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-Chemokines in Human Peripheral Blood Monocytes Through a CD4-Independent Mechanism1
Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-chemokines in
cultured monocytes/macrophages. Treatment of either freshly isolated
1-day-cultured monocytes or 7-day-cultured monocyte-derived macrophages
(MDM) with recombinant gp120-IIIB resulted in a specific and
dose-dependent enhancement of secretion of monocyte chemoattractant
protein-1, macrophage inflammatory protein-1, and RANTES as well as
a clear-cut increase in transcript accumulation. The expression of
these mRNA was increased, but not superinduced, in the presence of
cycloheximide. -Chemokine secretion was also induced after exposure
of monocyte cultures to gp120-JRFL and aldrithiol-2-inactivated R5 and
X4 HIV-1 strains, retaining conformational and functional integrity of
envelope proteins. In contrast, no -chemokine secretion was
triggered by X4 and R5 gp120 or aldrithiol-2-inactivated virus
treatment of monocytoid cell lines that were fully responsive to LPS.
The gp120-mediated effect was independent of its interaction with CD4,
as preincubation with soluble CD4 did not abrogate -chemokine
induction. Moreover, triggering of CD4 receptor by a specific Ab did
not result in any -chemokine secretion. Interestingly, engagement of
CCR5 and CXCR4 receptors by specific Abs as well as treatment with CCR5
and CXCR4 ligands induced -chemokine secretion. On the whole, these
results indicate that HIV-1 stimulates monocytes/macrophages to produce
-chemokines by a specific interaction of gp120 with HIV-1
coreceptors on the cell membrane. The expression of these related
polypeptides may represent an important cellular response for
regulating both the extent of viral infection and the recruitment of
immune cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chemokines) and the C-C
(-chemokines) families, according to their arrangement of cysteine
residues. The -chemokines are primarily active on neutrophils, but
some activity has also been reported on T lymphocytes (4).
In contrast, the -chemokines exhibit a wide spectrum of action, in
that they are active on multiple leukocyte populations, including
monocytes, granulocytes, T lymphocytes, NK, and dendritic cells
(5, 6). Recent evidence has clearly shown that chemokines
and their receptors may play an important role in the regulation of
HIV-1 infection (7, 8). In particular, (i.e., stromal
derived factor-1
(SDF-1)3) and
-chemokines (i.e., RANTES, macrophage inflammatory protein
(MIP)-1, MIP-1, and monocyte chemoattractant protein (MCP)-3)
have a potent suppressive effect on HIV-1 infection resulting from an
early postbinding block in virus fusion and entry (9, 10, 11, 12, 13, 14, 15, 16, 17).
Interestingly, some of these factors have also been reported to have a
stimulating effect on HIV attachment, replication, and cell-mediated
transmission (18, 19, 20, 21, 22). However, the in vivo role of
-chemokines in the pathogenesis of HIV disease remains to be fully
elucidated. Some studies have also shown that changes in the production
of specific chemokines occur in the course of HIV infection. In this
regard, an increased production of MIP-1, MIP-1, RANTES, and
MCP-1 has been observed in macrophages infected in vitro with HIV-1
(23, 24, 25, 26). Likewise, elevated levels of some chemokines
have been found in the CSF of patients with HIV encephalitis,
suggesting the involvement of these molecules in HIV-related and
associated pathology of the nervous system (27, 28, 29, 30). The
stimulation of chemokines production by HIV infection has been observed
in the presence (23, 24, 26) and in the absence
(25) of active viral replication. Although it has been
reported that the addition of exogenous Tat protein induced MCP-1
production in astrocytes (29) as well as in peripheral
blood monocytes (26), little information is currently
available on the roles of other viral products.
