Journal of Leukocyte Biology eBioscience full spectrum cell analysis
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Originally published online as doi:10.1189/jlb.0503206 on July 22, 2003

Published online before print July 22, 2003
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jlb.0503206v1
74/5/676    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lee, C.
Right arrow Articles by Collman, R. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, C.
Right arrow Articles by Collman, R. G.
(Journal of Leukocyte Biology. 2003;74:676-682.)
© 2003 by Society for Leukocyte Biology

Macrophage activation through CCR5- and CXCR4-mediated gp120-elicited signaling pathways

ChuHee Lee*, Qing-Hua Liu{dagger}, Brian Tomkowicz*, Yanjie Yi*, Bruce D. Freedman{dagger} and Ronald G. Collman*,1

* Departments of Medicine, School of Medicine, and
{dagger} Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia

1Correspondence: University of Pennsylvania School of Medicine, 522 Johnson Pavilion, 36th & Hamilton Walk, Philadelphia, PA 19104. E-mail: collmanr{at}mail.med.upenn.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 ION CHANNEL ACTIVATION
 [Ca2+]i MOBILIZATION
 PROTEIN KINASE ACTIVATION
 gp120 SIGNALING IN...
 CONCLUSIONS
 REFERENCES
 
Macrophages are major targets for infection by human immunodeficiency virus type 1 (HIV-1). In addition to their role as productive viral reservoirs, inappropriate activation of infected and uninfected macrophages appears to contribute to pathogenesis. HIV-1 infection requires initial interactions between the viral envelope surface glycoprotein gp120, the cell-surface protein CD4, and a chemokine receptor CCR5 or CXCR4. Besides their role in HIV-1 entry, CCR5 and CXCR4 are G protein-coupled receptors that can activate multiple intracellular signaling pathways. HIV-1 gp120 has been shown to activate signaling pathways through the chemokine receptors in several cell types including lymphocytes, neurons, and astrocytes. In some cell types, these consequences may cause cellular injury. In this review, we highlight our data demonstrating diverse signaling events that occur in primary human macrophages in response to gp120/chemokine receptor interactions. These responses include K+, Cl–, and nonselective cation currents, intracellular Ca2+ increases, and activation of several kinases including the focal adhesion-related tyrosine kinase Pyk2, mitogen-activated protein kinases (MAPK), and phosphoinositol-3 kinase. Activation of the MAPK leads to gp120-induced expression of chemokines such as monocyte chemoattractant protein-1 and macrophage-inflammatory protein-1ß and the proinflammatory cytokine tumor necrosis factor {alpha}. These responses establish a complex cytokine network, which may enhance or suppress HIV-1 replication. In addition, dysregulation of macrophage function by gp120/chemokine receptor signaling may contribute to local inflammation and injury and further recruit additional inflammatory and/or target cells. Targeting these cellular signaling pathways may have benefit in controlling inflammatory sequelae of HIV infection such as in neurological disease.

Key Words: signal transduction • chemokine receptor • AIDS dementia • HIV encephalopathy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
ION CHANNEL ACTIVATION
 [Ca2+]i MOBILIZATION
 PROTEIN KINASE ACTIVATION
 gp120 SIGNALING IN...
 CONCLUSIONS
 REFERENCES
 
Human immunodeficiency virus type 1 (HIV-1) entry is initiated by binding of the viral envelope (Env) glycoprotein gp120 to CD4 followed by interactions with a G protein-coupled chemokine receptor (GPCR), CCR5 or CXCR4, on the surface of target cells (reviewed in ref. [1 ]). Primary CD4+ T cells and macrophages express CCR5 and CXCR4 in conjunction with CD4, and CD4+ cell lines generally express only CXCR4. Macrophage (M) tropic (R5) viruses infect macrophages and primary CD4+ T cells using CCR5, and dual tropic (R5X4) viruses infect all three target cell types through CCR5 or CXCR4. T-tropic (X4) viruses infect primary CD4+ T cells and transformed T cell lines thorough CXCR4; however, only a subset of X4 viruses are able to infect macrophages through CXCR4 [2 3 4 ].

Although engagement of CD4 and a chemokine receptor by gp120 is the initial step required for entry and infection, this interaction can also occur apart from infection as a result of defective virions or soluble gp120 shed from virus particles or infected cells. Recent studies demonstrate that gp120 can activate intracellular signals in multiple cell types, which may provide an additional mechanism of pathogenesis along with direct infection. In some CD4-negative cell types, gp120 has been shown to activate signals by binding to the chemokine receptor directly [5 , 6 ], although high-affinity, efficient gp120–chemokine interactions typically require that gp120 first binds to CD4 to undergo conformational changes that induce the chemokine receptor binding site [1 ]. gp120-triggered signaling has been extensively explored in CD4+ T lymphocytes, where it has been implicated in causing dysfunction and apoptosis [7 , 8 ]. In CD4+ T cells, many gp120-elicited responses are activated through CD4, which is principally linked to the Src kinase p56lck, so it is important to distinguish signals mediated by the chemokine receptors apart from those activated through CD4. Primary macrophages express CD4 and chemokine receptors but lack p56lck [9 ].

Here, we will discuss our studies on the intracellular signaling pathways activated in macrophages through CCR5 and CXCR4 in response to envelope proteins from R5 or X4 viruses and contrast them with results in other cell types. Better understanding of HIV-1 gp120-mediated signaling and determining the role of CD4 versus chemokine receptor ligation may provide important insights into mechanisms of HIV-mediated immune dysfunction and suggest new avenues for therapeutic intervention.


