| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Clincial Immunology Section, Laboratory of Clinical Investigation, and
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, and
Molecular Immunogenetics and Vaccine Research Section, Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
§
Immunex Corporation, Seattle, WA 98101
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, MIP-1ß, and RANTES and diminished
surface expression of CCR5. Based on these findings, the functional
role of CD40LT stimulation on the ability of DCs to replicate and
transmit HIV viral infection was studied. The addition of CD40LT to
cocultures of naive CD4+ T cells and autologous DCs (T/DC)
infected with the macrophage-tropic isolate, HIVBaL, caused
a striking reduction in reverse transcriptase (RT) activity after 10
and 14 days of culture. The addition of a mixture of Abs against
CC-chemokines abrogated the decrease in RT activity, demonstrating that
the inhibitory effect mediated by CD40LT was CC-chemokine-dependent. In
contrast, the presence of CD40LT in T/DC cocultures infected with the T
cell-tropic isolate, HIVIIIB, caused an increase in RT
activity that was CC-chemokine-independent. Of note, CD40LT stimulation
also inhibited RT activity in cultures containing macrophage-tropic
virus (HIVBaL)-infected DC only. However, in contrast to
the results seen in the T/DC cocultures, CD40LT stimulation inhibited
RT activity in cultures of DCs alone in a CC-chemokine-independent
manner. Together, these results show that CD40LT stimulation of DCs
suppresses HIV replication and transmission to CD4+ T cells
by two potentially different mechanisms. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, IL-1,
IL-1ß, IL-6, and IL-8, from macrophages and dendritic cells (DCs)
5, 6, 7 . Furthermore, in one report, CD40 stimulation also resulted in
production of the CC-chemokine macrophage inflammatory protein
(MIP)-1 by monocytes and cord blood-derived DCs 3 . This raised the
question of whether other CC-chemokines might be induced from APCs
through CD40/CD40L stimulation. In assessing the effect of CD40/CD40L stimulation on CC-chemokine production, Kornbluth et al. 8 recently demonstrated that macrophages are a potent source of CC-chemokines following stimulation by cells transfected with CD40L. In addition, supernatants from these CD40L-stimulated monocytes diminished the ability of HIVSF-162, a strain of HIV-1 that uses CCR5 as a coreceptor, to infect CD4+ T cells. These data clearly supported a CC-chemokine-dependent pathway by which CD40L-stimulated monocytes could limit HIV transmission to CD4+ T cells. These data are in contrast to earlier work in which CD40/CD40L stimulation enhanced HIV-1 replication in DC cocultures with CD4+ T cells. It should be noted, however, that these studies were done using the HIVLAI strain, which was subsequently shown to use CXCR4 as a coreceptor 9 . While these discrepancies are likely explained by the coreceptor usage of the particular strain of HIV used, we were interested in determining the net biologic effects that stimulation of CD40 by exogenous CD40L exerted on both macrophage (M)-tropic and T cell (T)-tropic HIV-1 replication in vitro. To this end, we used a soluble trimeric CD40L agonist (CD40LT) protein to examine whether such exogenous CD40/CD40L stimulation enhanced production of CC-chemokines from CD14+ monocyte-derived DCs and whether this had an impact on the replication of HIV in cocultures with CD4+ T cells. In an attempt to mimic events that occur in vivo, DCs were infected with HIV-1 and then cultured with or without purified autologous CD4+ T cells in the presence or absence of CD40LT. Cells were cultured for a period of 2 wk, during which time HIV replication was monitored by reverse transcriptase (RT) activity. We demonstrate that stimulation with CD40LT diminished RT activity from infected DCs alone and in cocultures with T cells plus autologous DC (T/DC) in a CC-chemokine-independent and -dependent manner, respectively. The potential physiologic role of CD40/CD40L stimulation in regulating the ability of DCs to serve as reservoirs of HIV, as well as to transmit virus to CD4+ T cells, is discussed.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Complete medium consisting of RPMI 1640 supplemented with 10% heat-inactivated human AB sera (Sigma, St. Louis, MO), penicillin (100 U/ml), streptomycin (100 U/ml), and L-glutamine (2 mM) were used in all cultures. Lymphocyte separation medium was purchased from Organon Teknika (Durham, NC).
