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-Induced Secretion of C-C Chemokines Modulates C-C Chemokine Receptor 5 Expression on Peripheral Blood Lymphocytes
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Laboratory of Immunology and
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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delays the surface expression of CCR5 on PBLs after activation
and diminishes CCR5 irrespective of its initial level. Functional loss
of CCR5 is reflected in a decreased capability of the treated cells to
migrate and signal calcium after MIP-1ß stimulation. The effect is
mediated via the p80 type II TNF receptor (TNFR2), which induces
NF-
B among other factors, leading to an enhanced secretion of the
chemokines macrophage-inflammatory protein-1,
macrophage-inflammatory protein-1ß, and RANTES. Expression of these
chemokines directly down-regulates CCR5. These findings reveal a new
regulatory mechanism utilized by activated peripheral T cells to
modulate their chemotaxis and potentially other functions mediated by
CCR5, including the infection of T lymphocytes by macrophage-tropic HIV
strains. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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achieves signals ranging from cellular activation and
proliferation to cytotoxicity and apoptosis. These responses may
involve the differential usage of two distinct TNF receptors, p60
(TNFR1) and p80 (TNFR2) and their respective signaling cascades
(4, 5, 6). A variety of cell types, both hemopoietic and
stromal, have been described to produce TNF (for review, see Ref.
1). Cells of the myeloid lineage such as monocytes
and macrophages are potent TNF producers. T lymphocytes also
produce TNF, especially in response to recent TCR stimulation (7, 8).
TNF- can be produced as a normal immune defense mechanism against
viruses (9) and tumors (10, 11, 12). However,
TNF- is also associated with many inflammatory and autoimmune
pathological processes (1). For example, the dominant role
of TNF- in the pathogenesis of rheumatoid arthritis
(RA)2 and idiopathic
inflammatory bowel diseases has been demonstrated by successful
clinical treatment trials using anti-TNF Abs (13, 14).
It was proposed that the inflammatory effect of TNF may be mediated by
preferential signaling through TNFR2. TNFR2 induces a widely used gene
transactivator: NF-B, which is known for its role in the
transcriptional induction of many immune mediators (for a review, see
Refs. 15, 16). NF-B has an additional important role
in preventing cell death (15, 16, 17). NF-B has been found
to be a potent inducer of many chemokines (18, 19, 20).
Chemokines are proinflammatory cytokines that attract and activate
specific subsets of leukocytes (21). The chemokine
superfamily is divided into subgroups based on structural and genetic
considerations. The CXC, CC, C, and CX3C families are characterized by
the distance of the two cysteines nearest the amino terminus. The CC
chemokines RANTES and macrophage-inflammatory protein (MIP-1)
promote lymphocyte activation (22, 23). These chemokines
as well as MIP-1ß bind to CCR5. Besides CCR5, RANTES and MIP-1
also bind to CCR1, and RANTES binds to CCR3 and CCR4. Chemokine
receptors are seven-transmembrane receptors that couple to G proteins,
which in turn can lead to an intracellular calcium signal and protein
tyrosine kinase activation (for reviews, see Refs.
24, 25, 26).
CCR5 is an important coreceptor for HIV, and humans lacking its
expression are generally resistant to HIV infection, with few
exceptions (27, 28, 29, 30, 31, 32). Several reports have shown that LPS
in macrophages (33) or CD40L in a macrophage/T cell system
(34) can influence the HIV coreceptor expression in vitro.
However, published reports give contradictory results concerning the
CCR5 expression (33, 35, 36, 37). Recently, it has been
suggested that the TNF- necessary for the maturation of dendritic
cells can also influence the expression of chemokine receptors on these
cells and cause CCR5 down-modulation (38, 39). It has also
been reported that TNF- decreases the CCR5 expression in peripheral
blood monocytes and alveolar macrophages by the production of RANTES
(40). However, the effect of TNF- on CCR5 expression by
T cells is not known. This issue is particularly relevant because T
cells are important producers of TNF- and CCR5 plays a significant
role in mediating T cell migration and infection by HIV. Our study
addresses the interaction between TNF- and CCR5 in activated human
peripheral blood T lymphocytes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Eagle Hanks’ amino acid (EHAA; Click’s medium) was used for PBLs (Biofluids, Rockville, MD), supplemented with 10% heat-inactivated FCS, penicillin (100 U/ml), streptomycin (100 U/ml), and L-glutamine (2 mM).