   ION CHANNEL ACTIVATION
TOP
 ABSTRACT
 INTRODUCTION
 ION CHANNEL ACTIVATION
[Ca2+]i MOBILIZATION
 PROTEIN KINASE ACTIVATION
 gp120 SIGNALING IN...
 CONCLUSIONS
 REFERENCES
 
GPCR are frequently linked to ion channels [10 , 11 ], and in macrophages, ionic signals are important regulators of many functions including innate host defense and secretory responses such as cytokine production, respiratory burst activity, nitric oxide production, and other effects [12 , 13 ]. Therefore, we determined the effect of gp120/chemokine receptor interactions on ionic signaling in primary human monocyte-derived macrophages (MDM). Using whole-cell patch-clamp analysis, we found that chemokine receptor stimulation in macrophages opens several ion channels in MDM [14 ]. Instantaneous reversal potentials, pharmacological inhibitors, and ion substitution experiments showed that an initial transient, outward K+ current and subsequent slow, inward Cl– current were activated by gp120 and by macrophage-inflammatory protein-1ß (MIP-1ß; CCL4) and stromal derived factor-1{alpha} (SDF-1{alpha}; CXCL12), the natural ligands for CCR5 and CXCR4, respectively (Table 1 ). Chelating extracellular calcium with EGTA inhibited the K+ current, indicating a calcium-activated potassium (KCa) current. We also found that gp120 activated a calcium-permeable, nonselective cation current that was not elicited by the chemokines. When macrophages were pretreated with the CXCR4 antagonist AMD3100 [15 ], they failed to activate currents in response to X4 gp120 and SDF-1{alpha} but responded to R5 gp120 and MIP-1ß, and macrophages from donors homozygous for a nonfunctional allele of CCR5 [16 ] responded to X4 gp120 and SDF-1{alpha} but not to R5 gp120 and MIP-1ß. These results indicate that ionic currents result from specific signaling through the chemokine receptors and not via CD4, as CD4 would remain accessible to gp120 despite CXCR4 blocking or the absence of CCR5.


View this table:
[in this window]
[in a new window]
  		Table 1. Ionic Currentsa and Intracellular Calcium Elevationsb Elicited in Macrophages by Recombinant gp120 and Chemokines

 
The overall patterns of ionic signaling activated by R5 and X4 gp120 were similar, but we found less-frequent K+ current activation by the X4 envelope. The lower propensity to activate the KCa current may be a result of the fact that X4 gp120 elicited lower [Ca2+]i levels (Table 1 and discussed below). Other functional responses differ between R5 and X4 gp120 as well, such as differential mitogen-activated protein kinase (MAPK) activation (discussed further below). Although blocking CXCR4 and CCR5 eliminated all gp120 and chemokine-elicited current responses in MDM, there were distinctions between Env and the natural ligands, as the nonselective cation channel was activated by gp120 but not by chemokines. This difference raises the question of whether there is differential signaling by the two types of ligands mediated exclusively by the chemokine receptors or whether gp120 responses through CCR5 and CXCR4 are modified by prior engagement of CD4, although CD4 engagement alone does not evoke a response. Thus, gp120 binds to macrophage chemokine receptors as a specific ligand and transduces ion channel-activating signals.

Ionic signaling in response to gp120 has been reported in other cell types as well. Exposure of primary rat or human astrocytes to gp120 or HIV virions stimulates Na+/H+ antiport and K+ conductance [17 , 18 ]. These signals lead to the release (or inhibit reuptake) of glutamate, a neurotransmitter that activates excitatory amino acid receptors on neurons, inducing increases in neuronal [Ca2+]i and cellular death. These mechanisms have been proposed to contribute to neuronal injury in the pathogenesis of HIV-associated dementia (HAD) and suggest that drugs that block gp120-induced changes in [Ca2+]i in neurons and astrocytes may help in the treatment of HAD [19 , 20 ].

The specific domain of gp120 responsible for triggering chemokine receptor activation has not been formally investigated. However, a multibranched peptide derived from the V3 loop of gp120 has been shown to trigger a potent, inward Cl– current in Xenopus oocytes expressing human CXCR4 [21 ]. Although the V3 loop is not the main chemokine receptor-binding region of gp120, this domain does interact with the chemokine receptor and is a main determinant of CCR5 versus CXCR4 selectivity [22 ]. Recently, peptides representing V3 from R5 or X4 gp120 were shown to mimic the ß-hairpin structure of the respective chemokines [23 ]. These data together raise the possibility that the V3 domain of gp120 could be interacting with the receptors in a manner that recapitulates chemokine interactions, thereby eliciting chemokine-like activation. Thus, the molecular interaction responsible for triggering chemokine receptor signaling by gp120 may be related to but distinct from the interaction responsible for inducing the conformational changes in Env that ultimately lead to fusion.


   [Ca2+]i MOBILIZATION
TOP
 ABSTRACT
 INTRODUCTION
 ION CHANNEL ACTIVATION
 [Ca2+]i MOBILIZATION
PROTEIN KINASE ACTIVATION
 gp120 SIGNALING IN...
 CONCLUSIONS
 REFERENCES
 
[Ca2+]i regulates a broad range of secondary signals and functional responses (reviewed in ref. [24 ]), and CCR5 and CXCR4 elevate [Ca2+]i in a variety of cell types in response to chemokine stimulation. Using Fura-2-loaded primary human macrophages, we found that R5 and X4 gp120 induced [Ca2+]i elevations (Table 1) [14 ]. However, the peak [Ca2+]i elicited by R5 gp120 was nearly twice that elicited by X4 gp120, with higher steady-state levels as well. We suspect that the higher [Ca2+]i elicited by R5 gp120 underlies the greater propensity to activate KCa currents compared with X4 gp120. It remains to be determined whether higher [Ca2+]i levels elicited by R5 compared with X4 gp120 reflect differences in receptor expression [25 ], the higher affinity of CD4-triggered R5 gp120 for CCR5 compared with CD4-triggered X4 gp120 for CXCR4 [26 ], or distinct, intrinsic signaling properties of the receptors.

A major focus of interest relevant to gp120-elicited [Ca2+]iincreases has been as a possible determinant of viral entry and/or post-entry events in infection, particularly in macrophages. It is well established that chemokine receptor signaling is dispensable for HIV-coreceptor function in cell lines [27 , 28 ]. However, the first report of gp120-triggered, chemokine receptor-mediated [Ca2+]i elevations in T cells showed detectable elevations by Env from macrophage-tropic but not nonmacrophage-tropic HIV and simian immunodeficiency virus (SIV) strains [29 ]. This result was intriguing, as all SIV strains use CCR5, and macrophage tropism appears to be determined at a post-entry step [30 ] and suggested that differences in intracellular signaling might influence post-entry steps of infection. Subsequently, it was reported that HIV-1 and SIV strains with gp120 envelopes that did not elevate [Ca2+]i in macrophages failed to complete replication, and this failure could be complemented by the natural ligand MIP-1ß, which converted nonproductive infection to productive infection [31 ]. This issue remains unclear, however, as other reports have suggested that Ca2+ mobilization and the signaling capacity of CCR5 are dispensable for infection even in primary human macrophages [32 ].

