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University of California at Los Angeles (UCLA) AIDS Institute,
Center for Interdisciplinary Research in Immunology and Disease, and Departments of
Medicine,
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Microbiology, Immunology, and Molecular Genetics, and
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Pathology and Laboratory Medicine, UCLA School of Medicine, Los Angeles, CA 90095
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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were
markedly suppressed; TNF-
, IL-1ß, IL-2, IL-4, and IL-6 were mildly
suppressed; and levels of IL-12 were not significantly altered. The
addition of either exogenous IFN- or IL-10 abrogated the effect of
NE on virus production. Thus PKA-dependent suppression of cytokine
production appears to mediate the enhancement of HIV-1 replication by
NE. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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S subunit of a heterotrimeric G protein linked
to the adenylyl cyclase-cAMP-protein kinase A (PKA) signaling cascade
(6, 7, 8). Adrenoreceptor ligation alters several aspects of lymphocyte
function in vitro, including cellular activation, cytokine production,
cell traffic and adhesion, and cytotoxic activity (6, 9, 10, 11, 12, 13, 14, 15). However,
little is known about the effects of SNS activation on disease
pathogenesis. The innervation of lymphoid tissue by the SNS may be particularly relevant to HIV infection, since lymphoid organs represent the primary site of HIV pathogenesis. Long before the onset of clinical illness, high concentrations of virus and large numbers of infected CD4+ T lymphocytes are present in the lymph node paracortex, splenic periarteriolar lymphoid sheath, and a variety of other secondary lymphoid structures (16, 17, 18). These sites are also richly innervated by SNS neurons (3, 4), raising the possibility that SNS activation could conceivably influence HIV pathogenesis. In the present study, we examine the effect of the SNS neuroeffector molecule NE on HIV-1 replication in an in vitro model of CD4+ T lymphocyte infection.
In vivo the vast majority of T lymphocytes are quiescent. These cells
are vulnerable to infection by HIV-1 but are incapable of fully
reverse-transcribing the viral genome (19, 20). Activation of infected
T lymphocytes leads to complete reverse transcription and rapid viral
replication (20, 21, 73). To model this process, we infected quiescent
PBMCs with a CXCR-4-tropic strain of HIV-1 and activated those cells
with Abs to CD3, the signaling component of the T cell receptor, and
Abs to CD28, a critical costimulatory molecule (22, 23, 24, 25). To examine the
effect of SNS activation on HIV-1 replication, NE was added
simultaneously with CD3/CD28 costimulation. Previous research indicates
that the pharmacologic inducers of cAMP can increase HIV-1 replication
in continuously cycling cell lines (26, 27). However, it is not known
whether physiologic cAMP inducers such as NE can increase HIV-1
replication or whether such effects occur in normal lymphocytes that
are activated in a physiologically relevant manner. In addition, the
mechanism by which cAMP affects HIV-1 replication remains unknown.
Here, we demonstrate that NE accelerates HIV-1 replication in freshly
infected PBMCs. We also show that this effect is transduced via the
ß-adrenoreceptor-adenylyl cyclase-cAMP-PKA signaling pathway and is
mediated by the pronounced suppression of IFN- and IL-10.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Healthy donor PBMCs were infected with
HIV-1NL4-3 (0.05 infectious units/cell) for 2 h
in the presence of 10 µg/ml polybrene. Following infection, cells
were washed and costimulated with Abs to CD3 (0.1 µg/ml adhered to
flask by goat anti-mouse Ab; Southern Biotechnology Associates,
Birmingham, AL) and CD28 (0.1 µg/ml soluble; Biodesign,
Kennebunkport, ME). Unstimulated control cells received no exogenous
Abs. Cells were cultured for 6 to 8 days at 3 x
105/ml in RPMI 1640 supplemented with 10% (v) human AB
serum, 100 U/ml penicillin, 100 µg/ml streptomycin, and 2 mM
glutamine at 37°C in an atmosphere of 5% CO2. NE
([-]-Arterenol; Sigma, St. Louis, MO) and other reagents were added
once, at activation. Other reagents added at activation included the
adenylyl cyclase activator forskolin (Sigma) (28); the
membrane-permeable cAMP analogue N6,
2'-O-dibutyryl adenosine-3', 5'-cyclic monophosphate
(db-cAMP; Sigma) (29); the membrane permeable PKA antagonist
adenosine-3', 5'-cyclic monophosphothioate, rp isomer (rp-cAMP;
Calbiochem, La Jolla, CA) (30); human IFN- (R&D Systems,
Minneapolis, MN), IL-2 (Genzyme, Cambridge, MA), IL-4 (Genzyme), and
IL-10 (R&D Systems). To determine whether the effects of NE were
mediated by ß-adrenoreceptors, infected PBMCs were incubated in the
presence of the receptor antagonist sotalol (ICN Biomedicals, Costa
Mesa, CA) or dl-propranolol HCl (ICN Biomedicals) for 1 h before
activation in the presence of NE. Cell viability was assessed by trypan
blue exclusion and did not differ between NE-treated and untreated
cultures at 2, 4, 6, or 8 days postinfection. Cell viability was also
not altered by the addition of adrenoreceptor blockers (propranolol,
sotalol, phentolamine) or PKA antagonists (rp-cAMP) to NE-treated
cultures. Apoptosis rates were assessed by a flow cytometric
measurement of annexin V-FITC (Brand Applications) and propidium iodide
binding. Apoptosis rates did not differ across cultures of costimulated
cells, cultures costimulated in the presence of NE, or NE supplemented
by adrenoreceptor blockers or PKA antagonists.