Subjects
PBLs from healthy, normal individuals were obtained from buffy
coats from the Department of Transfusion Medicine, Clinical Center,
National Institutes of Health, collected by countercurrent elutriation
from apheresed subjects from a normal donor pool or by heparin-free
phlebotomy. Multiple blood samples were obtained from several CCR5
32 homozygous and heterozygous individuals, who gave informed
consent as part of an established clinical protocol approved by
Institutional Review Board (IRB; 91-I-0140).
Antibodies
Goat anti-human Abs to MIP-1, MIP-1ß, RANTES, and
isotype-matched control Abs were obtained from R&D Systems
(Minneapolis, MN). Anti-CCR5 FITC and anti-CD45RO PE were obtained
from PharMingen (San Diego, CA). Abs against TNFR2 and TNFR1 were from
R&D Systems.
Cell preparation
Blood was diluted with PBS 1/5, and Ficoll-Paque (Pharmacia,
Piscataway, NJ) was carefully underlayered. After a 15-min spin (2000
rpm, room temperature), the cells at the interphase were collected,
treated with ACK lysis buffer (Biofluids) and washed. Cells in complete
EHAA were stimulated with 5 µg/ml Con A (Boehringer Mannheim,
Indianapolis, IN) for 48–72 h. After treatment with 10 mg/ml
-methyl mannoside (Sigma, St. Louis, MO) for 30 min at 37°C, cells
were washed and cultured in complete EHAA with 400 U IL-2 (Proleukin,
Midwest Medical, Earth City, MO). The PBL cultures were fed twice per
week until they were >2 mo old. CD4+ T cells
were obtained by column separation (human T cell CD4 subset column kit;
R&D Systems), following the manufacturer’s recommendations.
Assessment of chemokine production
Stimulated PBLs were incubated with the indicated amounts of
TNF- for the indicated time periods in 6-well or 24-well plates. The
supernatants were subjected to ELISA analysis for MIP-1, MIP-1ß,
and RANTES (R&D Systems) using the manufacturers’ directions.
Flow-cytometric analysis
PBLs were stained with 1/50 diluted Abs in the presence or
absence of TNF- or anti-TNFR2. Stained cell
populations were analyzed on a FACSCalibur with CellQuest Software
(Becton Dickinson, Mountain View, CA). Live gates were determined by
forward light scatter and side light scatter and verified with
propidium iodide staining.
Chemotaxis
A total of 5 x 106 untreated and
TNF--treated PBLs in 100 µl was added to the top chamber of a
5-µm pore size 24-Transwell plate (Costar, Fisher Scientific,
Pittsburgh, PA) in a final volume of 1 ml in complete medium. To the
bottom part edge, MIP-1ß (Pepro Tech, Rocky Hill, NJ) was added at
the indicated concentrations in triplicates. After 3 h, the
inserts containing the cells were removed, and 200-µl aliquots of
cells in the bottom chamber were subjected to flow cytometry in a
constant volume for 30 s. Total cell numbers obtained were
analyzed relative to the migration that had occurred without any
chemokine added. Approximately 10% of the cells migrated within this
time frame.
Statistical analysis
Statistical analysis was performed using Microsoft Excel (Redmond, WA).
Calcium analysis
PBLs were resuspended in HBSS with 1% FCS and 10 mM HEPES containing 10 mM CaCl2 and 10 mM MgCl2 and loaded with 2 µM Indo-1 and 150 µg/ml pluronic acid (Molecular Probes, Eugene, OR) at 30°C for 30 min with constant agitation. Cells were washed twice. The calcium flux was detected using a FACSVantage (Becton Dickinson) dual laser flow cytometer with a time zero injection module (Cytek, Fremont, CA). The data were analyzed with Flowjo Software (Tree Star, Stanford).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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modulates the CCR5 surface expression on activated PBLs
PBLs were stimulated in vitro with Con A, treated with TNF-,
and analyzed for CCR5 expression. We observed a decrease in CCR5
surface expression that was detectable within 24 h and almost
complete by 48 h (Fig. 1
A). We found that this effect
involved the CD45RO+ cells, which were the main
population expressing CCR5 (Fig. 1B) (41, 42, 43, 44).
