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Laboratories of
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Molecular Immunoregulation and
Leukocyte Biology, Division of Basic Sciences, National Cancer Institute, Frederick Cancer Research and Development Center,
Intramural Research Support Program and
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AIDS Vaccine Program, SAIC Frederick, and
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Advanced BioScience Laboratories-Basic Research Program, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, MD 21702; and
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Uniformed Services University of the Health Sciences, Bethesda, MD 20814
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although CD4+ T lymphocyte depletion is a central feature of the immunosuppression in AIDS patients, monocyte-macrophages are also targets of HIV-1 infection. Earlier studies demonstrated that monocytes from AIDS patients exhibited a significantly compromised capacity to migrate in response to several chemotactic factors, including activated complement component C5a, the bacterial peptide FMLP, and undefined lymphocyte-derived chemotactic factors (19). Incubation of monocytes with soluble gp120 also has been reported to suppress the expression of receptors for C5a and FMLP (20). Since chemokines are important mediators of host defense, we postulated that shed gp120, which can be present in copious quantities in AIDS patients (21), may also inhibit the monocyte response to chemokines, thus contributing to the anti-inflammatory and immunosupressive effects of HIV-1. Our study shows that preincubation with gp120 from various strains of HIV-1 can suppress monocyte responses to a variety of chemokines as well as to FMLP in association with CD4 signal-dependent down-regulation of chemokine receptors.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Natural gp120 was isolated from the culture fluid of HIV-1 (MN or RF)-infected H9 cells by immunoaffinity chromatography (22). Recombinant gp120 (strains MN and IIIB) and recombinant soluble CD4 were purchased form Intracel (Cambridge, MA). At the highest concentration tested, the gp120 preparations had <0.2 ng/ml of endotoxin activity. Anti-CD4 mAbs were purchased from Biogenesis (Poole, U.K.). Both clones A6 and E9 were able to stain CD4 on the cell surface, and clone E9 was able to block HIV binding, as described by the manufacturer. Anti-CD14 mAb (clone K4) was purchased from Dako (Carpinteria, CA). Recombinant chemokines were obtained from PeproTech (Rocky Hill, NJ). Radioiodinated chemokines were purchased from DuPont-New England Nuclear (Boston, MA). Human PBMC were isolated from buffy coat (National Institutes of Health Clinical Center, Transfusion Medicine Department, Bethesda, MD) enriched for mononuclear cells using iso-osmotic Percoll gradient as previously described (23). Neutrophils were isolated from buffy coat blood with dextran sedimentation as previously described (23). The purity of the cell preparations was examined by morphology and was >90% for monocytes and >98% for neutrophils. The CCR5-transfected HEK 293 cells were a gift from Dr. P. Gray (ICOS, Seattle, WA). CCR1 and CXCR4/fusin cDNA were isolated in this laboratory and were transfected into 293 cells as previously described (24). CCR2b cDNA was supplied by Dr. I. Charo (University of California, San Francisco, CA) and was stably transfected into 293 cells in this laboratory. The viability of monocytes or HEK 293 cells before and after gp120 treatment was examined by trypan blue exclusion and was >95% after up to 18-h treatment at 37°C.
Calcium mobilization
Ca2+ mobilization was performed using FACS analysis through the courtesy of Ms. L. Finch (SAIC Frederick, Frederick, MD). Monocytes (107 cells) loaded with indo-1 were treated with gp120 (MN; 50 nM) or medium (RPMI 1640; 10 mg/ml BSA) alone for 60 min at 37°C. The loaded cells were washed, resuspended in fresh medium, then stimulated with gp120 (MN; 50 nM), chemokines (10 nM), or FMLP (10 nM). The bound/free ratio of indo-1 was continuously recorded using EPICS 753 (Coulter, Miami, FL). The percentage of responding cells was estimated.