Subjects
Monocytes were obtained via countercurrent elutriation from apheresed subjects from the National Institutes of Health normal donor pool. Autologous, highly enriched T cells were also obtained from the same donors and cryopreserved.
Recombinant cytokines
Human rIL-4 was purchased from Genzyme (Cambridge, MA). Human recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) and CD40LT were gifts from Immunex (Seattle, WA).
Antibodies
Goat anti-human Abs to MIP-1, MIP-1ß, RANTES, and
control Abs were purchased from R&D Systems (Minneapolis, MN).
Cell preparation
Fresh elutriated human monocytes (90% CD14+) were cultured in 6-well dishes (Costar, Cambridge, MA) at a concentration of 106 cells/ml. Cells were cultured in AIM-V (Gibco, Grand Island, NY) medium supplemented with 5% FCS with exogenous IL-4 (100 ng/ml) and GM-CSF (50 ng/ml) added every 2–3 days for 7 days. Highly purified autologous CD4+ T cells (>95%) were obtained by positive selection using CD4 magnetic beads and Detach-a-Bead (Dynal, Lake Success, NY) according to the manufacturer’s instructions.
Induction of chemokine production
DCs were harvested after 7 days’ culture in GM-CSF plus IL-4 and washed three times in HBSS. DCs (5 x 105 cells/ml) were added to 24-well plates (Costar) in the presence or absence of CD40LT (2 µg/ml). Supernatants were collected at 48 h and stored at -70°C until used. It should be noted that endotoxin content in the CD40LT preparations was <5 endotoxin U/ml. In addition, to rule out an effect of LPS in the cultures, we demonstrated that CC-chemokine production was not diminished by addition of polymixin-B to cultures (data not shown). Supernatants from the CD4+ T cell/DC cocultures infected with HIVBaL or HIVIIIB (see below) were similarly collected and stored at days 7, 10, and 14.
Measurement of chemokine induction
ELISAs specific for each CC-chemokine (MIP-1, MIP-1ß,
and RANTES) were used (R&D Systems; the lower limit of detection
for these assays was 32 pg/ml). Results for all chemokines represent
the mean of duplicate wells. The SEM was <10% for all experiments.
Flow cytometric analysis
DCs were dual-stained with anti-CD83 (HB15A; a generous gift from T. Tedder, Duke University, Durham, NC) and anti-CCR5 FITC (PharMingen, Torrance, CA) and isotype control Abs after 48 h in the presence or absence of CD40LT. Stained-cell populations were analyzed on a FACScan (Becton Dickinson, Mountain View, CA).
HIV infection
DCs were incubated with HIV-1BaL or HIV-1IIIB strains at a multiplicity infection of 0.01–0.001 for 2 h and then washed three times. CD4+ T cells were isolated as previously described. HIV-pulsed DCs were added to flat-bottom 96-well plates (Costar) at 1 x 104 cells/well in 100 µl of medium. CD4+ T cells were added at 1 x 105 cells/well in 100 µl of medium. The cocultures were incubated at 37°C for 14 days. Medium was exchanged on days 7 and 10. Before medium exchange, 10 µl aliquots of culture supernatants were harvested and stored at -70°C. Samples were assayed at days 7, 10, and 14 for RT activity by a microtiter method 10 .