In this study we report that the treatment of monocytes/macrophages
with HIV-1 gp120 as well as with inactivated R5 and X4 HIV-1 strains
results in the production of MCP-1, MIP-1, and RANTES. Notably,
-chemokine secretion is also induced following engagement of CCR5
and CXCR4, but not CD4 receptors, by specific Abs or ligands. These
results indicate that early interactions between monocyte/macrophage
cell surface and HIV external components can stimulate -chemokine
secretion in the absence of a productive infection. The expression of
these different, but related, polypeptides after stimulation of
monocytes/macrophages with HIV-1 may represent an important response
for regulating both viral spreading and the type of immune cells
recruited during the course of viral infection.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PBMC were obtained from 18- to 40-year-old healthy men as previously described (31). Monocytes were separated from lymphocytes by Percoll gradient centrifugation (32). Cells were then cultured in endotoxin-free Iscove’s medium containing 15% FCS (0.22-µm pore size filter) for 24 h (defined here as 1-day monocytes) or 7 days (7-day monocyte-derived macrophages (MDM)). Cytochemical (i.e., sodium fluoride-inhibited esterase activity) and surface marker (i.e., CD14 Ag) analysis revealed that the adherent cell population consisted of >95% monocytes.
Cell lines
U937 cells, a well-known human promonocytic cell line, were cultured in RPMI 1640 containing 10% heat-inactivated FCS. THP-1 cells were cultured in the same medium containing 5 x 10-5 M 2-ME.
Reagents
LPS and cycloheximide (CHX) were purchased from Sigma (St.
Louis, MO). mAb to human CD4 (SIM 4, catalog no. 724) and soluble CD4
(catalog no. 1813) were provided by the National Institutes of Health
AIDS Research and Reference Reagent Program. Recombinant HIV-1 gp120
(strain IIIB) was purchased from Intracel (London, U.K.) and
ImmunoDiagnostics (Bedford, MA). Recombinant HIV-1 gp120 (strain JRFL)
was provided by R. Doms. mAbs to human CCR5 (clone 45529.111) and CXCR4
(clone 44717.111) were purchased from R&D Systems (Minneapolis, MN).
SDF-1, SDF-1, and MIP-1 were purchased from PeproTech (London,
U.K.). LPS contamination of reagents was excluded by checking their
endotoxin activity by the Limulus amebocyte assay (Charles
River Endosafe, Charleston, SC; detection limit, 0.125 endotoxin U/ml).
The endotoxin content determined in gp120-IIIB, gp120-JRFL, and Ab to
CXCR4 and CCR5 preparations was <0.125 endotoxin U/ml. The gp120 was
inactivated by boiling the protein for 30 min.
Virus inactivation procedure
For HIV-1 IIIB and BaL inactivation, a 100 mM stock solution of the compound 2,2'-dithiodipyridine (aldrithiol-2; AT-2) was prepared and added directly to viral stocks at a final concentration of 1 mM. Virus preparations were treated for 1 h at 37°C and then kept on ice for 2 h. At the end of the inactivating procedure, treatment agent was removed by ultracentrifugation at 17,000 x g for 1 h at 4°C. Viral pellets were resuspended in endotoxin-free Iscove’s medium containing 15% FCS.
Measurements of MCP-1, MIP-1, and RANTES
The levels of MCP-1, MIP-1, and RANTES present in culture
supernatants were measured using ELISAs. ELISA kits were purchased from
R&D Systems. The detection limit was 5 pg/ml for MCP-1 and RANTES and 4
pg/ml for MIP-1.
RT-PCR detection of MCP-1, MIP-1, and RANTES mRNA
Total RNA was extracted by the method of Chirgwin
(33) and reverse transcribed as previously described
(31). A 1/10 dilution of the cDNA product was amplified in
a 20-µl reaction mixture (31) containing 0.5 U of Taq
polymerase (Perkin-Elmer, Foster City, CA). Amplification (40 s at
94°C, 1 min at 62°C, and 1 min at 72°C) was performed for 17–20
cycles with MCP-1 primers and for 20–25 cycles with GAPDH, RANTES, and
MIP-1 primers; amplification was preceded by a denaturation step (3
min at 94°C) and was followed by a final extension period (10 min at
72°C). PCR products were analyzed by 2.5% agarose gel
electrophoresis and visualized by ethidium bromide staining. The
sequences of the GAPDH, MCP-1, MIP-1, and RANTES primers have been
previously described (24, 31, 34, 35).