Chemotaxis assays
Chemotaxis assays were performed using a 48-well chemotaxis chamber (Neuroprobe, Cabin John, MD) as described previously (23). Chemoattractants were placed in the lower wells of the chamber, 50 µl of cells (monocytes or neutrophils at 2 x 106/ml, HEK 293 cells at 1 x 106/ml) were placed in the upper wells. The upper and lower wells were separated by a polycarbonate filter (5-µm pore size). For 293 cells the filter of 10-µm pore size was precoated with collagen IV as previously described (25). After incubation (90 min for monocytes, 60 min for neutrophils, 5 h for 293 cells) at 37°C, the filters were removed and stained, and the cells migrated across the filters were counted after coding the samples. Results were calculated as the mean (±SD) number of migrated cells in three high powered light microscopy fields in triplicate samples. The chemotaxis index was calculated as follows: chemotaxis index = number of migrated cells in response to chemoattractant/number of randomly migrated cells (in response to medium). In chemotaxis deactivation experiments, monocytes (or neutrophils) and HEK 293 cells transfected with chemokine receptors were preincubated with chemoattractants or gp120 for 30 or 60 min at 37°C, then washed three times with PBS. The cell migration in response to various chemoattractants was assessed and computed as described above. After subtraction of background migration (in response to medium), the percent deactivation of chemotaxis to a given chemoattractant was calculated by the formula: 1 - migration of cells preincubated with gp120/migration of cells preincubated with medium x 100%.
Binding assays
Binding assays were performed by preincubating duplicate samples of monocytes (2 x 106/sample) or chemokine receptor-transfected 293 cells (1 x 106/sample) with different concentrations of gp120 for 60 min at 37°C in a volume of 200 µl/sample of binding medium (RPMI 1640, 1% BSA, 5 mM HEPES, and 0.05% NaN3). Radiolabeled chemokines (0.12 nM) were then added to each sample. To parallel duplicate samples, different concentrations of gp120 or unlabeled chemokines (as control) were added simultaneously with radiolabeled chemokines. After incubation at room temperature for 40 min, the cells were centrifuged through a 10% sucrose/PBS cushion, and the cell-associated radioactivity was measured in a gamma counter. The percent reduction of chemokine binding to monocytes by gp120 treatment was calculated by the formula: 1 - (counts per minute associated with cells preincubated with gp120/counts per minute associated with cells incubated with medium alone) x 100.
To determine the change in the number of binding sites and the affinity for a given chemokine, cells were preincubated with or without gp120 (25 nM) for 60 min at 37°C. The duplicate monocyte samples were then incubated with 0.12 nM radiolabeled chemokines in the presence of increasing concentrations of unlabeled chemokines. The cells were pelleted after 40 min at room temperature and measured for radioactivity. The binding data were analyzed and plotted with a Macintosh computer program, LIGAND (Dr. P. Muson, Division of Computer Research and Technology, National Institutes of Health, Bethesda, MD).
Confocal microscopy
HEK 293 cells expressing CXCR4 with and without intact CD4 were
pretreated for 3 h at 37°C with SDF-1
, recombinant gp120
(IIIB, MN, or CM; 25 nM) or anti-CD4 mAb (A6; 5 µg/ml). The cells
were centrifuged onto slides and permeabilized. The slides were then
stained with an anti-CXCR4/fusin mAb (12G5) followed by incubation
with FITC-labeled goat anti-mouse IgG F(ab')2. Slides
were examined using a Zeiss 310 Confocal Laser Scanning Microscope
(Carl Zeiss, New York, NY). Nomarski, FITC (488 nm; green), and DAPI
(UV 364 nm; blue) images were prepared for each specimen, and colored
images were superimposed on Nomarski.