Statistical analysis
Statistical analysis was performed using Microsoft Excel (Redmond, WA).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
It had been previously reported that activated fresh human
monocytes stimulated with CD40L-transfected cells were induced to
secrete CC-chemokines MIP-1, MIP-1ß, and RANTES 8 . We sought to
extend these findings by determining whether monocyte-derived DCs were
also a potent source of CC-chemokines using CD40LT. To this end, fresh
elutriated monocytes were stimulated for 7 days with GM-CSF plus IL-4,
and cells were evaluated by surface staining to determine their
phenotype. The starting population of monocytes (day 0) were
CD14high, CD4+, CD54+,
CD86+, HLA-DR+, and CD80-,
CD1a-, CD83-, or CD40-. After 7
days in culture with GM-CSF plus IL-4, cells were CD14-
with increased expression of CD40, CD54, CD86, and HLA-DR compared with
the starting population. In addition, cells had enhanced
expression of CD1a but remained CD83low (data not shown).
Phenotypically, these cells were consistent with immature DCs 4 .
CD40LT induces CC-chemokine production from DCs
To determine whether exogenous CD40LT stimulation induced and/or
enhanced CC-chemokine production from DCs, elutriated monocytes
cultured for 7 days with GM-CSF plus IL-4 were thoroughly washed and
placed in secondary cultures in the presence or absence (medium) of
CD40LT. As shown in Fig. 1
, DCs
constitutively produced MIP-1 and MIP-1ß but not RANTES when
cultured in medium alone. Addition of CD40LT to cultures resulted in a
4-fold increase in production of MIP-1 (Fig. 1A) and a
2-fold increase in MIP-1ß (Fig. 1B). Moreover, CD40LT
stimulation induced substantial production of RANTES (Fig. 1C). Thus, CD40LT stimulation strikingly enhanced production
of CC-chemokines from DCs.
|
In addition to the aforementioned effects of CD40LT
stimulation on CC-chemokine production by DCs, CD40/CD40L stimulation
has also been shown to induce DC maturation 3, 4 . Moreover, it has
been reported recently that down-regulation of CCR5 expression is
coincident with phenotypic maturation of DCs after culturing in the
presence of monocyte-conditioned medium 11 . To determine the effect
of stimulation with CD40LT on DC maturation and expression of CCR5,
elutriated monocytes were first cultured for 7 days with GM-CSF plus
IL-4 to generate DCs. Cells were then washed and cultured in the
presence or absence of CD40LT for 48 h, at which time CCR5 and
CD83 expression was determined by FACS analysis. As shown in Fig. 2A, fresh monocytes
constitutively express CCR5, which is diminished after 7 days of
culture in the presence of GM-CSF plus IL-4. Addition of CD40LT to
cultures resulted in a significant further down-regulation of CCR5
(Fig. 2A) while simultaneously enhancing the expression of
CD83. Furthermore, the CD40LT-induced down-regulation of CCR5
expression was abrogated in the presence of neutralizing Abs to the
CC-chemokines (Fig. 2B). It should be noted, however,
that neutralization of the endogenous CC-chemokines did not affect
CD40LT enhancement of CD83 expression. Together, these data support a
role for CD40LT stimulation in the differentiation of DCs (as assessed
by CD83 expression) and show that its ability to induce
CC-chemokines has a biologic effect in down-regulating expression
of CCR5.
|
Because CD40LT stimulation resulted in a significant effect on
CC-chemokine induction from DCs, we determined the functional role that
CD40LT had in regulating HIV viral replication using an in vitro model.
DCs were exposed to either HIVBaL (M-tropic) or
HIVIIIB (T-tropic) strains, washed extensively, and placed
in culture with or without autologous CD4+ T cells (T/DC)
in the presence (T/DC plus CD40LT) or absence of CD40LT. HIV-1
replication was assessed 7, 10, and 14 days later by RT activity. It
should be noted that these conditions are sufficient to induce HIV
replication in the absence of mitogenic stimulation or addition of
exogenous IL-2 12 . Cultures containing T/DC in which DCs were
infected with HIVBaL demonstrated a progressive increase in
RT activity over the 14-day culture period (Fig. 3, A and B).