Nevertheless, it is uncertain how [Ca2+]i increases might facilitate infection. Following entry, the nucleocapsid must migrate to the nucleus, a process that is believed to involve use of host-cell cytoskeletal pathways [33 ]. We found that gp120-induced Ca2+ elevations in macrophages activate the cytoskeletal-associated focal adhesion-related kinase Pyk2 (discussed further below). In some cell types, gp120 is also known to activate the related cytoskeleton-associated focal adhesion kinase (FAK). Thus, it is conceivable that [Ca2+]i mobilization may activate cytoskeletal-associated kinases that participate in post-entry steps of infection through cytoskeletal rearrangement and enhanced nuclear migration.

As noted above, [Ca2+]i mobilization in response to gp120 has been observed in several cell types. In cultured human and rodent neuronal cells, gp120 appears to disrupt neuronal Ca2+ homeostasis directly, resulting in Ca2+ overload that renders neurons vulnerable to excitotoxicity, cellular dysfunction, and death [34 35 36 37 ]. These findings have provided the rationale for testing whether drugs that stabilize cellular Ca2+ homeostasis might protect neurons against the toxic effects of gp120 in HAD.


   PROTEIN KINASE ACTIVATION
TOP
 ABSTRACT
 INTRODUCTION
 ION CHANNEL ACTIVATION
 [Ca2+]i MOBILIZATION
 PROTEIN KINASE ACTIVATION
gp120 SIGNALING IN...
 CONCLUSIONS
 REFERENCES
 
Nonreceptor protein kinases are also frequently activated by GPCR stimulation [38 ], and so, we addressed several protein kinases that play central roles in immune-cell function. Pyk2 is a focal adhesion-related tyrosine kinase that links GPCR, ionic signals, and other downstream pathways in several cell models [39 , 40 ]. As shown in Figure 1A , gp120 and chemokine stimulation of macrophages induced phosphorylation of Pyk2 [41 ]. Similar results have been reported in T cells, where Pyk2 and FAK are activated by gp120 [42 , 43 ]. Pyk2 is often Ca2+-regulated [39 ], and we found that [Ca2+]i elevations link CCR5 stimulation and Pyk2 activation in macrophages, as extracellular chelation with EGTA or antagonists of specific Ca2+ channels (particularly calcium release-activated calcium channels) blocked gp120-induced Pyk2 phosphorylation (data not shown). In contrast, CCR5-mediated Pyk2 activation in macrophages was not sensitive to pertussis toxin (PTx), which inhibits G{alpha}i but not the G{alpha}s, G{alpha}q, G{alpha}12/13 subunits, indicating that it is not coupled through G{alpha}i. These results suggest that CCR5 signaling in macrophages is coupled to pathways other than G{alpha}i. Indeed, in other cell types, GPCR activation of various kinases is associated with G{alpha}i- and G{alpha}q-coupled pathway [40 , 44 ]. Alternatively, it is possible that other signaling pathways independent of G proteins may be responsible, as occurs with several other GPCR [45 , 46 ]. As noted above, the functional importance of Pyk2 or FAK activation is uncertain, although modification of the cytoskeleton is one possible effect.



View larger version (30K):
[in this window]
[in a new window]
  		Figure 1. Monocytes from healthy donors were plated at 5 x 105 cells per well in 24-well plates, cultured for 6 days to allow differentiation into MDM, cultured under serum-free conditions for an additional 24 h, stimulated with gp120, and analyzed by Western blot as described [41 ]. (A) Cells were treated with recombinant gp120 (2.5 µg/ml) generated in a vaccinia virus system from the R5 prototype strain JRFL and X4 prototype IIIB for 5 min (Pyk2) or 5–15 min (MAPK). Cell lysates were separated on 8% sodium dodecyl sulfate-polyacrylamide gel electrophoresis, transferred to nitrocellulose membranes, and subjected to Western blot with antibodies specific for phosphorylated forms of Pyk2, c-jun NH2-terminal kinase (JNK)/stress-activated protein kinase (SAPK), and p38 MAPK. The membranes were then stripped and re-probed with antibodies that detect total Pyk2, JNK/SAPK, and p38 MAPK. Cntl, Control. (B) MDM were treated with the p38 MAPK inhibitor for SB202190 for 60 min and then exposed to JRFL gp120 for 24 h. MIP-1ß and monocyte chemoattractant protein-1 (MCP-1) production in supernatant was detected by enzyme-linked immunosorbent assay.

 
MAPK are central regulators of many important cellular activities [47 ]. We found that gp120 stimulation of macrophages activated two MAPK, JNK/SAPK and p38 MAPK (Fig. 1A) . Of note, R5 gp120 reliably activated these kinases, and X4 gp120 activation was inconsistent, indicating another difference between the CCR5- and CXCR4-mediated pathways. Like Pyk2, activation of macrophage MAPK was not blocked by PTx, again indicating G{alpha}i independence (data not shown). Other groups have investigated activation of MAPK pathways as well. Using CD4+/CXCR4+ cell lines, it was reported that binding of X4 HIV-1 gp120 activated extracellular-regulated kinase (ERK), another member of the MAPK family [48 ]. However, that response was mediated by CD4, as CD4-independent X4 gp120 did not activate ERK through CXCR4, although the natural CXCR4 ligand SDF-1{alpha} did. In contrast, using cell lines engineered to express CCR5 as well as CD4, they found that binding of R5 SIV virions (but not gp120 alone) activated JNK and p38 MAPK as well as ERK through CCR5 [49 ]. Those data suggested that R5 and X4 gp120 interact differently with their respective chemokine receptors; that gp120 and chemokines differentially induce MAPK activation through the chemokine receptors; and that cross-linking or multivalency may be required for gp120 to activate intracellular signals through the chemokine receptors. CXCR4-mediated, CD4-independent activation of JNK and p38 has been reported in other cells as well [50 ]. Thus, in addition to differences between gp120 and chemokines and between CCR5 and CXCR4 responses, the signals activated through these receptors are likely to be highly cell type-specific as well.