Statistical analysis
All experiments were performed at least three times unless specified, and the results presented are either from a representative experiment or from a pool of experiments. The significance of the difference between experimental and control groups was analyzed with Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Since the chemotactic response of monocytes from AIDS patients has
been reported to be defective (19), and soluble gp120 suppresses the
expression of receptors for C5a and FMLP on normal monocytes (20), we
initially investigated the effect of gp120 on the capacity of monocytes
to respond to chemokines as well as to FMLP. We confirmed a previous
report (25) that both native and recombinant gp120 were also weakly
chemotactic for human monocytes. However, gp120 was not chemotactic for
HEK 293 cells transfected with CCR5 or CXCR4, which did show
significant migration in response to the chemokines SDF-1 and
MIP-1ß (data not shown), suggesting that gp120 can only induce
CD4-expressing cells to migrate. The recombinant gp120 of the MN strain
at a concentration range of 1 to 100 nM did not induce significant
Ca2+ mobilization in monocytes (Fig. 1
A and data not shown). This
gp120 also did not desensitize the subsequent (within 100 s)
monocyte response to chemokines or FMLP (not shown), suggesting that
the gp120 used in the assay did not activate the receptors for FMLP or
for the chemokines tested. However, preincubation of monocytes with
increasing concentrations of gp120 for 1 h at 37°C significantly
reduced the monocyte response to a number of chemokines and the
bacterial chemotactic peptide FMLP. Figure 1 shows that at 50 nM, gp120
of the MN strain almost completely abolished the Ca2+
mobilization induced by MIP-1, RANTES, SDF-1 (10 nM), as well as
FMLP (10 nM; Fig. 1B). The Ca2+ mobilization
induced by MCP-1 (10 nM) was also significantly reduced by
preincubation of monocytes with gp120 (Fig. 1B).
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, the ligand
for CXCR4/fusin (Table I). In Table I,
the effect of gp120 (MN) at 10 nM is shown. The inhibition of monocyte
migration by gp120 could also be demonstrated for FMLP (Table I), which
uses a seven-transmembrane receptor structurally related to chemokine
receptors. Since gp120 had previously been considered to be a ligand
for CD4, the contribution of CD4 to these desensitizing effects of
gp120 was evaluated. In fact, gp120 failed to inhibit directional
migration of chemokine receptor transfected HEK 293 cells lacking CD4
in response to their respective chemokines (data not shown). In
addition, as shown in Table I, preincubation of gp120 with soluble CD4
completely abolished the inhibitory effect of gp120 on monocyte
migration induced by chemokines and FMLP, suggesting a critical role of
cell membrane CD4 molecules in mediating this suppressive activity of
gp120. The inhibitory effect of gp120 on monocyte migration was also
totally eliminated by preincubation with an anti-gp120 mAb (data
not shown). The gp120 did not affect the chemotactic response of
neutrophils to FMLP or IL-8 (data not shown), further supporting a
requirement for cell surface CD4 for the gp120 effect.
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To test whether gp120 might compete with chemokines for binding
sites on monocytes, soluble recombinant or purified natural gp120 (MN)
(22) and radiolabeled chemokines were added simultaneously to human
peripheral blood monocytes as previously described (23). While all
unlabeled chemokines (60–120 nM) showed the expected competition for
binding by radiolabeled ligands (Fig. 2,
horizontal lines), gp120 showed little or no direct competition with
radiolabeled chemokines for binding sites on monocytes or neutrophils
(Fig. 2, open circles).