Addition of exogenous CD40LT (T/DC plus CD40LT) reduced RT activity at
all time points tested (Fig. 3, A and B). This
suppression was abrogated by addition of a mixture of
anti-CC-chemokine Abs. Furthermore, the addition of exogenous
CC-chemokines to control cocultures (T/DC plus CC-chemokine) that did
not contain CD40LT reduced RT activity in a manner similar to that
observed by stimulation with CD40LT (Fig. 3A). As a control,
the addition of anti-CC-chemokines to T/DC cultures (T/DC plus
anti-CC-chemokine) resulted in similar RT activity to that of T/DC
alone (Fig. 3B). Together, these data strongly suggest that
CD40LT induction of CC-chemokines from DCs was able to inhibit
replication of HIVBaL in CD4+ T cells
stimulated with infected DCs. Over seven independent
experiments, the median inhibition in RT activity observed was 83%
(range, 66–97%). To verify that CC-chemokines were induced in the
T/DC cocultures, we measured the production of MIP-1, MIP-1ß, and
RANTES on days 7, 10, and 14. As shown in Table I, production of MIP-1 and MIP-1ß
but not of RANTES was detected in the supernatants from the T/DC
cocultures. Addition of exogenous CD40LT enhanced production of all
three CC-chemokines, consistent with the data presented in Fig. 1
.
|
|
C). Over seven independent experiments, the
mean enhancement of RT activity was 2.5-fold (range, 1.5- to 4.0-fold).
Of note, addition of anti-CC-chemokines to cultures containing
CD40LT (T/DC plus CD40LT plus anti-CC chemokines) did not abrogate
the enhancement in RT activity. These data suggest that for
HIVIIIB, CD40LT can enhance replication independent
of the CC-chemokines MIP-1, MIP-1ß, and RANTES. It should
also be noted that the addition of exogenous CC-chemokines (T/DC plus
CC-chemokines) also resulted in a modest increase in RT activity
compared with T/DC alone. This observation was reproducible in all
experiments. These latter data are consistent with recent reports
showing that CC-chemokines can enhance T-tropic replication 13, 14 .
Together, these data suggest that CD40LT leads to the differential
regulation of HIV-1 replication by reducing M-tropic but increasing
T-tropic replication in a T/DC coculture system. CD40LT diminishes M-tropic HIV replication in DC in a CC-chemokine-independent fashion
As a control in Fig. 3A, it was noted that RT activity
from infected DC alone was suppressed by the addition of CD40LT to the
cultures. Because DCs may serve as a reservoir for HIV, we further
examined whether CD40LT alters HIV replication in DCs. Similar to the
experiment illustrated in Fig. 3A, DCs were exposed to
HIVBaL for 2 h, extensively washed, and then cultured
in the presence or absence of CD40LT. As shown in Fig. 4A, the addition of CD40LT (DC
plus CD40LT) markedly diminished RT activity at days 10 and 14 compared
with DC-only cultures. Over six independent experiments, the median
inhibition of HIVBaL RT activity was 84% (range,
70–93%). Moreover, addition of anti-CC-chemokine Abs did not
significantly change RT activity in HIVBaL-infected DC
cultures in any experiments, whether in the presence or absence of
CD40LT (Fig. 4A). Therefore, in contrast to
HIVBaL-infected T cell/DC cocultures, in which CD40LT
inhibited RT activity in a CC-chemokine-dependent manner (Fig. 3B), the ability of CD40LT to diminish RT activity in DCs
occurred in a CC-chemokine-independent fashion. The inability of
CC-chemokines to regulate RT activity in HIV-infected DCs is further
supported by the observation that even in the absence of CD40LT, the
addition of anti-CC-chemokines (DC plus anti-CC-chemokines) did
not enhance or diminish RT activity. A final point is that DCs exposed
to HIVIIIB demonstrated little RT activity in the presence
or absence of CD40LT (Fig. 4B). These data are consistent
with some previous reports demonstrating that T-tropic strains of HIV
do not infect or replicate in DCs as efficiently as do M-tropic strains
using CCR5 coreceptor for entry 15, 16, 17 . It should be noted, however,
that other reports have failed to note this dichotomy 18, 19 .