As evident in comparing Fig. 1, A and B, we found
that individuals differed in the degree to which separate populations
of CCR5-expressing cells were demarcated, but in all cases the CCR5
level was reduced by TNF. The decrease in CCR5 surface expression was
directly correlated with the amount of TNF- added to the culture and
reached a plateau at 10 ng/ml (Fig. 1C). A small subset of
cells expressed CCR5 even at maximal doses of TNF-. These results
indicate that TNF- is a regulator of CCR5 expression on T cells,
most prominently on the CD45RO+ subset.
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To investigate whether the effect of TNF- is limited to
lymphocytes expressing substantial levels of CCR5, or also affects
cells expressing low levels of CCR5, we analyzed individuals expressing
low CCR5 due to the 32 genetic mutation in the CCR5 gene. The 32
allele is due to a gene deletion of 32 bp that produces a mutant
protein that expresses a unique 32-aa sequence instead of its last two
transmembrane domains and is not expressed on the cell surface
(29, 30, 32). First, we determined CCR5 surface expression
after the stimulation of the cells (Fig. 2A) and compared it with the T
cell activation marker CD25 (Fig. 2B). We found that CCR5 is
not significantly expressed when the cells peak in activation (between
days 3 and 5; data not shown), but slowly increases as the activation
marker CD25 decreases between days 10 and 20 (compare Fig. 2, A and B). In cases in which the 32 mutation is
homozygous, the individuals lack CCR5 surface expression (32/32,
Fig. 2A). Heterozygotes for 32 had greater CCR5
expression, and wild-type individuals with two normal alleles of CCR5,
although variable, generally had the greatest CCR5 expression. These
differences between individuals were independent of the degree of
cellular activation because all samples appeared to be comparably
activated, as indicated by CD25 expression (Fig. 2B). Table I shows the range of CCR5 expressed in
repeated tests on the individuals used in this study. Following TNF-
stimulation for 48 h, we found that both wild-type individuals and
32 heterozygous individuals show a comparable decrease in their
individual specific surface expression (Fig. 2C). Only very
little CCR5 remains on the cell surface of the heterozygous individuals
after TNF- stimulation due to their initial lower expression.
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delays the up-regulation of CCR5 during PBL activation
We treated PBLs early in the activation process (before CCR5
expression) with TNF- to determine how TNF- affects the
up-regulation of CCR5. The result shown indicates that the addition of
TNF- significantly delays the expression of CCR5 on the cell surface
(Fig. 3). Interestingly, the T cells
eventually overcame the initial TNF- suppression at about day 13 if
no further TNF- was added to the cell culture. Conversely, the cells
again decreased CCR5 if TNF- was administered to the cultures at day
14 (black triangle). Desensitization toward TNF- signals is not
evident at this time because the CCR5 expression is diminished to a
comparable degree by TNF- whether or not the cells had been
previously treated with TNF- (black triangle vs filled circle).
Taken together, the above results suggest that TNF- may be a
physiological regulator of CCR5-mediated T cell functions.
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To determine whether one of the two TNF- receptors (TNFRs) or
both could mediate the signal leading to decreased CCR5 expression, we
analyzed the cell surface expression of the TNFRs. We found
continuously high expression of TNFR2 in all individuals tested after
activation, but found no detectable TNFR1 (data not shown).
Correspondingly, we found that treatment with an anti-TNFR2 agonist
Ab led to a decrease in CCR5 expression, whereas TNFR1 Abs had no
effect (Fig. 4A, and data not
shown). Thus, the signal leading to the decrease in CCR5 surface
expression is mediated by TNFR2, which itself is not down-modulated
after TNF- treatment (data not shown). For example, we found no
down-modulation of the TNFR2 during the recovery of the CCR5 expression
at late times after TNF- administration (Fig. 4B).
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, and MIP-1ß are secreted after
TNF- stimulation
TNFR2 is well known to activate the transcription factor NF-B
(45). Furthermore, it had been reported that the
chemokines RANTES, MIP-1, and MIP-1ß have NF-B-responsive
elements in their promoters (18, 46). Therefore, it seemed
possible that these chemokines were induced by TNF- stimulation.