Statistical analysis
Statistical analysis of data was performed using the nonparametric Kruskal-Wallis test. Values of p < 0.05 were considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and RANTES by HIV-1 gp120
We have investigated the effect of X4 gp120 (HIV-1 IIIB strain) on
the production of -chemokines in monocytes at different stages of
differentiation. As shown in Fig. 1
, 1-day monocytes spontaneously released variable amounts of MIP-1
and, to a greater extent, MCP-1. The secretion of these chemokines was
generally increased during in vitro differentiation. In contrast,
barely detectable levels of RANTES were occasionally found in
monocytes/macrophages independently of the differentiation stage. The
addition of HIV-1 gp120 to monocytes/macrophages markedly enhanced the
secretion of MCP-1 and MIP-1 and, to a lesser extent, RANTES
compared with unstimulated cultures (Fig. 1). The capacity of
monocytes/macrophages to secrete -chemokines in response to gp120
was not related to their differentiation state, as comparable levels of
induction were found in 1-day monocytes and 7-day MDM. Similar results
were obtained with R5 gp120 (JRFL strain; data not shown). Experiments
were then conducted to evaluate the minimal amount of gp120 required to
induce -chemokine secretion in 7-day MDM. As shown in Fig. 2, gp120 induced MCP-1, MIP-1, and
RANTES secretion in a dose-dependent manner. Macrophages from all
donors consistently secreted MCP-1 and MIP-1 in response to gp120
concentrations of 1000 and 300 ng, respectively, whereas only the
higher gp120 concentration (1000 ng/ml) induced RANTES secretion in all
donors. At lower doses (100 and 30 ng/ml) no significant induction was
observed (Fig. 2).
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-chemokines
As LPS is an inducer of -chemokines (36), we first
excluded any detectable presence of this molecule in our gp120
preparations using the Limulus amebocyte assay. Notably,
gp120 was even more effective than LPS in inducing the secretion of
MCP-1 and MIP-1 (Table I). Moreover,
no induction of chemokine secretion was detected after treatment with
heat-inactivated gp120. In this regard, it is worthwhile to mention
that LPS is thermostable and not inactivated at 120°C for 30 min
(37). The capacity of gp120 to induce -chemokine
secretion was not restricted to X4 gp120 (IIIB strain), as similar
results were obtained after treatment with R5 gp120 (JRFL strain; Table I). To further support the specificity of gp120-induced -chemokine
production, 7-day MDM were exposed to AT-2-inactivated HIV-1 virions.
In contrast to conventional methods of inactivation (i.e., heat or
formalin treatment), this inactivation procedure allows viruses to
retain conformational and functional integrity of viral surface
proteins (38). As shown in Table I, exposure of 7-day MDM
to AT-2-inactivated R5 and X4 HIV-1 strains resulted in a marked
induction of MCP-1 and MIP-1 secretion and, to a lesser extent,
RANTES.
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-chemokines in monocytic
cell lines
Previous studies have shown that -chemokine production can be
induced in monocytic cell lines in response to HIV infection
(26). Therefore, experiments were conducted to establish
whether gp120 treatment could induce -chemokine secretion in some
monocytic cell lines. As shown in Table II, although LPS induced a clear-cut
secretion of MCP-1, MIP-1, and RANTES in THP-1 and U937 cells, no
increase over the basal levels of these chemokines was detected after
gp120 treatment, indicating a specificity of the gp120 effect on
primary monocytes.
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, and RANTES transcripts expression by
gp120
Experiments were then conducted to investigate whether the
increased secretion of -chemokines induced by gp120 was associated
with an enhanced accumulation of the corresponding mRNA. As shown in
Fig. 3, gp120 induced a clear-cut
accumulation of MCP-1, MIP-1, and RANTES mRNA in 7-day MDM. In
addition, a typical protein synthesis inhibitor, such as CHX, also
induced a marked increase in the steady state levels of MCP-1,
MIP-1, and RANTES transcripts. However, the simultaneous addition of
CHX and gp120 did not further induce mRNA accumulation.