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
CD40LT stimulation enhances production of CC-chemokines but diminishes CCR5 expression on DCs
In addition to its effects on enhancing production of CC-chemokines, this study shows that CD40LT stimulation causes a decrease in the expression of CCR5 on DCs. With regard to the effect of cytokines on CCR5 expression, a recent report by DiMarzio et al. 20 showed that GM-CSF caused a rapid decrease in CCR5 mRNA in monocytes that correlated with decreased viral entry. Furthermore, a recent report by Wang et al. 21 showed that fresh monocytes cultured with GM-CSF and IL-4 also had diminished CCR5 expression. It should be noted, however, that in this latter study 21 , cells cultured in GM-CSF alone actually had an increase in CCR5 expression. Our study demonstrates that DCs generated from monocytes cultured in GM-CSF and IL-4 for 7 days had a marked reduction in CCR5 expression. Furthermore, stimulation with CD40LT caused a further down-regulation of CCR5 expression that was abrogated by the addition of anti-CC chemokine Abs to cultures. These data are consistent with a previous report showing rapid and extensive down-regulation and internalization of CCR5 by RANTES 22 . Finally, it should be noted that while CD40LT stimulation diminished expression of CCR5, it also increased expression of CD83, a marker often used to characterize "mature" or more fully differentiated DCs 23 . These data are consistent with recent work by Delgado et al. 11 , who showed that CCR5 expression was strikingly reduced when immature DCs were further differentiated in monocyte-conditioned medium. Together, these studies suggest that CCR5 expression may vary in the course of DC differentiation.
The role of CD40/CD40L stimulation in the regulation of HIV infection by CD4+ T cells and DCs
In earlier studies examining the role of CD40/CD40L stimulation in
HIV replication, Pinchuk et al. 9 showed that cross-linking mAbs
against CD40 increased DC transmission of HIV-1 to CD4+ T
cells. This augmentation in HIV transmission was blocked by
anti-CD80 Abs or a soluble fusion protein of the CD80 ligand,
CTLA4Ig. It should be noted, however, that these studies used the
T-tropic strain, HIVLAI. Subsequently, Weissman et al.
24 , using another T-tropic strain, HIVIIIB, demonstrated
that mature CD80+/CD83+ DCs were substantially
more proficient at passing HIV-1 infection in vitro to
CD4+ T cells as compared with immature DCs not expressing
high levels of CD80/CD83 or with blood monocytes. Indeed, our results
using exogenous CD40LT to stimulate DCs via CD40 support the notion
that stimulation of DCs in this manner increases viral replication in
T/DC cocultures infected with T-tropic HIV-1. Furthermore, the
CD40LT-mediated enhancement of T-tropic replication appeared to be
independent of CC-chemokines (Fig. 3C). This latter
observation may be due to the fact that CD40LT enhances maturation of
DCs and up-regulates expression of B7 costimulatory molecules (data not
shown), thereby leading to enhanced CD4+ T cell activation.
These observations underscore the important role of enhanced immune
activation 25 in HIV-1 transmission, particularly in the setting of
T-tropic infection, and suggest that the propagation of T-tropic
strains may be more sensitive to higher levels of activation based on
the variable regulation of CXCR4 vs CCR5 26 . In contrast to the
results using T-tropic HIV-1, the ability of CD40LT to enhance
production of CC-chemokine from DCs was shown to be functionally
important using M-tropic HIV-1. In this regard, the presence of CD40LT
in T/DC cocultures caused a striking reduction in RT activity that was
abrogated by anti-CC-chemokine Abs. These data clearly demonstrate
that for the M-tropic strain of HIV-1 (HIVBaL), the ability
of CD40LT to inhibit viral replication is CC-chemokine dependent.