Indeed, we found up to a 10-fold increase of these chemokines released
after TNF- stimulation (Fig. 5A). Furthermore, we analyzed
whether levels of NF-B could influence TNF- induction of the
chemokines. For this purpose, we used the NF-B-inhibitory peptide
(KBI), which strongly interferes with the translocation of the p50/p65
complex to the nucleus (44). We have shown that the KBI
peptide prevents the accumulation of the nuclear NF-B complex
detectable by mobility shift electrophoresis (17). We
found that KBI caused a substantial decrease in the TNF--stimulated
chemokine secretion (Fig. 5B). The blockade was not
complete, possibly due to the limited potency of the inhibitory peptide
or to alternate mechanisms of chemokine induction. Nevertheless, the
results allow us to conclude that TNF--induced transcription factors
such as NF-B account for at least part of the increase in chemokines
after TNF- treatment, although clearly other factors also play an
important role.
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B participates in the down-regulation of CCR5 expression
induced by TNF-
In light of the fact that CCR5 down-regulation was greatest at
about 48 h after TNF- addition, it seemed likely that new gene
synthesis could be involved. The previous result clearly indicated a
role for NF-B in the synthesis of the chemokines. Therefore, we
tested the influence of KBI on CCR5 expression after TNF- treatment
and found a significantly weaker response to TNF- in the presence of
KBI compared with the control KBC peptide (Fig. 6). Thus, an NF-B signal is important
for the CCR5 down-modulation induced by TNF-.
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, and MIP-1ß
prevents the TNF--induced down-regulation of the CCR5 expression
The previous results strongly suggest a role for CCR5-binding
chemokines in the CCR5 down-modulation. This hypothesis demands that a
blockade of the chemokines that are induced by TNF- should diminish
the TNF--induced CCR5 down-regulation. To test this possibility, we
incubated the TNF--treated samples with either control Ab (Ab ctrl)
or a combination of Abs against the three CCR5-binding chemokines,
RANTES, MIP-1, and MIP-1ß (Ab mix). We found that the mixture of
chemokine-blocking Abs strongly prevented the down-regulation of CCR5
by TNF- (Fig. 7). This result directly
implicates chemokine production as the link between TNF- treatment
and decreased CCR5.
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treatment causes decreased calcium signaling and chemotaxis
function
We investigated whether the decrease in CCR5 induced by the
TNF- treatment has functional consequences for the
CD45RO+ cells. Activated lymphocytes were treated
with TNF- for 48 h and then analyzed for their capacity to flux
calcium in response to CCR stimulation. We observed a significant
decrease in MIP-1ß-stimulated calcium flux in cells that were
pretreated with TNF-. By contrast, the same cells gave strong
calcium responses after stromal cell-derived factor (SDF) stimulation
(Fig. 8A). We also examined
whether pretreatment with TNF- affected the migration of T cells
toward the MIP-1ß chemokine. We found that TNF- treatment
decreased the capacity of T cells to migrate in response to MIP-1ß
(Fig. 8B). A similar effect was observed when we examined
purified CD4+ cells, which also expressed less
CCR5 after TNF- treatment (data not shown). Purified
CD4+ cells exhibited lower mobility toward
MIP-1ß after TNF- treatment (Fig. 8C). This finding
indicates that the amount of endogenous chemokines produced by
CD4+ T cells themselves is sufficient to have an
impact on the level of functional CCR5 and that
CD8+ cells are not required for this process.
Thus, TNF- can regulate CCR5 expression in
CD4+ T cells, which is a key target cell
population for HIV infection.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, an important
inflammatory protein, potently influences the expression of CCR5, which
is the receptor for the proinflammatory chemokines RANTES, MIP-1,
and MIP-1ß on T cells and a critical coreceptor for HIV. CCR5 is
up-regulated by Ag receptor stimulation of lymphocytes at the point
when the activation marker CD25 decreases and is predominantly
expressed on CD45RO+ cells. The TNF- signal
that reduces CCR5 surface expression is mainly delivered through TNFR2.
TNFR2 can activate NF-B, which participates in the production and
secretion of the chemokines RANTES, MIP-1, and MIP-1ß. It is
evident that the synthesis of these chemokines is necessary to achieve
CCR5 down-regulation, presumably by binding to the receptor. CCR5
suppression by TNF- treatment has clear functional effects. Fewer
cells migrate toward a chemotactic signal, and treated samples were not
capable of manifesting a strong calcium signal after MIP-1ß
stimulation. Thus, we have identified an inverse correlation between
TNF-, which can be produced by activated T cells or monocytes, and
the functional level of the CCR5 chemokine receptor.