HIV-1 quantification
Virus production was quantified by ELISA for HIV-1 p24 core protein (Coulter, Maastricht, The Netherlands). p24 levels were compared across treatments by ANOVA followed by Duncan’s multiple range test for specific comparisons. Dose-response and kinetic profiles were analyzed by linear regression on log p24 values. p24 levels were graphed as the mean plus SE. To confirm the equality of viral inoculation, we also examined the proviral load at 14 h postinfection using PCR (AA55 and M667 primer sequences for the R/U5 region of the viral long terminal repeat, quantified relative to input cell number as indicated by ß-globin primers LA1 and LA2) (20). Briefly, one primer of each pair was radio end-labeled, and amplification was conducted for 25 cycles in parallel with control standards consisting of linearized cloned HIV-1 DNA and known quantities of cellular DNA. Radiolabeled, amplified products were resolved on a 6% polyacrylamide gel and quantified by radioanalytic image analysis in comparison with standard curves.
Cytokine quantification and identification of cytokine-producing cells
ELISAs were used to measure the supernatant concentrations of
human IL-1ß (R&D Systems), IL-2 (Genzyme), IL-4 (Genzyme), IL-6
(Innogenetics, Zwijndrecht, Belgium), IL-10 (Immunotech, Westbrook ME),
TNF- (Genzyme), IFN- (Biosource International, Westlake Village,
CA), and IL-12 p70; capture Ab 12H4 and detection Ab C8.6 were kindly
provided by G. Trinchieri, (Wistar Institute, Philadelphia, PA).
Concentrations of each cytokine were determined in parallel at 0, 2, 4,
and 6 days postinfection across three independent experiments and
graphically expressed as the mean plus SE. Differences in cytokine
production were analyzed by the Student t test. Total
cytokine production was quantified as the area under the curve of the
cytokine level over time (as in Fig. 3
); the statistical significance
of differences in total cytokine production was determined by the
Student t test.
