transcription. Hyperthermia alone did
not significantly increase HIV-1 or TNF-
transcription. HSPs may
enhance the ability of viral proteins to regulate cellular functions.
An emerging role for HSPs is in the induction of immune responses. HSPs
from virally infected cells and cancer cells can induce an immune
response and stimulate TNF-
production (2, 24, 28, 29). The ability
of HSPs to enhance viral regulation of cellular function may play an
important role in many immune responses. Heat as well as other stresses
may enhance HIV-1 replication by stimulating HSP production and leading
to further disease progression.
![]() |
ACKNOWLEDGEMENTS |
---|
pHIV-1CAT was obtained from Dr. Gary Nabel and Dr. Niel Perkins
through the AIDS Research and Reference Reagent Program (Division of
AIDS, National Institute of Allergy and Infectious Diseases, National
Insitutes of Health, Bethesda, MD). We thank Dr. Lois Geist (University
of Iowa, Iowa City, IA) for the gift of the tumor necrosis factor- construct.
![]() |
FOOTNOTES |
---|
This material is based on work supported by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: G. K. Iwamoto, 2211 Lomas Blvd. NE 5-ACC, Albuquerque, NM 87131 (E-mail: giwamoto{at}unm.edu).
Received 12 April 1999; accepted in final form 25 June 1999.
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