It is well established that cell surface expression of CCR5 can be
modulated by internalization, which occurs as a consequence of binding
of the cognate chemokines or the chemokine derivative AOP-RANTES
(47, 48, 49, 50, 51, 52). The internalization mechanism is still under
investigation, but appears to involve the G protein-coupled receptor
kinases (GRKs) (48), of which GRK2 and GRK3 are expressed
in human PBLs. The kinases associate with the receptor and cause the
phosphorylation of serines 336, 337, 342, and 349, which is important
for the internalization process (48, 50). Also, dynamin is
associated with CCR5, causing the internalization to take place through
the formation of clathrin vesicles (51). Another report
shows an enhancement of tyrosine phosphorylation of CCR5 and the
association of Janus kinase 1/STAT5 with CCR5 after activation by
RANTES (53). Furthermore, RANTES can lead to focal
adhesion kinase association with CCR5 and Zap70; Lck and Pyk2 are
activated after ligand binding (53, 54, 55, 56). How these signals
participate in the internalization process or other signaling events is
not yet established. CCR5 down-modulation could affect signaling
elicited by the chemokines or, potentially, the HIV envelope protein
(55, 57), which may profoundly influence lymphocyte
responses because the two crucial signal molecules Lck and Zap70 are
affected. It is also important to note that under circumstances in
which the TCR is strongly reengaged (for a review, see Ref.
6), TNF- had been shown to be part of the mechanism by
which these cells undergo apoptosis (8). In the system
used in this study, we observed a maximum of 15% cell death with the
TNF- doses used, which is much less than the regression in CCR5
expression and does not account for the loss of
CCR5+ cells. The reason for the lack in death
under these circumstances is likely the fact that the sensitization or
competency signal through the TCR (58, 59) was not
provided, because we avoided TCR cross-linking by washing the cells
after the Con A treatment.
Productive infection by HIV does not involve coreceptor internalization
(47), but is strongly dependent on the level of coreceptor
expression. CD4+ cells produce sufficient amounts
of chemokines to achieve a coreceptor down-modulation exposed with TNF.
Therefore, it is likely that macrophage-tropic HIV particles cannot
efficiently enter and infect the T cells that have down-modulated CCR5
after TNF- exposure, as was demonstrated for macrophages (33, 47, 60, 61, 62). However, TNF--induced NF-B activation also
leads to an induction of the HIV long terminal repeat promoter in
previously infected T cells (63). Hence, a counterbalance
between these effects may determine the ultimate effect of TNF- on
the progression of HIV infection.
We suggest that TNF- not only enhances the migration of the
lymphocytes toward a site of inflammation by increasing chemokine
secretion, but may also influence the efficiency by which lymphocytes
migrate away from a site of inflammation through the CCR5
down-modulation. In this manner, the response to a strong inflammatory
stimulus is overcome and the lymphocyte may then migrate toward other
signals, for example, homing signals in secondary lymphoid tissue, and
away from the initial site of inflammation. The prompt exit of T cells
from the site of infection may be important for a proper immune
regulation because the inappropriate presence of T cells appears to be
a prominent pathologic effect of autoimmune diseases. In RA, for
example, the role of TNF- in disease exacerbation has been well
recognized. Only very recently a role for the chemokine receptor CCR5
in RA was confirmed, consistent with the elevated levels of RANTES
found in RA patients (64, 65). The lymphocytes found in
inflamed synovial joints of RA patients are CCR5+
(43, 66, 67). Studies on individuals with a variable CCR5
genotype revealed clinical amelioration in RA. In cases in which
heterozygosity of the 32 mutation occurred, the patients lacked
rheumatoid factor, and the swelling of the joints was decreased
compared with wild-type individuals (68, 69). In this
case, migration to the site of inflammation was reduced. In the case of
the CCR5-dependent homing, the cells may persist in the inflamed
location until the receptor is decreased. Therefore, the decrease in
receptor may be a valuable therapeutic target if internalization could
be specifically enhanced. In this case, the T cells on the site of
inflammation can execute a protective function, but then do not stay
long enough to do harm. One step in this direction is the study of
chemokine derivatives such as AOP-RANTES, which are believed to enhance
internalization and prevent receptor recycling to the surface. In vitro
AOP-RANTES is able to induce CCR5 down-modulation of RA patient cells
(66) and may have advantages compared with blocking the
chemokines with Abs if administered locally.