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were identified by flow cytometric analysis of
intracellular binding of anti-cytokine Abs following a 6-h
incubation in the presence of 10 µg/ml brefeldin A (following the
protocol of the Ab manufacturer). The CD4+/- and
CD8+/- phenotype of cytokine-producing cells was
determined by surface staining with anti-CD4 and anti-CD8 Abs
(Becton Dickinson, Mountain View, CA) before intracellular cytokine
staining. All flow cytometric data were acquired using a FACScan
instrument (Becton Dickinson) and analyzed using CellQuest software
(Becton Dickinson); dead cells and debris were excluded on the basis of
forward scatter vs side scatter profiles. Assessment of cellular activation
At 3 days postinfection, cellular activation was quantified by 1) the flow cytometric analysis of cell cycle stage via intracellular staining of RNA and DNA, 2) the cell surface expression of CD25 (IL-2R; expressed early in the cell cycle) and CD71 (transferrin receptor; expressed late in the cell cycle) by flow cytometry (Becton Dickinson Immunocytometry protocol), and 3) 6 h of [3H]thymidine uptake. In cell cycle staging, cells were permeabilized with saponin (0.004% w) and stained with 7-amino actinomycin D (Sigma) and pyronin Y (Calbiochem) to quantify intracellular DNA and RNA, respectively (31, 73). Cycling cells move from a 2N DNA/RNAlow state (G0/G1A) through a 2N DNA/RNAhigh state (G1B) to a 4N DNA/RNAhigh state (G2/M). DNA/RNA quadrants were set on the basis of a 2N DNA/RNAlow negative control that had been established by activating PBMCs in the presence of 5 mM N-butyrate (Sigma), which blocks cell cycle progression in G1A (32). The identification of cycling cells via RNA/DNA staining was highly specific, with <1% of cells falling in the cycling quadrant in the absence of costimulation (vs >65% of costimulated cells). The results of cell cycle staging correlated closely with the expression of the CD25 and CD71 activation Ags and with [3H]thymidine uptake. Dose-response relationships between NE concentration and the fraction of cycling cells were evaluated by linear regression.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To examine the effects of NE on HIV-1 replication, p24 levels were
assessed at 2, 4, 6, and 8 days postinfection (Fig. 1A). As expected,
costimulating HIV-1NL4-3-infected PBMCs with Abs to CD3 and
CD28 markedly increased viral replication relative to unstimulated
cultures. Identical costimulation in the presence of 10 µM NE led to
a significant additional increase in HIV replication. This effect
emerged reliably across 15 independent experiments, with NE increasing
day 6 p24 levels to an average of 337% of costimulated control levels
(p < 0.0001). In some donors, NE increased day
6 p24 levels by >11-fold. The effect of NE on HIV-1 replication was
dose-dependent, with day 6 p24 levels increasing approximately twofold
with each log increase in NE concentration over the range
10-8–10-5 M (Fig. 1B)
(p = 0.002). These differences emerged despite
the fact that a PCR analysis of the HIV-1 proviral load confirmed
equivalent initial viral inoculation (no difference in proviral
penetrance at 14 h postinfection; data not shown). PCR analysis
corroborated p24 ELISA results in documenting increased proviral spread
in NE-treated cultures at 6 to 8 days postinfection (data not
shown).
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In the classical NE signaling pathway, ligation of the cell
surface ß-adrenoreceptor activates adenylyl cyclase, which triggers
increased synthesis of cAMP and thereby activates the cAMP-dependent
kinase PKA. To determine whether the effect of NE on HIV-1 replication
is transduced by ligation of the ß-adrenoreceptor, infected PBMCs
were incubated in the presence of the ß antagonists sotalol (10 µM)
or propranolol (0.1 µM) for 1 h before activation in the
presence of 10 µM NE. Both adrenoreceptor antagonists abrogated the
effects of NE on HIV-1 replication, reducing p24 concentrations to
levels that were statistically indistinguishable from costimulated
control cultures (Table I). In contrast,
the -adrenoreceptor antagonist phentolamine (10 µM) failed to
block the enhancement of HIV replication by NE (Table I).
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).
To determine whether the effects of NE on HIV-1 replication were
mediated by increased activation of PKA, infected PBMCs were incubated
in the presence of the PKA inhibitor rp-cAMP (100 µM) for 1 h
before costimulation in the presence of NE. PKA blockade strongly
inhibited the effect of NE on HIV-1 replication (Table I), reducing p24
concentrations to levels that were statistically indistinguishable from
costimulated control cultures. Thus, the activation of the PKA
signaling cascade via the cell surface ß-adrenoreceptor appears to
mediate the effects of NE on HIV-1 replication.
Effect of NE on HIV-1 replication is not mediated by increased cellular activation
Cellular activation is critical to efficient HIV-1 replication
(20, 21). NE and other cAMP-inducing agents partially suppress cellular
activation in uninfected PBMCs (9), but their effect on cellular
activation in HIV-infected lymphocytes is unknown. A flow cytometric
assessment of cell cycling by analysis of intracellular DNA and RNA
indicated that NE decreased cellular activation in HIV-1-infected PBMCs
(Fig. 2). These effects were
dose-dependent, with the fraction of cycling cells declining by an
average of 15.3% per log increase in NE concentration over the range
10-7 to 10-5 M
(p < 0.0001 across four experiments). Similar
effects emerged in flow cytometric analyses of the early CD25 and the
late CD71 activation Ags and in measurements of 6-h
[3H]thymidine uptake (data not shown). Thus the effect of
NE on HIV-1 replication does not appear to be mediated by increased
cellular activation in HIV-infected cultures.