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-chemokines
To establish the relative importance of gp120 interactions with
CD4 and chemokine receptors to the gp120-induced secretion of
-chemokines, the effects of Abs directed against CD4, CXCR4, and
CCR5 receptors were investigated. As shown in Fig. 4, the CD4 engagement by a specific Ab
mimicking gp120 binding did not result in any MCP-1, MIP-1, and
RANTES induction in 7-day MDM. In addition, preincubation of gp120-IIIB
with soluble CD4 did not abolish the ability of gp120 to induce
-chemokine secretion. Similar results were obtained when gp120-JRFL
was used (data not shown). On the contrary, the engagement of the
chemokine receptors CXCR4 and CCR5 by means of specific Abs resulted in
a clear-cut induction of MCP-1, MIP-1, and, to a lesser extent,
RANTES secretion in 7-day MDM, suggesting a role for gp120-coreceptor
interactions in the induction of -chemokine secretion. To provide
further evidence for the involvement of chemokine receptors in the
gp120-mediated -chemokine secretion, the effects of CXCR4 and CCR5
ligands were analyzed. As shown in Fig. 4, treatment of 7-day MDM with
SDF-1 and SDF-1, specific CXCR4 ligands, resulted in the
induction of MCP-1, MIP-1, and RANTES secretion. Moreover, treatment
of 7-day MDM with MIP-1, a chemokine interacting with CCR5, resulted
in the induction of MCP-1 and MIP-1, but not RANTES, secretion. This
chemokine was chosen among others capable of binding to CCR5, including
RANTES and MIP-1, as its addition to monocyte cultures would not
have interfered with subsequent RANTES and MIP-1 determinations.
Furthermore, a similar induction of MCP-1 was obtained by treating
macrophages with RANTES or MIP-1, which also bind to CCR5 (data not
shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chemokines,
including MCP-1 and MIP-1, which are secreted in response to
inflammatory stimuli and, at the same time, are important targets of
chemokine action (1, 2, 3, 4, 5, 6). Chemokines are key factors
affecting the directional migration of immune cells. Because altered
patterns of cellular trafficking may influence the spread of infection,
it can be envisaged that HIV-induced changes in the physiological
levels of chemotactic factors play an important role in the
pathogenesis of AIDS.
In this study we have reported for the first time that HIV-1 gp120
protein, derived from either X4 (IIIB) or R5 (JRFL) HIV-1 strains, is a
potent inducer of -chemokine secretion, including MCP-1, MIP-1,
and RANTES, in primary human monocytes/macrophages through a
CD4-independent mechanism. Exposure of monocyte cultures to
AT-2-inactivated R5 and X4 HIV-1 strains also results in a consistent
secretion of -chemokines. Notably, this method of inactivation
allows the envelope proteins to retain their conformational and
functional integrity, and viral infectivity is completely abrogated by
subsequent modification of the nucleocapsid protein (38).
A number of studies have previously shown an enhanced production of
MIP-1, MIP-1, and MCP-1 in HIV-1-infected macrophage cultures
concomitantly with maximal virus production (23, 24, 26).