Another interesting aspect we have considered is that in internalizing
the receptor, the T cells actually decrease the amount of free
chemokines, which could be an important termination mechanism for the
inflammatory response. Such a mechanism has been suggested to be a
strategy by which human CMV escapes detection by the immune system.
Human CMV expresses U28, a protein homologous to chemokine receptors.
Although it can induce a calcium signal (70), its main
function may be the efficient internalization and disposal of secreted
chemokines (71). This example of a viral pathogen that
disposes of chemokines by internalization suggests that this could also
be a normal homostatic regulatory mechanism. It is notable that even
the low levels of CCR5 on 32 heterozygotes were subject to
TNF--mediated turnover. Given that the CCR5 promoter itself has an
NF-B binding site (72), which could potentially respond
to TNF-, the T cells may have developed a negative feedback loop for
limiting inflammatory responses induced by chemokines. Thus, TNF-
may play a key role in coordinating both positive and negative control
of chemokine responses.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: RA, rheumatoid arthritis; AOP, aminooxypentane; EHAA, Eagle Hanks’ amino acid; GRK, G protein-coupled receptor kinase; KBC, NF-B control peptide; KBI, NF-B-inhibitory peptide; MIP, macrophage-inflammatory protein; SDF, stromal cell-derived factor.
Received for publication January 6, 2000. Accepted for publication March 31, 2000.
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A. Glatzel, D. Wesch, F. Schiemann, E. Brandt, O. Janssen, and D. Kabelitz Patterns of Chemokine Receptor Expression on Peripheral Blood {gamma}{delta} T Lymphocytes: Strong Expression of CCR5 Is a Selective Feature of V{delta}2/V{gamma}9 {gamma}{delta} T Cells J. Immunol., May 15, 2002; 168(10): 4920 - 4929. [Abstract] [Full Text] [PDF]
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 Z. Zidek, D. Frankova, and A. Holy Activation by 9-(R)-[2-(Phosphonomethoxy)Propyl]Adenine of Chemokine (RANTES, Macrophage Inflammatory Protein 1alpha ) and Cytokine (Tumor Necrosis Factor Alpha, Interleukin-10 [IL-10], IL-1beta ) Production Antimicrob. Agents Chemother., December 1, 2001; 45(12): 3381 - 3386. [Abstract] [Full Text] [PDF]
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 S. W. Chensue Molecular Machinations: Chemokine Signals in Host-Pathogen Interactions Clin. Microbiol. Rev., October 1, 2001; 14(4): 821 - 835. [Abstract] [Full Text] [PDF]
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G. M. Bahr, E. C. A. Darcissac, N. Casteran, C. Amiel, C. Cocude, M.-J. Truong, J. Dewulf, A. Capron, and Y. Mouton Selective Regulation of Human Immunodeficiency Virus-Infected CD4+ Lymphocytes by a Synthetic Immunomodulator Leads to Potent Virus Suppression In Vitro and in hu-PBL-SCID Mice J. Virol., August 1, 2001; 75(15): 6941 - 6952. [Abstract] [Full Text]
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 B. Ebrahimi, B. M. Dutia, D. G. Brownstein, and A. A. Nash Murine Gammaherpesvirus-68 Infection Causes Multi-Organ Fibrosis and Alters Leukocyte Trafficking in Interferon-{{gamma}} Receptor Knockout Mice Am. J. Pathol., June 1, 2001; 158(6): 2117 - 2125. [Abstract] [Full Text] [PDF]
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R. L. Cotter, J. Zheng, M. Che, D. Niemann, Y. Liu, J. He, E. Thomas, and H. E. Gendelman Regulation of Human Immunodeficiency Virus Type 1 Infection, {beta}-Chemokine Production, and CCR5 Expression in CD40L-Stimulated Macrophages: Immune Control of Viral Entry J. Virol., May 1, 2001; 75(9): 4308 - 4320. [Abstract] [Full Text]
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). The graph is representative
of studies on four individuals.
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