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Previous research indicates that NE can suppress the production of
IL-2 and IFN- by activated (HIV-uninfected) PBMCs and mouse Th1
clones while sparing or enhancing IL-4 production by activated PBMCs
and Th2 clones (13, 33). The effects of NE on cytokine production in
HIV-infected PBMCs are unknown. However, effects on cytokine production
could play a role in altered viral replication, since HIV-1 production
can be suppressed by several immunoregulatory cytokines (e.g., IL-10,
and IL-12) and enhanced by several other proinflammatory cytokines
(e.g., TNF-, IL-6, and IL-1ß) (34, 35, 36).
Consistent with the partial suppression of cellular activation by
NE, ELISAs of supernatant cytokine concentrations showed a moderate
suppressive effect of NE on the production of IL-2 and IL-4 (Fig. 3). The total production of each cytokine
over time (area under curve) was reduced by 49% and 64% for IL-2 and
IL-4, respectively, with neither suppression reaching statistical
significance (p = 0.32 and 0.10, respectively).
NE similarly suppressed the proinflammatory cytokines IL-1ß (by 48%
over time, p = 0.017), IL-6 (48%, p =
0.008), and TNF- (41%, p = 0.052) (Fig. 3).
However, the most pronounced suppressive effects of NE were on IFN-
and IL-10 (Fig. 3), with the total production of IFN- suppressed by
96% (p = 0.006) and the total production of
IL-10 suppressed by 94% (p = 0.014). In
contrast to its suppressive effects on other cytokines, NE did not
significantly alter the level of IL-12 produced by HIV-infected PBMCs
(Fig. 3) (p = 0.610).
To determine whether the pronounced effects of NE on IFN- and IL-10
production were mediated by activation of the PKA signaling pathway, we
examined the ability of the PKA antagonist rp-cAMP to abrogate
NE-induced cytokine suppression. Preincubation with rp-cAMP blocked the
NE-induced suppression of IFN- by 79% and the NE-induced
suppression of IL-10 by 92% across three independent experiments (both
p = 0.008; data not shown). Concentrations of both
cytokines were restored to levels that were statistically
indistinguishable from those of costimulated control cultures (both
p > 0.41). Thus, the suppression of IFN- and IL-10
by NE appears to be mediated by the cAMP-PKA signaling pathway.
To determine which cellular sources of IFN- were affected by NE,
cytokine-producing cells were identified by flow cytometric analysis of
intracellular cytokine staining. As shown in Figure 4, NE suppressed IFN- production by
both CD4+ and CD8+ lymphocytes
(A and B), with 10 µM NE almost
totally abrogating the induction of IFN--producing cells
(C–E).
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and
IL-10
To determine whether altered cytokine production mediates the
effects of NE on HIV-1 replication, NE-treated cultures were
supplemented with either 500 pg/ml of exogenous IFN- or 500 pg/ml of
exogenous IL-10 (concentrations similar to those found in costimulated
control cultures). The restoration of either cytokine alone was
sufficient to completely abrogate the effect of NE on p24 levels (Fig. 5), indicating that the acceleration of
HIV-1 replication by NE is mediated by the simultaneous suppression of
both IFN- and IL-10. This effect is specific to IFN- and IL-10,
in that the addition of either 500 pg/ml of IL-2 or 50 pg/ml of IL-4 to
NE-treated cultures did not suppress viral replication (Fig. 5).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-10. The present results confirm previous observations
that cAMP can increase HIV-1 replication (26, 27) and identify a basis
for those effects in the suppression of HIV-limiting cytokines.
Consistent with its partial suppression of cellular activation, NE also
moderately suppressed the production of several proinflammatory
cytokines that are known to increase HIV-1 replication (IL-1ß, IL-6,
and TNF-). However, any replication-retarding effects of reduced
cellular activation or proinflammatory cytokine production appear to be
offset by the replication-enhancing effects of suppressing IFN- and
IL-10. The effects of NE on viral replication were dose-dependent over
a physiologically relevant range (3, 5), raising the possibility that
the activation of SNS neurons innervating lymphoid tissue could
conceivably influence HIV disease pathogenesis.