To conclude, in our T/DC coculture system, there is a dichotomy in the
mechanism by which CD40LT stimulation differentially regulates HIV
replication depending on the tropism of the virus. Thus, CD40LT
stimulation causes an increase in T-tropic replication and a decrease
in M-tropic replication. Moreover, the inhibition of M-tropic
replication is CC-chemokine-dependent, while the enhancement of
T-tropic replication is CC-chemokine-independent. With regard to this
latter point, however, two recent reports have demonstrated that the
presence of CC-chemokines enhanced T-tropic replication in T cells 13, 14 . Thus, in the experiments reported here, while the presence of
CD40LT in T/DC cocultures appeared to increase T-tropic replication in
a CC-chemokine-independent manner (Fig. 3C), it is possible
that under other experimental conditions, CD40LT-mediated enhancement
of CC-chemokine production could also effect T-tropic replication.
CD40/CD40L stimulation enhances maturation of DCs and inhibits their ability to replicate HIV
In addition to the role of DCs in transmitting HIV-1 infection to CD4+ T cells, HIV-infected blood and skin DCs may represent an important viral reservoir in disease pathogenesis. There are several conflicting reports in the literature with regard to HIV-1 replication in DCs. Several earlier studies suggested that HIV-1 can replicate actively in DCs 27, 28, 29 ; by contrast, others have shown a relatively low level of infection in DCs 30 . Moreover, this low level of infection occurred despite the efficient entry M-tropic and T-tropic strains 31 . Some of these discrepancies, however, may be accounted for by differences in cell populations as well as by the methods of cell culture and ultimate level of maturation of the DCs examined. There is recent evidence that immature DCs derived from monocytes selectively replicate M-tropic but not T-tropic HIV-1 strains, whereas mature DCs do not support replication of either 15 . Our results support a lack of efficient viral replication by T-tropic strains (HIVIIIB) in immature or mature DCs in contrast to the M-tropic strain (HIVBaL), which readily replicates in immature DCs. The treatment of DC cultures with CD40LT after HIV-1 pulse infection markedly reduced the level of HIVBaL replication compared with immature DCs. Of interest, addition of anti-CC-chemokine Abs to DC cultures treated with CD40LT had no effect on viral replication. This was in marked contrast to the reversal of suppression seen in T/DC-infected cocultures within the same experiment. These data support a CC-chemokine-independent pathway whereby CD40LT stimulation reduces M-tropic HIV-1 viral replication in DCs.
With regard to the CC-chemokine-independent mechanism by which CD40LT
inhibited viral replication in DC cultures, there remain several
possibilities. First, CD40LT could limit viral replication in DCs
through a decrease in viral entry. This is consistent with data shown
in Fig. 2 in which CCR5 expression was markedly diminished on DCs
cultured with CD40LT. However, in the experiments shown in Figs. 3 and 4, DCs were exposed to HIV before the addition of CD40LT. A second
possibility is that the addition of CD40LT to DC cultures after
infection could limit cell-to-cell spread by decreasing CCR5
expression. Because CD40LT stimulation diminished CCR5 expression
through enhancement of CC-chemokines (Fig. 2), the data in Fig. 4
showing that the addition of anti-CC-chemokines to DC cultures
stimulated with CD40LT did not affect viral replication makes this
latter mechanism less likely.
CD40LT also induced high levels of expression of CD83, MHC class II, CD80, CD86, and ICAM-1 and a notable morphologic change in dendrite formation (data not shown), suggesting that CD40LT enhances DC maturation. Consequently, these mature DCs do not support a high level of HIV-1 infection following CD40 triggering, in contrast to their immature precursors. Thus, CD40 stimulation may be an important mechanism whereby M-tropic HIV-1 spread is limited within the DC reservoir. It should be noted that while CD40LT substantially limits HIV replication to a very low level within mature DCs themselves, these cells are still able to pass virus to CD4+ T cells. These data are consistent with several reports demonstrating that mature DCs, despite a very low level of endogenous infection, still retain the ability to effectively spread HIV-1 infection to CD4+ T cells 30, 32, 33, 34, 35 . Thus, the capacity of DCs to initiate and propagate HIV-1 infection in neighboring CD4+ T cells appears to be distinct from HIV-1 replication within the DC reservoir itself 35, 36, 37 .