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, A–E, closed
circles). The IC50 for gp120 inhibition of monocyte binding
of chemokines (0.1, 1.0, and 5.0 nM for MIP-1, MIP-1ß, and RANTES,
respectively) was similar to the IC50 obtained by the
direct competitive effect of the native ligands (0.3, 0.6, and 1.0 nM
for MIP-1, MIP-1ß, and RANTES, respectively). Consequently,
preincubation of monocytes with gp120 not only inhibited their capacity
to bind MIP-1ß, which uses exclusively CCR5 (26, 27), but also
inhibited their binding of MIP-1 and RANTES, which, in addition, use
CCR1 (28, 29) and other C-C chemokine receptors (3, 26). Furthermore,
the capacity of monocytes to bind [125I]MCP-1 and
[125I]MCP-2 was inhibited up to 50% by preincubation of
the cells with gp120 (Fig. 2, D and E), even
though these chemokines have been reported to predominantly use CCR2b
(3, 26) and/or CCR1 (30), respectively. Preincubation with gp120 also
significantly inhibited the monocyte expression of the binding sites
for SDF-1, the only known ligand for the T tropic HIV-1 fusion
cofactor CXCR4 (Fig. 2F). The suppressive effect on monocyte expression
of chemokine binding sites was not limited to purified gp120 of the MN
strain. Preincubation with other native and recombinant gp120 from T
cell line-adapted virus, such as IIIB, as well as a recombinant gp120
from a monocyte tropic strain, CM, significantly interfered with
the capacity of monocytes to bind chemokines (data not shown). In
contrast, gp120 did not inhibit the neutrophil binding of the CXC
chemokine, IL-8, a potent chemotactic factor for neutrophils rather
than monocytes (data not shown). These results showed that the
reduction in chemokine binding to monocytes preincubated with soluble
gp120 is more generalized than the reported capacity of chemokines to
competitively inhibit HIV-1 entry and envelope-mediated cell fusion
(31, 32). Down-regulation of chemokine binding sites on monocytes by gp120 requires CD4
We examined whether the down-regulation by gp120 of chemokine
binding sites on monocytes also required the presence of CD4 as
manifested in chemotaxis experiments. Preincubation of HEK 293 cells
expressing functional CCR5, CCR1, or CXCR4 with gp120 from MN, IIIB, or
CM strains did not reduce their ability to bind chemokines (data not
shown), indicating that these chemokine receptors did not directly
interact with the gp120 tested. On the other hand, the inhibitory
effect of gp120 on monocyte binding of C-C chemokines was blocked by
pretreatment of gp120 with soluble CD4 (Table II), in correlation with the observation
in cell migration (Table I). This suggests that soluble CD4 sequesters
gp120 and prevents its binding to cell membrane-anchored CD4 and the
consequent down-regulation of chemokine receptors. To examine whether
the suppressive effect on monocyte expression of chemokine binding
sites was exclusive for gp120 or whether other activators of CD4 have a
similar effect, we used anti-CD4 mAbs. Preincubation with
anti-CD4 mAbs reproduced the effect of gp120 in inhibiting monocyte
binding of MIP-1ß, whereas anti-CD14 mAb had no effect (Fig. 3). The anti-CD4 Abs also reduced the
capacity of monocytes to bind other chemokines, such as SDF1, MCP-1,
and MCP-2 (data not shown).
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) in HEK 293 cells
transfected to express both CD4 and CXCR4/fusin, but not in cells
expressing CXCR4/fusin alone. The apparent requirement for initial
interaction of gp120 with CD4 is in agreement with the recent report
that preincubation of CD4+/fusin (CXCR4)+ T
cells with gp120 resulted in the formation of a gp120/CD4/fusin complex
that could be coprecipitated with Abs against any one of these three
molecules (33). Our results also indicate that ligation of CD4 with
anti-CD4 is sufficient to internalize chemokine receptors with the
resultant inhibition of the ability of CD4+ cells to bind
chemokines. Although in Figure 4, only the results obtained with gp120
IIIB and CXCR4/CD4/293 cells after 3-h treatment are presented, the
internalization was already significant at 1-h incubation, and similar
internalizing effects were obtained with gp120 of the MN and CM
strains. In addition, CCR5 was also markedly internalized by gp120 in
293 cells provided they were also transfected to express CD4 (data not
shown).
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The interaction of HIV-1 with CD4 and the coreceptors and the
resultant HIV-1-cell fusion were reported to be resistant to pertussis
toxin, suggesting that the virus competes for chemokine receptor
occupancy, resulting in fusion without requiring G protein signaling in
target cells (32, 34). However, interaction of gp120 with CD4 and
coreceptors has been reported to induce G protein activation (18) and
tyrosine kinase signaling events in T cells or transfected cells (35).