We also found functional evidence for phosphoinositol-3 kinase (PI-3K) activation by gp120. It has long been known that gp120 can induce macrophages to secrete tumor necrosis factor {alpha} (TNF-{alpha}) [51 , 52 ], and we determined that this response was blocked by a selective PI-3K inhibitor (data not shown). Similar results showing that soluble and virion-associated gp120 activates PI-3K in macrophages were recently reported [53 ], and furthermore, inhibition of this signaling pathway suppressed virus infection at a step post-entry but before gene expression.

In addition to affecting cytokine production and cellular function, previous studies have suggested that MAPK activation can facilitate HIV-1 replication through AP-1- and nuclear factor-{kappa}B-mediated pathways that enhance viral gene expression [54 , 55 ]. Thus, it is possible that MAPK activation by gp120 may contribute to viral replication in an autocrine or paracrine manner. It is interesting that a recent report showed that Env can induce HIV expression in latent resting T cells obtained from infected individuals [56 ]. Although FAK and ZAP-70 were activated in resting T cells by gp120, it was not clear as to what pathways were specifically responsible for HIV up-regulation.


   gp120 SIGNALING IN CHEMOKINE/CYTOKINE SECRETION
TOP
 ABSTRACT
 INTRODUCTION
 ION CHANNEL ACTIVATION
 [Ca2+]i MOBILIZATION
 PROTEIN KINASE ACTIVATION
 gp120 SIGNALING IN...
CONCLUSIONS
 REFERENCES
 
Chemokines and cytokines play important roles in inflammation and in sustaining viral infection through immune cell activation and recruitment of new target cells. Changes in the production of specific chemokines have been demonstrated during the course of HIV infection and may be particularly important in the brain where immune cell activation and recruitment appear to have an important role in HAD pathogenesis [57 58 59 ]. Many studies over the past decade have demonstrated that macrophages produce cytokines, chemokines, and other soluble mediators after exposure to gp120 or virions [60 61 62 63 ], although the pathways and mechanisms had not been defined. We found that macrophages exposed to gp120 produced MCP-1 and MIP-1ß, consistent with other reports. In addition, production of these mediators in response to gp120 was triggered by chemokine receptor activation. Upon further investigation, we determined that this was dependent on the p38 MAPK pathway, as a specific p38 MAPK inhibitor (SB202190) blocked their secretion (Fig. 1B) [41 ]. We also found that HIV gp120 induced macrophage TNF-{alpha} production (as reported previously [63 ]) and that the PI-3K blocker LY294002 and ERK-1/2 (p44/42) MAPK inhibitor PD98059 suppressed this effect (data not shown). Thus, PI-3K and ERK activation appear to be involved in gp120-induced TNF-{alpha} production.

Macrophage cytokine and chemokine production elicited by gp120 may have several important effects. Chemotactic and proinflammatory mediators can cause cellular recruitment and activation that may contribute to the pathogenesis of local disease (discussed further below). In addition, many secretory molecules can regulate viral replication in a positive and negative manner. The ß-chemokines can block virus entry by competing with gp120 for binding to chemokine receptors [64 , 65 ]. At the same time, many factors elicited by gp120 stimulation activate cellular signals that modulate HIV-1 replication leading to up- and down-regulation (reviewed in ref. [66 ]).


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 ION CHANNEL ACTIVATION
 [Ca2+]i MOBILIZATION
 PROTEIN KINASE ACTIVATION
 gp120 SIGNALING IN...
 CONCLUSIONS
REFERENCES
 
gp120-elicited macrophage signaling in pathogenesis
Env-mediated signaling may contribute to several aspects of disease. In T cells, indirect mechanisms of cell killing appear to play an important role in pathogenesis, and gp120-induced apoptosis of T cells is well described. Although CD4 engagement is the principal factor inducing T cell apoptosis [67 ], chemokine receptor engagement can modulate the mechanism of apoptosis [68 ]. gp120 signaling may also lead to T cell anergy, although CD4-mediated pathways seem to play a central role in this phenomenon [7 ].

In contrast to T cells, macrophages are not depleted during the course of HIV infection. However, inappropriate macrophage activation appears to play a major role in the pathogenesis of important complications that occur during the course of AIDS. The activation pathways identified here (Fig. 2 ) may contribute to these macrophage activation-dependent sequelae. Up to one-quarter of infected individuals develop HAD, which is characterized by infection of macrophage/microglia cells in the brain, elevated levels of multiple cytokines and chemokines (including TNF-{alpha}, MCP-1, and others), and activation of uninfected and infected macrophages/microglia. In vitro studies have demonstrated that gp120 exposure and direct infection induce macrophages to produce a variety of inflammatory mediators that may contribute to cellular activation and recruitment as well as substances with direct, neurotoxic potential [66 ]. Ultimately, neuronal apoptosis may mediate HIV-induced injury. Although the importance of gp120/macrophage interactions in eliciting inflammatory and neurotoxic products that contribute to HAD pathogenesis has been recognized for many years, the molecular mechanisms of gp120 activation have been obscure. We have identified specific signaling pathways activated by Env through the chemokine receptors that may be responsible. In addition, gp120 itself may interact with chemokine receptors on neurons or astrocytes to elicit Ca2+ elevations and other pathogenic responses that lead finally to neuronal apoptosis. Thus, signaling pathways linked to chemokine receptor activation may be an important mechanism of direct and indirect neuronal injury in HAD.