The simultaneous suppression of both IFN- and IL-10 was necessary
for accelerated HIV-1 replication. Replacement of either cytokine alone
abrogated the effects of NE. In humans, both IFN- and IL-10 regulate
cellular immune responses (37, 38, 39, 40). However, altered cellular immunity
is not likely to explain the present data, because viral replication
differences emerged over periods of time that were too short to support
the development of an acquired immune response in vitro (41, 42, 43). Both
IFN- and IL-10 are produced at high rates throughout HIV infection
(44, 45, 46, 47, 48). Both of these cytokines also regulate HIV-1 replication (35, 49, 50, 51, 52, 53), although the mechanisms by which they do so remain
incompletely understood (54, 55, 56, 57). In the present studies, virus
production kinetics lagged behind IFN- and IL-10 expression
kinetics, even though these cytokines were shown to mediate the effects
of NE on viral replication. Because the HIV life cycle takes 
2 days
under optimal conditions, effects on virus production can lag up to two
days behind any potential cytokine influences. In addition, cytokine
alterations may influence the viral life cycle via downstream events
that require further time to develop. The identification of such
downstream mediators represents an important focus for further
research.
The suppression of IFN- by NE appears to occur at the level of the
cytokine-producing cell itself (primarily CD8+ and
CD4+ T lymphocytes), because the production of IL-12, the
major exogenous trigger for IFN- production (58, 59, 60), was not
altered. A direct effect on the cytokine-producing cell is consistent
with the presence of a cAMP response element in the IFN- promoter
(61, 62, 63) as well as with the NE-induced suppression of IFN-
production in isolated murine T cell clones (13). Direct suppressive
effects of NE on human IL-10 production have not been demonstrated
previously, but the IL-10 promoter does contain a cAMP response element
(64). The presence of cAMP-linked ß2-adrenoreceptors on
both CD4+ and CD8+ T lymphocytes provides a
structural basis for direct effects of NE on cytokine-producing
cells (8, 13).
The simultaneous suppression of both IFN- and IL-10 by NE is
consistent with an emerging body of evidence suggesting that the
innervation of lymphoid tissue by SNS may function as a natural
mechanism for selectively suppressing cellular immune responses while
sparing or enhancing other aspects of immune system function (e.g.,
humoral immune responses) (33, 65, 66, 67, 68, 69). As such, analyzing the
mechanisms by which the SNS alters lymphocyte function may lead to
novel strategies for selectively manipulating immune responses in HIV
infection and other disease settings.
Our interest in the effects of SNS activation on the basic HIV life cycle led us to examine a model of CD4+ T cell infection in the absence of acquired immune responses (e.g., CD8 antiviral factors or HIV-specific CTLs) (41, 42, 43). Basic viral replication rates play a critical role in driving HIV pathogenesis and long-term disease progression (70). The present data indicate that the products of SNS activation can alter HIV-1 replication in activated PBMCs. Such effects underscore the critical role of immunomodulatory factors in altering HIV replication (35) and raise the possibility that the course of HIV could conceivably be affected by factors associated with SNS activation (e.g., physical or psychologic stress) (71, 72). Such results also suggest that it may be productive to address immunoregulatory influences from outside the Ag-immune system axis in attempts to suppress HIV replication over the extended periods of time that are necessary for sustained clinical benefit.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Steve W. Cole, Division of Hematology-Oncology, Department of Medicine, Factor 11–934, UCLA School of Medicine, Los Angeles, CA 90095-1678. E-mail address:
3 Abbreviations used in this paper: SNS, sympathetic nervous system; NE, norepinephrine; PKA, protein kinase A; db-cAMP, dibutyryl-cAMP; rp-cAMP.
4 Korin, Y. D., and J. A. Zack. Progression to the G1B stage of the cell cycle is required for completion of HIV-1 reverse transcription in T cells. Submitted for publication.
Received for publication December 15, 1997. Accepted for publication March 12, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Virology 194:345.[Medline]
and decreased IL-2 gene expression are associated with HIV infection. J. Immunol. 151:5031.[Abstract]
on tat-induced transactivation of HIV long terminal repeat. J. Biol. Chem. 267:20565. promoter mediates selective expression in T cells. J. Biol. Chem. 271:31964.This article has been cited by other articles:
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) of NE. NE suppressed the total production of IFN-