HIV replication was requested for this effect, as demonstrated by the
absence of chemokine up-regulation after infection in the presence of
3'-azido-3'-deoxythymidine (23, 24, 26). In contrast, some
studies reported the induction of chemokine secretion in the absence of
active viral replication as well as in uninfected cells exposed to HIV
products. In particular, viral replication was not required for the
up-regulation of RANTES production observed in HIV-infected PBMC
(25). Likewise, induction of -chemokine secretion was
observed in macrophages (26) and astrocytes
(29) stimulated with exogenous Tat. We have previously
reported increased expression of an -chemokine (i.e., IL-8) in
monocytes/macrophages treated with gp120 (40). Moreover,
it has been shown that HIV-2 external glycoproteins that are involved
in the early virus-host interaction can induce the secretion of some
-chemokines (i.e., MIP-1, MIP-1, and RANTES) in total PBMC,
although the cell types involved in this effect have not been
characterized (41). The ensemble of these results,
apparently contradictory, suggests that chemokine induction during the
course of HIV infection can be triggered by different mechanisms. In
productively infected cells, the active viral replication can play a
role in triggering chemokine secretion, which generally occurs
concomitantly with the peak of viral production. In contrast, bystander
cells can be stimulated to secrete chemokines by soluble viral
products, such as Tat and gp120, locally released from the infected
cells. In this regard, it is worth mentioning that gp120 is released
into the circulation of HIV-infected subjects, and it is thought to
have a role in the progressive immune derangement observed in these
patients (42). The availability of gp120 in AIDS patients
has been documented in a number of reports, either as free protein or
complexed by anti-gp120 Ab, suggesting that there could be ample
opportunity for virus-associated or shed gp120 to interact with surface
components of immune cells. In particular, Oh and coworkers
(43) found that the amount of gp120 released in the serum
of HIV-infected patients ranged from 12 to 92 ng/ml. Notably, we report
that as little as 300 ng/ml of gp120 significantly enhanced the
production of MCP-1 and MIP-1 in all donors assessed, whereas
slightly higher concentrations of gp120 were needed for consistent
secretion of RANTES. We envisage that gp120 concentrations suitable for
the induction of at least some chemokines can be locally achieved in
vivo, thus contributing to the up-regulation of -chemokine
production observed in the course of HIV infection. Interestingly, the
capacity of gp120 to induce -chemokine secretion appears to be
restricted to primary monocytes/macrophages. In fact, our results
clearly indicate that although monocytic cell lines are fully
responsive to LPS in terms of -chemokine secretion, the production
of -chemokines induced by R5 and X4 recombinant gp120 occurs only in
primary macrophages. Likewise, no -chemokine secretion was observed
after exposure to AT-2-inactivated R5 and X4 HIV-1 strains of monocytic
cell lines (Table II
). These results represent a further example of the
remarkable differences frequently observed between primary
monocytes/macrophages and established monocytic cell lines in terms of
functional responses to HIV infection.
The results of the RT-PCR experiments described in this article
indicate that gp120 induces MCP-1, MIP-1, and RANTES mRNA
accumulation over the basal levels normally expressed in macrophages.
Although a clear-cut increase in these transcripts was observed in the
presence of CHX, treatment of macrophages with gp120 in the presence of
this protein synthesis inhibitor did not result in any further
accumulation of -chemokine mRNA. These results suggest that MCP-1,
MIP-1, and RANTES transcripts, although constitutively transcribed,
can undergo a rapid turnover. Moreover, the response of these cells to
gp120 does not require de novo protein synthesis. This primary response
may be due to an enhancement of the basal level of transcription or to
a stabilization of MCP-1, MIP-1, and RANTES mRNA, both of which
would result in the accumulation of these transcripts. Additional
experiments are needed to precisely define the mechanism of action of
gp120 in the regulation of -chemokine mRNA expression.
Much attention has been focused on how the gp120 envelope protein may
interact with chemokine receptors, and considerable information has
been generated concerning the interaction of HIV-1 with CD4 and
chemokine receptors on T cells and transfected cells. In contrast, the
nature of the interaction of gp120 with CD4 and cofactors on
monocytes/macrophages has not been carefully characterized. It has been
suggested that after binding of gp120 to CD4, a conformational change
endows an epitope of gp120 with the capacity to bind chemokine
receptors (8). Recently, it has been demonstrated that
gp120 acts as a functional ligand of CXCR4 and CCR5 in primary
monocytes (44). Interestingly, distinct responses were
evoked by gp120 and chemokines despite the use of the same receptors
(44). Our results clearly show that the capacity of gp120
to induce -chemokine expression is independent of its interaction
with CD4 receptors. In fact, we show that preincubation of gp120 with
an excess amount of soluble CD4 does not interfere with its capacity to
stimulate -chemokine secretion. In this regard, some studies have
reported association of gp120 with CXCR4 in a CD4-independent manner.