View larger version (28K):
[in this window]
[in a new window]
  		Figure 2. Signal transduction pathways elicited by Env interaction with chemokine receptors on macrophages. Our results provide a possible mechanism for gp120/chemokine receptor-induced macrophage activation, which may lead to immune dysregulation through intracellular calcium mobilization, protein tyrosine kinase activation, and cytokine production such as TNF-{alpha}. These responses may play a role in the pathogenesis of disease where inappropriate macrophage activation is seen, such as HIV-associated dementia. Signaling molecules that we have confirmed to be activated by gp120 are shown in black, and confirmed pathways are shown with a solid line [14 41 ]. Suspected factors that may be involved are shown in white, and potential pathways are shown with dotted lines. PLC, Phospholipase C; MAPKKK, MAPK kinase (MAPKK) kinase.

 

Received May 7, 2003; revised June 26, 2003; accepted June 27, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 ION CHANNEL ACTIVATION
 [Ca2+]i MOBILIZATION
 PROTEIN KINASE ACTIVATION
 gp120 SIGNALING IN...
 CONCLUSIONS
 REFERENCES
 

  1. Berger, E. A., Murphy, P. M., Farber, J. M. (1999) Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease Annu. Rev. Immunol. 17,657-700[CrossRef][Medline]
  2. Simmons, G., Reeves, J. D., McKnight, A., Dejucq, N., Hibbitts, S., Power, C. A., Aarons, E., Schols, D., De Clercq, E., Proudfoot, A. E., Clapham, P. R. (1998) CXCR4 as a functional coreceptor for human immunodeficiency virus type 1 infection of primary macrophages J. Virol. 72,8453-8457[Abstract/Free Full Text]
  3. Yi, Y., Rana, S., Turner, J. D., Gaddis, N., Collman, R. G. (1998) CXCR-4 is expressed by primary macrophages and supports CCR5-independent infection by dual-tropic but not T-tropic isolates of human immunodeficiency virus type 1 J. Virol. 72,772-779[Abstract/Free Full Text]
  4. Yi, Y., Isaacs, S. N., Williams, D. A., Frank, I., Schols, D., De Clercq, E., Kolson, D. L., Collman, R. G. (1999) Role of CXCR4 in cell-cell fusion and infection of monocyte-derived macrophages by primary human immunodeficiency virus type 1 (HIV-1) strains: two distinct mechanisms of HIV-1 dual tropism J. Virol. 73,7117-7125[Abstract/Free Full Text]
  5. Misse, D., Esteve, P. O., Renneboog, B., Vidal, M., Cerutti, M., St Pierre, Y., Yssel, H., Parmentier, M., Veas, F. (2001) HIV-1 glycoprotein 120 induces the MMP-9 cytopathogenic factor production that is abolished by inhibition of the p38 mitogen-activated protein kinase signaling pathway Blood 98,541-547[Abstract/Free Full Text]
  6. Missé, D., Cerutti, M., Noraz, N., Jourdan, P., Favero, J., Devauchelle, G., Yssel, H., Taylor, N., Veas, F. (1999) A CD4-independent interaction of human immunodeficiency virus-1 gp120 with CXCR4 induces their cointernalization, cell signaling, and T-cell chemotaxis Blood 93,2454-2462[Abstract/Free Full Text]
  7. Marschner, S., Hunig, T., Cambier, J. C., Finkel, T. H. (2002) Ligation of human CD4 interferes with antigen-induced activation of primary T cells Immunol. Lett. 82,131-139[CrossRef][Medline]
  8. Selliah, N., Finkel, T. H. (2001) HIV-1 NL4–3, but not IIIB, inhibits JAK3/STAT5 activation in CD4(+) T cells Virology 286,412-421[CrossRef][Medline]
  9. Pelchen-Matthews, A., da Silva, R. P., Bijlmakers, M. J., Signoret, N., Gordon, S., Marsh, M. (1998) Lack of p56lck expression correlates with CD4 endocytosis in primary lymphoid and myeloid cells Eur. J. Immunol. 28,3639-3647[CrossRef][Medline]
  10. Dascal, N. (2001) Ion-channel regulation by G proteins Trends Endocrinol. Metab. 12,391-398[CrossRef][Medline]
  11. Wickman, K., Clapham, D. E. (1995) Ion channel regulation by G proteins Physiol. Rev. 75,865-885[Abstract/Free Full Text]
  12. Stafford, J. L., Neumann, N. F., Belosevic, M. (2002) Macrophage-mediated innate host defense against protozoan parasites Crit. Rev. Microbiol. 28,187-248[CrossRef][Medline]
  13. Qiu, M. R., Campbell, T. J., Breit, S. N. (2002) A potassium ion channel is involved in cytokine production by activated human macrophages Clin. Exp. Immunol. 130,67-74[CrossRef][Medline]
  14. Liu, Q. H., Williams, D. A., McManus, C., Baribaud, F., Doms, R. W., Schols, D., De Clercq, E., Kotlikoff, M. I., Collman, R. G., Freedman, B. D. (2000) HIV-1 gp120 and chemokines activate ion channels in primary macrophages through CCR5 and CXCR4 stimulation Proc. Natl. Acad. Sci. USA 97,4832-4837[Abstract/Free Full Text]
  15. Donzella, G. A., Schols, D., Lin, S. W., Este, J. A., Nagashima, K. A., Maddon, P. J., Allaway, G. P., Sakmar, T. P., Henson, G., De Clercq, E., Moore, J. P. (1998) AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor Nat. Med. 4,72-77[CrossRef][Medline]
  16. Samson, M., Libert, F., Doranz, B. J., Rucker, J., Liesnard, C., Farber, C. M., Saragosti, S., Lapoumeroulie, C., Cogniaux, J., Forceille, C., Muyldermans, G., Verhofstede, C., Burtonboy, G., Georges, M., Imai, T., Rana, S., Yi, Y., Smyth, R. J., Collman, R. G., Doms, R. W., Vassart, G., Parmentier, M. (1996) Resistance to HIV-1 infection of Caucasian individuals bearing mutant alleles of the CCR5 chemokine receptor gene Nature 382,722-725[CrossRef][Medline]
  17. Benos, D. J., McPherson, S., Hahn, B. H., Chaikin, M. A., Benveniste, E. N. (1994) Cytokines and HIV envelope glycoprotein gp120 stimulate Na+/H+ exchange in astrocytes J. Biol. Chem. 269,13811-13816[Abstract/Free Full Text]
  18. Holden, C. P., Haughey, N. J., Nath, A., Geiger, J. D. (1999) Role of Na+/H+ exchangers, excitatory amino acid receptors and voltage-operated Ca2+ channels in human immunodeficiency virus type 1 gp120-mediated increases in intracellular Ca2+ in human neurons and astrocytes Neuroscience 91,1369-1378[CrossRef][Medline]
  19. Kaul, M., Garden, G. A., Lipton, S. A. (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia Nature 410,988-994[CrossRef][Medline]