Therapeutic potential of CD40LT in HIV infection
CD40LT stimulation has differential effects on HIV-1 replication that vary according to viral tropism. CD40LT reduces M-tropic HIV-1 replication in CD4+ T cells but enhances T-tropic HIV-1 replication. While the protective effects from M-tropic HIV-1 on CD4+ T cells are mediated primarily through the induction of CC-chemokines from DCs, the reduction in M-tropic HIV-1 replication in DCs themselves appears to be a direct effect of CD40LT acting to induce DC maturation. This "antiviral" role of CD40LT stimulation, combined with recent studies showing an "immune enhancing" role of CD40/CD40L stimulation in restoring CTL activity in the absence of CD4+ T cell help 38, 39, 40 , provides a rationale for considering CD40LT as a therapeutic modality for HIV infection. Furthermore, CD40LT enhancement of DC function may increase CD8+ T cell activity, which could limit HIV replication through both CC-chemokine-dependent and -independent mechanisms 41, 42 . One caveat, however, is that CD40LT therapy could alter or enhance HIV-1 viral selection toward a T-tropic predominance. The potential enhancement in CTL activity, however, combined with the availability of potent antiviral chemotherapy, may obviate this concern.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Robert A. Seder, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Building 10, Room 11C215, 9000 Rockville Pike, Bethesda, MD 20892. E-mail address:
3 Abbreviations used in this paper: CD40L, CD40 ligand; CD40LT, soluble trimeric CD40 ligand; DC, dendritic cell; RT, reverse transcriptase; T/DC, cultures of T cells plus autologous dendritic cells; MIP, macrophage inflammatory protein; M-tropic, macrophage-tropic; T-tropic, T cell tropic; GM-CSF, granulocyte-macrophage colony-stimulating factor.
Received for publication October 15, 1998. Accepted for publication December 16, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
. J. Exp. Med. 179:1109.-dependent internalization of the chemokine receptor CXCR4 contributes to inhibition of HIV replication. J. Exp. Med. 186:139.
32CCR5 allele as a model. AIDS Res. Hum. Retroviruses 14:1109.[Medline]
This article has been cited by other articles:
|
|
 |
|
  C. Dong, A. M. Janas, J.-H. Wang, W. J. Olson, and L. Wu Characterization of Human Immunodeficiency Virus Type 1 Replication in Immature and Mature Dendritic Cells Reveals Dissociable cis- and trans-Infection J. Virol., October 15, 2007; 81(20): 11352 - 11362. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Kornbluth and G. W. Stone Immunostimulatory combinations: designing the next generation of vaccine adjuvants J. Leukoc. Biol., November 1, 2006; 80(5): 1084 - 1102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Ancuta, P. Autissier, A. Wurcel, T. Zaman, D. Stone, and D. Gabuzda CD16+ Monocyte-Derived Macrophages Activate Resting T Cells for HIV Infection by Producing CCR3 and CCR4 Ligands J. Immunol., May 15, 2006; 176(10): 5760 - 5771. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Granelli-Piperno, I. Shimeliovich, M. Pack, C. Trumpfheller, and R. M. Steinman HIV-1 Selectively Infects a Subset of Nonmaturing BDCA1-Positive Dendritic Cells in Human Blood J. Immunol., January 15, 2006; 176(2): 991 - 998. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. L. Hodara, M. C. Velasquillo, L. M. Parodi, and L. D. Giavedoni Expression of CD154 by a Simian Immunodeficiency Virus Vector Induces Only Transitory Changes in Rhesus Macaques J. Virol., April 15, 2005; 79(8): 4679 - 4690. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Chougnet Role of CD40 Ligand dysregulation in HIV-associated dysfunction of antigen-presenting cells J. Leukoc. Biol., November 1, 2003; 74(5): 702 - 709. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Messmer, B. Messmer, and N. Chiorazzi The global transcriptional maturation program and stimuli-specific gene expression profiles of human myeloid dendritic cells Int. Immunol., April 1, 2003; 15(4): 491 - 503. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Fong, M. Mengozzi, N. W. Abbey, B. G. Herndier, and E. G. Engleman Productive Infection of Plasmacytoid Dendritic Cells with Human Immunodeficiency Virus Type 1 Is Triggered by CD40 Ligation J. Virol., October 2, 2002; 76(21): 11033 - 11041. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Frank, M. Piatak Jr., H. Stoessel, N. Romani, D. Bonnyay, J.D. Lifson, and M. Pope Infectious and Whole Inactivated Simian Immunodeficiency Viruses Interact Similarly with Primate Dendritic Cells (DCs): Differential Intracellular Fate of Virions in Mature and Immature DCs J. Virol., February 22, 2002; 76(6): 2936 - 2951. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-Q. Zhao, X.-L. Huang, P. Gupta, L. Borowski, Z. Fan, S. C. Watkins, E. K. Thomas, and C. R. Rinaldo Jr. Induction of Anti-Human Immunodeficiency Virus Type 1 (HIV-1) CD8+ and CD4+ T-Cell Reactivity by Dendritic Cells Loaded with HIV-1 X4-Infected Apoptotic Cells J. Virol., February 22, 2002; 76(6): 3007 - 3014. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Cotter, J. Zheng, M. Che, D. Niemann, Y. Liu, J. He, E. Thomas, and H. E. Gendelman Regulation of Human Immunodeficiency Virus Type 1 Infection, {beta}-Chemokine Production, and CCR5 Expression in CD40L-Stimulated Macrophages: Immune Control of Viral Entry J. Virol., May 1, 2001; 75(9): 4308 - 4320. [Abstract] [Full Text]
|
|
|
|
|
|
Y. Bakri, C. Schiffer, V. Zennou, P. Charneau, E. Kahn, A. Benjouad, J. C. Gluckman, and B. Canque The Maturation of Dendritic Cells Results in Postintegration Inhibition of HIV-1 Replication J. Immunol., March 15, 2001; 166(6): 3780 - 3788. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Chougnet, C. Freitag, M. Schito, E. K. Thomas, A. Sher, and G. M. Shearer In Vivo CD40-CD154 (CD40 Ligand) Interaction Induces Integrated HIV Expression by APC in an HIV-1-Transgenic Mouse Model J. Immunol., March 1, 2001; 166(5): 3210 - 3217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Howard and S. D. Miller Autoimmune Intervention by CD154 Blockade Prevents T Cell Retention and Effector Function in the Target Organ J. Immunol., February 1, 2001; 166(3): 1547 - 1553. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Kornbluth The emerging role of CD40 ligand in HIV infection J. Leukoc. Biol., September 1, 2000; 68(3): 373 - 382. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Jourdan, J.-P. Vendrell, M.-F. Huguet, M. Segondy, J. Bousquet, J. Pene, and H. Yssel Cytokines and Cell Surface Molecules Independently Induce CXCR4 Expression on CD4+ CCR7+ Human Memory T Cells J. Immunol., July 15, 2000; 165(2): 716 - 724. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Hornung, G. Scala, and M. J. Lenardo TNF-{alpha}-Induced Secretion of C-C Chemokines Modulates C-C Chemokine Receptor 5 Expression on Peripheral Blood Lymphocytes J. Immunol., June 15, 2000; 164(12): 6180 - 6187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Borges, R. E. Miller, J. Jones, K. Ariail, J. Whitmore, W. Fanslow, and D. H. Lynch Synergistic Action of fms-Like Tyrosine Kinase 3 Ligand and CD40 Ligand in the Induction of Dendritic Cells and Generation of Antitumor Immunity In Vivo J. Immunol., August 1, 1999; 163(3): 1289 - 1297. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Chougnet, S. S. Cohen, T. Kawamura, A. L. Landay, H. A. Kessler, E. Thomas, A. Blauvelt, and G. M. Shearer Normal Immune Function of Monocyte-Derived Dendritic Cells from HIV-Infected Individuals: Implications for Immunotherapy J. Immunol., August 1, 1999; 163(3): 1666 - 1673. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