In particular, it has been shown that gp120 can induce apoptosis
through a direct interaction with CXCR4 in neuronal (45)
and CD8 T cells (46), both lacking CD4 receptor. Likewise,
Liu and colleagues (44) showed that gp120-specific ionic
channel activation is not caused by signaling through CD4, as no effect
was induced by R5 gp120 binding in CCR5-negative MDM or in
ADM3100-treated macrophages stimulated with X4 gp120. In keeping with
these observations, we have also shown that a mAb (SIM4) that binds to
the same epitope as Leu 3a and blocks HIV/CD4 binding and infection has
no effect on -chemokine expression. In contrast, specific Abs
recognizing the CCR5 or CXCR4 receptors induce a marked secretion of
MCP-1 and MIP-1 and, to a lesser extent, RANTES. Likewise, SDF-1,
the natural CXCR4 ligand, and MIP-1, one of the chemokines
interacting with CCR5, also induce some secretion of -chemokines. In
addition, treatment of monocyte cultures with MIP-1 and RANTES
results in a consistent secretion of MCP-1 (data not shown). Consistent
with these results, both AT-2-inactivated R5 and X4 HIV-1 strains,
exposing a fully functional gp120 at their surface, induce marked
secretion of -chemokines independently of their coreceptor
usage.
Contrasting results have been obtained by different groups, including
ours, on the expression of CXCR4 and CCR5 during the course of monocyte
differentiation to macrophages. In particular, we have shown that the
differentiation process is accompanied by a consistent reduction in the
expression of CXCR4 and CCR5 (32). However, comparable
levels of -chemokine induction were detected in 1- and
7-day-cultured monocytes (Fig. 1). These results suggest that even low
receptor expression is sufficient to induce a clear-cut response to
gp120. In this regard it has been reported that differentiated
macrophages expressing low levels of CXCR4 can support X4 HIV-1 strain
replication (47). Likewise, it has been shown that while
the majority of CCR5-using viruses do not infect T cell lines, a small
subset of primary R5 HIV-1 strains is able to infect
CD4+ T cell lines by virtue of its capacity to
exploit low levels of CCR5 for infection (48). Moreover,
the involvement of CCR5 as a coreceptor for HIV-1-BaL entry has been
demonstrated by chemokine competition experiments, even though CCR5
expression was undetectable by FACS analysis (49). In this
regard it is of interest that different subclones of U937 cells,
expressing comparable levels of functional CXCR4, efficiently support
fusion with cells expressing HIV-IIIB Env, but differ in their
susceptibility to the infection with X4 HIV-1 strains
(50). Overall, these results strongly suggest that the
levels of coreceptor expression are not the sole determinants of the
response to HIV infection.
Together, our results indicate that the capacity of gp120 to induce
-chemokines in monocytes/macrophages is not restricted to specific
viral strains, suggesting that this gp120-mediated effect can be
operative during all stages of disease. Thus, the interaction of both
X4 and R5 HIV-1 envelope glycoproteins with chemokine receptors can,
even in the absence of HIV-1 entry and replication, result in the
activation of signal transduction pathways leading to chemokine
expression. These soluble mediators, produced by both infected cells
and bystander uninfected cells triggered by viral products (i.e., Tat
and gp120), may regulate the course of HIV infection by either directly
controlling the extent of viral infection or through their
chemoattractive effect on immune cells. The production of chemokines
may represent a protective response of macrophages to HIV infection and
contribute to limit viral spreading by blocking specific coreceptor
usage in uninfected cells. At the same time, these factors may play an
important role in the HIV immune response by recruiting specific immune
cell populations. In contrast, hyperproduction of chemokines during the
course of infection may enhance viral spreading, favoring the infection
of newly recruited immune cells, thus contributing to the pathogenesis
of HIV infection. Although the in vivo biological relevance for the
enhanced chemokine production remains to be elucidated, it is
reasonable to assume that the balance of their negative vs positive
effects on HIV spreading may contribute to different outcomes of HIV
disease.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Sandra Gessani, Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
3 Abbreviations used in this paper: SDF-1, stromal derived factor-1; MIP, macrophage inflammatory protein; MCP, monocyte chemoattractant protein; MDM, monocyte-derived macrophages; CHX, cycloheximide; AT-2, aldrithiol-2.