  20. Navia, B. A., Dafni, U., Simpson, D., Tucker, T., Singer, E., McArthur, J. C., Yiannoutsos, C., Zaborski, L., Lipton, S. A. (1998) A phase I/II trial of nimodipine for HIV-related neurologic complications Neurology 51,221-228[Abstract/Free Full Text]
  21. Carlier, E., Mabrouk, K., Moulard, M., Fajloun, Z., Rochat, H., De Waard, M., Sabatier, J. M. (2000) Ion channel activation by SPC3, a peptide derived from the HIV-1 gp120 V3 loop J. Pept. Res. 56,427-437[CrossRef][Medline]
  22. Kwong, P. D., Wyatt, R., Robinson, J., Sweet, R. W., Sodroski, J., Hendrickson, W. A. (1998) Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody Nature 393,648-659[CrossRef][Medline]
  23. Sharon, M., Kessler, N., Levy, R., Zolla-Pazner, S., Gorlach, M., Anglister, J. (2003) Alternative conformations of HIV-1 V3 loops mimic beta hairpins in chemokines, suggesting a mechanism for coreceptor selectivity Structure (Camb) 11,225-236
  24. Taylor, C. W. (2002) Controlling calcium entry Cell 111,767-769[CrossRef][Medline]
  25. Lee, B., Sharron, M., Montaner, L. J., Weissman, D., Doms, R. W. (1999) Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages Proc. Natl. Acad. Sci. USA 96,5215-5220[Abstract/Free Full Text]
  26. Hoffman, T. L., Canziani, G., Jia, L., Rucker, J., Doms, R. W. (2000) A biosensor assay for studying ligand-membrane receptor interactions: binding of antibodies and HIV-1 Env to chemokine receptors Proc. Natl. Acad. Sci. USA 97,11215-11220[Abstract/Free Full Text]
  27. Farzan, M., Choe, H., Martin, K. A., Sun, Y., Sidelko, M., Mackay, C. R., Gerard, N. P., Sodroski, J., Gerard, C. (1997) HIV-1 entry and macrophage inflammatory protein-1ß-mediated signaling are independent functions of the chemokine receptor CCR5 J. Biol. Chem. 272,6854-6857[Abstract/Free Full Text]
  28. Atchison, R. E., Gosling, J., Monteclaro, F. S., Franci, C., Digilio, L., Charo, I. F. G. (1996) Multiple extracellular elements of CCR5 and HIV-1 entry: dissociation from response to chemokines Science 274,1924-1926[Abstract/Free Full Text]
  29. Weissman, D., Rabin, R. L., Arthos, J., Rubbert, A., Dybul, M., Swofford, R., Venkatesan, S., Farber, J. M., Fauci, A. S. (1997) Macrophage-tropic HIV and SIV envelope proteins induce a signal through the CCR5 chemokine receptor Nature 389,981-985[CrossRef][Medline]
  30. Mori, K., Ringler, D. J., Desrosiers, R. C. (1993) Restricted replication of simian immunodeficiency virus strain 239 in macrophages is determined by env but is not due to restricted entry J. Virol. 67,2807-2814[Abstract/Free Full Text]
  31. Arthos, J., Rubbert, A., Rabin, R. L., Cicala, C., Machado, E., Wildt, K., Hanbach, M., Steenbeke, T. D., Swofford, R., Farber, J. M., Fauci, A. S. (2000) CCR5 signal transduction in macrophages by HIV and SIV envelopes J. Virol. 74,6418-6424[Abstract/Free Full Text]
  32. Amara, A., Vidy, A., Boulla, G., Mollier, K., Garcia-Perez, J., Alcamí, J., Blanpain, C., Parmentier, M., Virelizier, J. L., Charneau, P., Arenzana-Seisdedos, F. (2003) G protein-dependent CCR5 signaling is not required for efficient infection of primary T lymphocytes and macrophages by R5 HIV-1 isolates J. Virol. 77,2550-2558[Abstract/Free Full Text]
  33. Thelen, M. (2001) Dancing to the tune of chemokines Nat. Immunol. 2,129-134[CrossRef][Medline]
  34. Kaul, M., Lipton, S. A. (1999) Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis Proc. Natl. Acad. Sci. USA 96,8212-8216[Abstract/Free Full Text]
  35. Lo, T. M., Fallert, C. J., Piser, T. M., Thayer, S. A. (1992) HIV-1 envelope protein evokes intracellular calcium oscillations in rat hippocampal neurons Brain Res. 594,189-196[CrossRef][Medline]
  36. Lannuzel, A., Lledo, P. M., Lamghitnia, H. O., Vincent, J. D., Tardieu, M. (1995) HIV-1 envelope proteins gp120 and gp160 potentiate NMDA-induced [Ca2+]i increase, alter [Ca2+]i homeostasis and induce neurotoxicity in human embryonic neurons Eur. J. Neurosci. 7,2285-2293[CrossRef][Medline]
  37. Haughey, N. J., Mattson, M. P. (2002) Calcium dysregulation and neuronal apoptosis by the HIV-1 proteins Tat and gp120 J. Acquir. Immune Defic. Syndr. 31((Suppl. 2)),S55-S61
  38. Marinissen, M. J., Gutkind, J. S. (2001) G-protein-coupled receptors and signaling networks: emerging paradigms Trends Pharmacol. Sci. 22,368-376[CrossRef][Medline]
  39. Lev, S., Moreno, H., Martinez, R., Canoll, P., Peles, E., Musacchio, J. M., Plowman, G. D., Rudy, B., Schlessinger, J. (1995) Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions Nature 376,737-745[CrossRef][Medline]
  40. Dikic, I., Tokiwa, G., Lev, S., Courtneidge, S. A., Schlessinger, J. (1996) A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation Nature 383,547-550[CrossRef][Medline]
  41. Del Corno, M., Liu, Q. H., Schols, D., deClercq, E., Gessani, S., Freedman, B. D., Collman, R. G. (2001) 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 98,2909-2916[Abstract/Free Full Text]
  42. Cicala, C., Arthos, J., Ruiz, M., Vaccarezza, M., Rubbert, A., Riva, A., Wildt, K., Cohen, O., Fauci, A. S. (1999) Induction of phosphorylation and intracellular association of CC chemokine receptor 5 and focal adhesion kinase in primary human CD4+ T cells by macrophage-tropic HIV envelope J. Immunol. 163,420-426[Abstract/Free Full Text]
  43. Davis, C. B., Dikic, I., Unutmaz, D., Hill, C. M., Arthos, J., Siani, M. A., Thompson, D. A., Schlessinger, J., Littman, D. R. (1997) Signal transduction due to HIV-1 envelope interactions with chemokine receptors CXCR4 or CCR5 J. Exp. Med. 186,1793-1798[Abstract/Free Full Text]
  44. Sugden, P. H., Clerk, A. (1997) Regulation of the ERK subgroup of MAP kinase cascades through G protein-coupled receptors Cell. Signal. 9,337-351[CrossRef][Medline]
  45. Hall, R. A., Spurney, R. F., Premont, R. T., Rahman, N., Blitzer, J. T., Pitcher, J. A., Lefkowitz, R. J. (1999) G protein-coupled receptor kinase 6A phosphorylates the Na(+)/H(+) exchanger regulatory factor via a PDZ domain-mediated interaction J. Biol. Chem. 274,24328-24334[Abstract/Free Full Text]