In our study, the need to preincubate monocytes at 37°C for 1 h
with gp120 to down-regulate chemokine binding sites suggested that
binding of CD4 by gp120 may transduce signals. It has been observed
previously that gp120 triggers intracellular signals, such as
translocation of protein kinase C and the production of metabolites of
arachidonic acid in monocytes (36, 37). It has also been reported that
PMA, a protein kinase C activator, down-regulated an HIV-1 fusion
cofactor, later identified as CXCR4/fusin (33), and inhibited T cell
viral entry (38). We therefore investigated whether the suppressive
effect of gp120 on chemoattractant receptors requires CD4-dependent
protein kinase activation. We confirmed that gp120 as well as
anti-CD4 Ab enhanced the PKC activation in monocytes (G. Evans and
H. Ueda, unpublished observation) and pretreatment of monocytes
with the protein kinase inhibitor, staurosporine, prevented the
down-regulation of MIP-1ß binding sites on monocytes by gp120 (Fig. 5). The ability of monocytes to bind
other CC chemokines and SDF-1 could also be protected by
pretreatment with staurosporine before the addition of gp120 (not
shown). A more specific PKC inhibitor, calphostin C, could mimic the
protective effect of staurosporine (data not shown). These observations
suggest that binding of gp120 to CD4 on monocytes activates
intracellular protein kinase activity, which, in turn, down-regulates
chemoattractant receptor expression and function. This was further
investigated by comparing the response to gp120 of HEK 293 cells
transfected with tail-less or intact CD4. The ability of HEK 293 cells
to bind MIP-1ß could not be inhibited by preincubation of the cells
with gp120 or anti-CD4 Ab if the cells expressed CCR5 and a CD4
lacking its cytoplasmic tail, whereas the binding capacity of the
CCR5/293 cells transfected with intact CD4 was inhibited by gp120 or
anti-CD4 Ab (Table III), again
suggesting that CD4 is an active rather than passive participant in the
down-regulation of chemoattractant receptor expression by gp120.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In contrast with T cells, the nature of the interaction of gp120 with
CD4 and cofactors on monocytes has not been as well characterized. CD4
on monocytes/macrophages is known to act as a HIV-1 fusion cofactor for
monocyte tropic strains. In this study, we demonstrated for the first
time that HIV-1 gp120 markedly inhibited monocyte responses to a
variety of chemokines in association with down-regulation of the
receptor expression on the cell surface via a CD4-dependent pathway.
This inhibition was apparently not due to a direct competition with
chemokines for binding sites by gp120, but required CD4-mediated
signaling events operationally resembling heterologous desensitization.
This was demonstrated by the facts that 1) the effect of gp120 required
a period of preincubation and was observed only on CD4-positive
monocytes and HEK 293 cells transfected to express intact CD4; 2)
anti-CD4, but not anti-CD14, mAbs emulated the inhibitory
effect of gp120 on both monocytes and CD4+/HEK 293 cells;
3) the effect was observed on HEK 293 cells expressing only intact CD4,
which retains the cytoplasmic domain, but not on cells expressing a
tail-less CD4; and 4) monocytes pretreated with protein kinase
inhibitors such as staurosporine (Fig. 5) and calphostin C (data not
shown), but not pertussis toxin, were protected from the inhibitory
effect of gp120. In addition, preincubation of monocytes with gp120 at
37°C for 1 h markedly inhibited Ca2+ mobilization
and chemotactic migration in response to chemokines as well as FMLP.