Received for publication May 22, 2000. Accepted for publication February 20, 2001.
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 M. Del Corno, M. C. Gauzzi, G. Penna, F. Belardelli, L. Adorini, and S. Gessani Human Immunodeficiency Virus Type 1 gp120 and Other Activation Stimuli Are Highly Effective in Triggering Alpha Interferon and CC Chemokine Production in Circulating Plasmacytoid but Not Myeloid Dendritic Cells J. Virol., October 1, 2005; 79(19): 12597 - 12601. [Abstract] [Full Text] [PDF]
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 C. Lee, B. Tomkowicz, B. D. Freedman, and R. G. Collman HIV-1 gp120-induced TNF-{alpha} production by primary human macrophages is mediated by phosphatidylinositol-3 (PI-3) kinase and mitogen-activated protein (MAP) kinase pathways J. Leukoc. Biol., October 1, 2005; 78(4): 1016 - 1023. [Abstract] [Full Text] [PDF]
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J. F. Foley, C.-R. Yu, R. Solow, M. Yacobucci, K. W. C. Peden, and J. M. Farber Roles for CXC Chemokine Ligands 10 and 11 in Recruiting CD4+ T Cells to HIV-1-Infected Monocyte-Derived Macrophages, Dendritic Cells, and Lymph Nodes J. Immunol., April 15, 2005; 174(8): 4892 - 4900. [Abstract] [Full Text] [PDF]
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L. Fantuzzi, C. Purificato, K. Donato, F. Belardelli, and S. Gessani Human Immunodeficiency Virus Type 1 gp120 Induces Abnormal Maturation and Functional Alterations of Dendritic Cells: a Novel Mechanism for AIDS Pathogenesis J. Virol., September 15, 2004; 78(18): 9763 - 9772. [Abstract] [Full Text] [PDF]
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 J. E. Kirkley and F. A. Robey Inhibition of U937 Cytokine Secretion by HIV-1 gp120 C4-Derived Peptide Constructs Journal of Bioactive and Compatible Polymers, May 1, 2004; 19(3): 173 - 195. [Abstract] [PDF]
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A. M. Masci, M. Galgani, S. Cassano, S. De Simone, A. Gallo, V. De Rosa, S. Zappacosta, and L. Racioppi HIV-1 gp120 induces anergy in naive T lymphocytes through CD4-independent protein kinase-A-mediated signaling J. Leukoc. Biol., December 1, 2003; 74(6): 1117 - 1124. [Abstract] [Full Text]
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C. Lee, Q.-H. Liu, B. Tomkowicz, Y. Yi, B. D. Freedman, and R. G. Collman Macrophage activation through CCR5- and CXCR4-mediated gp120-elicited signaling pathways J. Leukoc. Biol., November 1, 2003; 74(5): 676 - 682. [Abstract] [Full Text] [PDF]
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L. Fantuzzi, F. Belardelli, and S. Gessani Monocyte/macrophage-derived CC chemokines and their modulation by HIV-1 and cytokines: A complex network of interactions influencing viral replication and AIDS pathogenesis J. Leukoc. Biol., November 1, 2003; 74(5): 719 - 725. [Abstract] [Full Text] [PDF]
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W. Choe, D. J. Volsky, and M. J. Potash Induction of Rapid and Extensive beta -Chemokine Synthesis in Macrophages by Human Immunodeficiency Virus Type 1 and gp120, Independently of Their Coreceptor Phenotype J. Virol., November 15, 2001; 75(22): 10738 - 10745. [Abstract] [Full Text] [PDF]
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M. Del Corno, Q.-H. Liu, D. Schols, E. de Clercq, S. Gessani, B. D. Freedman, and R. G. Collman HIV-1 gp120 and chemokine activation of Pyk2 and mitogen-activated protein kinases in primary macrophages mediated by calcium-dependent, pertussis toxin-insensitive chemokine receptor signaling Blood, November 15, 2001; 98(10): 2909 - 2916. [Abstract] [Full Text] [PDF]
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, donor 2; 
, donor 3). Data are
the mean values of duplicate samples. The intersample SD did not exceed
10%.