  46. Heuss, C., Gerber, U. (2000) G-protein-independent signaling by G-protein-coupled receptors Trends Neurosci 23,469-475[CrossRef][Medline]
  47. Chang, L., Karin, M. (2001) Mammalian MAP kinase signalling cascades Nature 410,37-40[CrossRef][Medline]
  48. Popik, W., Hesselgesser, J. E., Pitha, P. M. (1998) Binding of human immunodeficiency virus type 1 to CD4 and CXCR4 receptors differentially regulates expression of inflammatory genes and activates the MEK/ERK signaling pathway J. Virol. 72,6406-6413[Abstract/Free Full Text]
  49. Popik, W., Pitha, P. M. (1998) Early activation of mitogen-activated protein kinase kinase, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and c-Jun N-terminal kinase in response to binding of simian immunodeficiency virus to Jurkat T cells expressing CCR5 receptor Virology 252,210-217[CrossRef][Medline]
  50. Misse, D., Esteve, P. O., Renneboog, B., Vidal, M., Cerutti, M., St Pierre, Y., Yssel, H., Parmentier, M., Veas, F. (2001) HIV-1 glycoprotein 120 induces the MMP-9 cytopathogenic factor production that is abolished by inhibition of the p38 mitogen-activated protein kinase signaling pathway Blood 98,541-547
  51. Merrill, J. E., Koyanagi, Y., Chen, I. S. Y. (1989) Interleukin-1 and tumor necrosis factor {alpha} can be induced from mononuclear phagocytes by human immunodeficiency virus type 1 binding to the CD4 receptor J. Virol. 63,4404-4408[Abstract/Free Full Text]
  52. Clouse, K. A., Cosentino, L. M., Weih, K. A., Pyle, S. W., Robbins, P. B., Hochstein, H. D., Natarajan, V., Farrar, W. L. (1991) The HIV-1 gp120 envelope protein has the intrinsic capacity to stimulate monokine secretion J. Immunol. 147,2892-2901[Abstract]
  53. François, F., Klotman, M. E. (2003) Phosphatidylinositol 3-kinase regulates human immunodeficiency virus type 1 replication following viral entry in primary CD4+ T lymphocytes and macrophages J. Virol. 77,2539-2549[Abstract/Free Full Text]
  54. Cohen, P. S., Schmidtmayerova, H., Dennis, J., Dubrovsky, L., Sherry, B., Wang, H., Bukrinsky, M., Tracey, K. J. (1997) The critical role of p38 MAP kinase in T cell HIV-1 replication Mol. Med. 3,339-346[Medline]
  55. Yang, X., Gabuzda, D. (1999) Regulation of HIV-1 infectivity by the ERK mitogen-activated protein kinase signaling pathway J. Virol. 73,3460-3466[Abstract/Free Full Text]
  56. Kinter, A. L., Umscheid, C. A., Arthos, J., Cicala, C., Lin, Y., Jackson, R., Donoghue, E., Ehler, L., Adelsberger, J., Rabin, R. L., Fauci, A. S. (2003) HIV envelope induces virus expression from resting CD4+ T cells isolated from HIV-infected individuals in the absence of markers of cellular activation or apoptosis J. Immunol. 170,2449-2455[Abstract/Free Full Text]
  57. Cinque, P., Vago, L., Mengozzi, M., Torri, V., Ceresa, D., Vicenzi, E., Transidico, P., Vagani, A., Sozzani, S., Mantovani, A., Lazzarin, A., Poli, G. (1998) Elevated cerebrospinal fluid levels of monocyte chemotactic protein-1 correlate with HIV-1 encephalitis and local viral replication AIDS 12,1327-1332[Medline]
  58. Kelder, W., McArthur, J. C., Nance-Sproson, T., McClernon, D., Griffin, D. E. (1998) ß-Chemokines MCP-1 and RANTES are selectively increased in cerebrospinal fluid of patients with human immunodeficiency virus-associated dementia Ann. Neurol. 44,831-835[CrossRef][Medline]
  59. Williams, K. C., Hickey, W. F. (2002) Central nervous system damage, monocytes and macrophages, and neurological disorders in AIDS Annu. Rev. Neurosci. 25,537-562[CrossRef][Medline]
  60. Fantuzzi, L., Canini, I., Belardelli, F., Gessani, S. (2001) HIV-1 gp120 stimulates the production of beta-chemokines in human peripheral blood monocytes through a CD4-independent mechanism J. Immunol. 166,5381-5387[Abstract/Free Full Text]
  61. Choe, W., Volsky, D. J., Potash, M. J. (2001) Induction of rapid and extensive beta-chemokine synthesis in macrophages by HIV-1 and gp120, independently of their coreceptor phenotype J. Virol. 75,10738-10745[Abstract/Free Full Text]
  62. Canque, B., Rosenzwajg, M., Gey, A., Tartour, E., Fridman, W. H., Gluckman, J. C. (1996) Macrophage inflammatory protein-1{alpha} is induced by human immunodeficiency virus infection of monocyte-derived macrophages Blood 87,2011-2019[Abstract/Free Full Text]
  63. Merrill, J. E., Koyanagi, Y., Zack, J., Thomas, L., Martin, F., Chen, I. S. Y. (1992) Induction of interleukin-1 and tumor necrosis factor alpha in brain cultures by human immunodeficiency virus type 1 J. Virol. 66,2217-2225[Abstract/Free Full Text]
  64. Simmons, G., Clapham, P. R., Picard, L., Offord, R. E., Rosenkilde, M. M., Schwartz, T. W., Buser, R., Wells, T. N. C., Proudfoot, A. E. (1997) Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist Science 276,276-279[Abstract/Free Full Text]
  65. Verani, A., Scarlatti, G., Comar, M., Tresoldi, E., Polo, S., Giacca, M., Lusso, P., Siccardi, A. G., Vercelli, D. (1997) C-C chemokines released by lipopolysaccharide (LPS)-stimulated human macrophages suppress HIV-1 infection in both macrophages and T cells J. Exp. Med. 185,805-816[Abstract/Free Full Text]
  66. Kedzierska, K., Crowe, S. M., Turville, S., Cunningham, A. L. (2003) The influence of cytokines, chemokines and their receptors on HIV-1 replication in monocytes and macrophages Rev. Med. Virol. 13,39-56[CrossRef][Medline]
  67. Banda, N. K., Bernier, J., Kurahara, D. K., Kurrle, R., Haigwood, N., Sekaly, R-P., Finkel, T. H. (1992) Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis J. Exp. Med. 176,1099-1106[Abstract/Free Full Text]
  68. Vlahakis, S. R., Algeciras-Schimnich, A., Bou, G., Heppelmann, C. J., Villasis-Keever, A., Collman, R. G., Paya, C. V. (2001) Chemokine-receptor activation by env determines the mechanism of death in HIV-infected and uninfected T lymphocytes J. Clin. Invest. 107,207-215[Medline]