Confocal microscopy clearly demonstrated internalization of CXCR4/fusin
by gp120 in the presence of CD4. The gp120 from various strains as well
as anti-CD4 Ab suppressed the expression and function of
chemoattractant receptors on monocytes. The down-regulation of CXCR4
and CCR5 on monocytes by gp120 of the MN or CM strain was confirmed by
FACS analyses using commercially available Abs. After 1-h incubation
with 50 nM gp120, CXCR4 or CCR5 staining on monocytes was reduced by
>50% (data not shown). These observations strongly suggest that
inhibition of chemoattractant receptor expression and function by gp120
is dependent on cross-talk between CD4 and the seven transmembrane
receptors. This cross-talk of CD4 and CXCR4 or CCR5 could also
initiate a cascade of signaling events that lead to the desensitization
of the receptors for other chemoattractants and IL-2 (18, 35). Further
studies are in progress to elucidate whether chemoattractant receptors
are phosphorylated by CD4-mediated kinase activation.
CD4 has been shown to play many roles that serve to either increase or
suppress immune responses. CD4 was originally identified as a
phenotypic marker and subsequently as a high affinity receptor for
HIV-1 envelope protein gp120 (39). CD4 facilitates T cell function by
binding to the nonpolymorphic region of the MHC class II Ags expressed
on the surface of APCs. However, an inhibitory role for CD4 in the
activation of T lymphocytes has been suggested by reports that
anti-CD4 Abs abrogate a variety of T lymphocyte effector functions
in vitro, including IL-2R 
-chain expression and IL-2-induced
lymphocyte proliferation, and graft rejection (39). CD4 participates in
signal transduction by its cytoplasmic domain through association with
the src-like protein tyrosine kinase lck in T
lymphocytes (39), and such signals may lead to down-regulation of TCR
as well as cytokine (IL-2) receptors. Our data suggest that signals
emanating from CD4 culminate in down-regulation of chemoattractant
receptors in monocytes. We have also observed in another study that
down-regulation of chemokine receptor CXCR4 by gp120 occurred in
resting CD4+ T lymphocytes, which involves active
participation of CD4. In CD4+, but not CD8+, T
cells, gp120 induced rapid tyrosine phosphorylation of the
src-like kinase p56lck,
associated with down-regulation of CXCR4 expression and function (S. S.
Su, G. C. Grimm, J. J. Oppenheim, and J. M. Wang, manuscript in
preparation). Pretreatment of the CD4 T cells with tyrosine kinase
inhibitor herbimycin A, but not staurosporine, completely restored the
ability of CD4 T cells to express functional CXCR4. These observations
suggest that although diverse signaling events are triggered by gp120
through CD4 in T cells and monocytes, each of them results in the
down-regulation of chemokine receptors.
In our study, natural and recombinant gp120 from T cell tropic strains MN, IIIB, and RF as well as the recombinant monocyte tropic CM strain all exhibited similar effects on monocytes, which differs from the restricted tropism exhibited during the viral fusion process. This could be due to the fact that the CD4 binding region is conserved in gp120 from primary isolates (40) and T cell line-adapted viruses, thus enabling gp120 from different HIV-1 strains to bind and activate monocyte CD4, with consequent down-regulation of chemoattractant receptor expression. Further efforts are being made in our laboratory to identify critical epitopes responsible for CD4 binding, and possibly signaling, on both mono- and T tropic viral envelope proteins. A 20-amino acid sequence of gp120 from the MN strain corresponding to the putative CD4 binding epitope has been found to be a potent chemoattractant for monocytes and to down-regulate chemokine receptor expression on the cells. The activity of this peptide was abolished by soluble CD4 (H. Ueda and J. M. Wang, unpublished observation), which provides additional evidence that CD4 on monocytes is capable of activating signaling pathways negatively affecting the cell response to other proinflammatory stimulants such as chemokines.
The availability of gp120 in AIDS patients has been documented in a number of reports. In the course of the HIV-1 infection, some of the gp120 detected in the sera of patients may, in fact, be complexed by anti-gp120. However, it is unlikely that the effects of gp120 are completely blocked by the Abs because there are considerable variations in the specificity, amount, and timing of anti-gp120 Ab production (41, 42, 43). In most patients, serum anti-gp120 Abs appear relatively late and were first detected only after p24 Ag and infectious virus titer in the peripheral blood had declined manyfold from their highest values (41). Many of the anti-gp120 Abs do not actually have the capacity to recognize the CD4 binding structure on gp120. This is manifested by the failure of these Abs to compete for gp120 binding to CD4 with a neutralizing anti-gp120 human mAb that does recognize the conformational CD4-binding structure on gp120 (43). Such neutralizing Ab appeared later in the patients’ sera than other anti-gp120 Abs that do not block the CD4 binding structure on gp120 (42). These observations suggest that there could be an ample opportunity for the virus-associated or "shed" gp120 (21) to interact with CD4 on immune cells. Furthermore, the binding of gp120 to CD4 is of high affinity, which is comparable to or even greater than the Ab affinities (44). In fact, gp120 that is not associated with viral particles can be detected on the surface of explanted CD4 T cells from patients (45). These observations strongly argue that gp120 can have biologic effects on the cells of infected individuals.
Our findings suggest that gp120 can have a number of intriguing effects on the host that require further evaluation. On the one hand, gp120 may recruit and activate monocytes during the course of viral infection. This activation of monocytes by gp120 results in the internalization of a number of chemoattractant receptors, including HIV-1 fusion coreceptors, which may contribute to the reported viral interference following initial infection (40) as well as to the suppression of monocyte-dependent inflammatory reactions. The inhibitory effects of gp120 on chemokine and other chemoattractant receptors can be exploited to develop anti-inflammatory agents that interfere with monocyte recruitment based on the structure and mechanism of gp120 action.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Ji Ming Wang, Laboratory of Molecular Immunoregulation, Division of Basic Sciences, National Cancer Institute, Frederick Cancer Research and Development Center, Building 560, Room 31-19, Frederick, MD 21702-1201. E-mail address:
3 Abbreviations used in this paper: CXCR, CXC chemokine receptor; CCR, CC chemokine receptor; SDF-1, stromal cell-derived factor; MIP, macrophage inflammatory protein; MCP, monocyte chemotactic protein.
Received for publication January 22, 1998. Accepted for publication June 11, 1998.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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S. B. Su, W. Gong, M. Grimm, I. Utsunomiya, R. Sargeant, J. J. Oppenheim, and J. Ming Wang Inhibition of Tyrosine Kinase Activation Blocks the Down-Regulation of CXC Chemokine Receptor 4 by HIV-1 gp120 in CD4+ T Cells J. Immunol., June 15, 1999; 162(12): 7128 - 7132. [Abstract] [Full Text] [PDF]
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S. B. Su, W.-h. Gong, J.-L. Gao, W.-P. Shen, M. C. Grimm, X. Deng, P. M. Murphy, J. J. Oppenheim, and J. M. Wang T20/DP178, an Ectodomain Peptide of Human Immunodeficiency Virus Type 1 gp41, Is an Activator of Human Phagocyte N-Formyl Peptide Receptor Blood, June 1, 1999; 93(11): 3885 - 3892. [Abstract] [Full Text] [PDF]
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S. B. Su, J.-l. Gao, W.-h. Gong, N. M. Dunlop, P. M. Murphy, J. J. Oppenheim, and J. M. Wang T21/DP107, A Synthetic Leucine Zipper-Like Domain of the HIV-1 Envelope gp41, Attracts and Activates Human Phagocytes by Using G-Protein-Coupled Formyl Peptide Receptors J. Immunol., May 15, 1999; 162(10): 5924 - 5930. [Abstract] [Full Text] [PDF]
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 Q.-H. Liu, D. A. Williams, C. McManus, F. Baribaud, R. W. Doms, D. Schols, E. De Clercq, M. I. Kotlikoff, R. G. Collman, and B. D. Freedman HIV-1 gp120 and chemokines activate ion channels in primary macrophages through CCR5 and CXCR4 stimulation PNAS, April 25, 2000; 97(9): 4832 - 4837. [Abstract] [Full Text] [PDF]
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