This article has been cited by other articles:


Home page
 J. Virol.Home page
B. Harmon and L. Ratner
Induction of the G{alpha}q Signaling Cascade by the Human Immunodeficiency Virus Envelope Is Required for Virus Entry
J. Virol., September 15, 2008; 82(18): 9191 - 9205.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
S. M. Wahl, T. Greenwell-Wild, and N. Vazquez
HIV accomplices and adversaries in macrophage infection
J. Leukoc. Biol., November 1, 2006; 80(5): 973 - 983.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
A. Bachis, S. A. Aden, R. L. Nosheny, P. M. Andrews, and I. Mocchetti
Axonal transport of human immunodeficiency virus type 1 envelope protein glycoprotein 120 is found in association with neuronal apoptosis.
J. Neurosci., June 21, 2006; 26(25): 6771 - 6780.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
F. Nimura, L. F. Zhang, K. Okuma, R. Tanaka, H. Sunakawa, N. Yamamoto, and Y. Tanaka
Cross-linking cell surface chemokine receptors leads to isolation, activation, and differentiation of monocytes into potent dendritic cells.
Experimental Biology and Medicine, April 1, 2006; 231(4): 431 - 443.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
C. Cicala, J. Arthos, E. Martinelli, N. Censoplano, C. C. Cruz, E. Chung, S. M. Selig, D. Van Ryk, J. Yang, S. Jagannatha, et al.
R5 and X4 HIV envelopes induce distinct gene expression profiles in primary peripheral blood mononuclear cells
PNAS, March 7, 2006; 103(10): 3746 - 3751.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
G. Ghaffari, D. L. Tuttle, D. Briggs, B. R. Burkhardt, D. Bhatt, W. A. Andiman, J. W. Sleasman, and M. M. Goodenow
Complex Determinants in Human Immunodeficiency Virus Type 1 Envelope gp120 Mediate CXCR4-Dependent Infection of Macrophages
J. Virol., November 1, 2005; 79(21): 13250 - 13261.
[Abstract] [Full Text] [PDF]

Home page
 GutHome page
S L-F Pender, V Chance, C V Whiting, M Buckley, M Edwards, R Pettipher, and T T MacDonald
Systemic administration of the chemokine macrophage inflammatory protein 1{alpha} exacerbates inflammatory bowel disease in a mouse model
Gut, August 1, 2005; 54(8): 1114 - 1120.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
K. Balabanian, J. Harriague, C. Decrion, B. Lagane, S. Shorte, F. Baleux, J.-L. Virelizier, F. Arenzana-Seisdedos, and L. A. Chakrabarti
CXCR4-Tropic HIV-1 Envelope Glycoprotein Functions as a Viral Chemokine in Unstimulated Primary CD4+ T Lymphocytes
J. Immunol., December 15, 2004; 173(12): 7150 - 7160.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
R. G. Collman, C.-F. Perno, S. M. Crowe, M. Stevenson, and L. J. Montaner
HIV and cells of macrophage/dendritic lineage and other non-T cell reservoirs: new answers yield new questions
J. Leukoc. Biol., November 1, 2003; 74(5): 631 - 634.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jlb.0503206v1
74/5/676    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lee, C.
Right arrow Articles by Collman, R. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, C.
Right arrow Articles by Collman, R. G.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH