(Journal of Leukocyte Biology. 2000;68:373-382.)
© 2000
by Society for Leukocyte Biology
The emerging role of CD40 ligand in HIV infection
Richard S. Kornbluth
Department of Medicine, University of California San Diego and the VA San Diego Healthcare System, La Jolla, California
Correspondence: Richard S. Kornbluth, Department of Medicine - 0679, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093.
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ABSTRACT
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CD40 ligand (also called CD40L, CD154, or TNFSF5) is a membrane
protein expressed mainly by activated CD4+ T cells, which
interacts with its receptor, CD40, on a variety of cells. The crucial
importance of the CD40L-CD40 system for many immune responses has been
extensively described. This review focuses on the multiple roles that
this system may play in HIV infection. In early HIV infection, CD40L
expression contributes to the immunological control of viral
replication by inducing HIV-suppressive chemokines and supporting the
production of anti-HIV antibodies and cytotoxic T cells. However, by
activating antigen-presenting cells, such as dendritic cells and
macrophages, CD40L can also lead to increased CD4+ T cell
activation, which promotes the replication of HIV in these lymphocytes.
Later, with the development of AIDS, CD40L-expressing CD4+
T cells become selectively depleted, perhaps as a result of a
gp120-induced signal through CD4 that down-regulates CD40L expression.
This acquired CD40L deficiency may explain the similarity between the
types of opportunistic infections that occur in AIDS and in congenital
CD40L deficiency. Vaccines or other strategies that promote the growth
of CD4+ T cells capable of expressing CD40L may help to
sustain host immunity against HIV and prevent AIDS-defining
opportunistic infections.
Key Words: CD40 ligand • HIV • CD4+ T cells
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INTRODUCTION
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CD40 ligand (CD40L) and its receptor, CD40, have become the
subject of intense investigation by immunologists because of their
fundamental roles in the development of cellular and humoral responses.
The inappropriate expression of CD40L has been causally related to
diseases as diverse as autoimmunity, transplant rejection,
atherosclerosis, and Alzheimer’s disease. Conversely, a deficiency of
CD40L stimulation has been linked to certain infections and cancers.
Further details about these associations can be found in comprehensive
reviews that portray the range and power of this ligand-receptor pair
[1
2
3
4
].
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THE CD40L/CD40 SYSTEM IS A CENTRAL REGULATOR OF ADAPTIVE IMMUNITY
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Numerous studies have indicated that CD40L is a major regulator of
immune responses. Briefly, CD40L affects the immune system in the
following four ways (5): (1) CD40L "activates" or "matures"
antigen-presenting cells (APCs, mainly macrophages and dendritic cells)
to express co-stimulatory molecules including B7 (CD80 and CD86, both
ligands for CD28), ICAM-1 (CD54), and CD44. These co-stimulatory
signals are needed for T cells to become fully activated, rather than
anergic, after T cell receptor (TCR)-stimulation. (2) CD40L induces
macrophages and dendritic cells to make interleukin-12 (IL-12), IL-18,
and other cytokines. In an immunological response, CD40L is the primary
stimulus for IL-12 production (in the absence of microbial invasion).
IL-12 and IL-18 stimulate NK cells for interferon-
(IFN-)
production. IL-12 causes CD4+ T cells to differentiate into
type 1 helper T cells (Th1) that mediate delayed-type hypersensitivity
responses. (3) CD40L-expressing CD4+ T cells are generally
required for the generation of cytotoxic T lymphocytes (CTLs) against
tumors and virus-infected cells. As in CD4+ T cell
activation, CD40L activates APCs to express the co-stimulatory
molecules needed to fully activate ("cross-prime") CTLs already
responding to antigen/MHC class I complexes [6
]. (4) CD40L promotes the
differentiation of activated B cells and, with few exceptions, is
required for the "class switch" from IgM to IgG production.
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CD40 SIGNAL TRANSDUCTION BY TRAF6
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CD40 (also called TNFRSF5) is a type 1 membrane protein in the TNF
receptor superfamily (TNFRSF) that is found on B cells, macrophages,
dendritic cells, endothelial cells, and even T cells (see Table 1
). The study of signal transduction by CD40 is an important area of
research that has been reviewed elsewhere [7
] and will only be touched
upon in this review. Most notably, CD40 signaling leads to the
activation of NF-
B, which in turn has anti-apoptotic effects [8
]
leading to the enhanced survival of macrophages [9
] and dendritic cells
[10
].
A recent area of emphasis has been the interactions of CD40 with TNF
receptor- associated factors (TRAFs). TRAF6 is particularly important
because it is an essential adapter protein in both Toll-like receptor
(Tlr) and IL-1 receptor pathways [11
] and in certain TNFRSF pathways,
particularly CD40, RANK [12
, 13
], and the neurotrophin receptor p75
protein [14
, 15
]. Whereas the Toll receptors and the IL-1 receptor bind
indirectly to TRAF6 through two cytoplasmic proteins, MyD88 and IL-1
receptor-associated kinase (IRAK) (Fig. 1)
, the cytoplasmic domains of ligated CD40, RANK [13
, 16
, 17
], or
neurotropin receptor p75 [14
] bind directly to TRAF6. For CD40, a high
density of CD40L molecules is needed to induce the degree of CD40
multimerization required for TRAF6 to bind to the CD40 cytoplasmic
domain [18
]. For macrophages [19
] and resting B cells [20
], CD40
stimulation is most efficiently provided by CD40L expressed on the
membranes of activated T cells, rather than by soluble forms of the
ligand [21
].
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Figure 1. CD40L recreates aspects of the "danger" stimulus for
antigen-presenting cells (APCs). A) In innate immune
responses, receptors that recognize "danger" (such as Tlr4, which
recognizes microbial products such as LPS or the IL-1 receptor) convey
signals that stimulate dendritic cells, macrophages, and B cells
through a MyD88/IRAK pathway that engages TRAF6 indirectly. This APC
stimulation leads to B7 expression (signal 2) and fully activates naive
T cells recognizing antigen presented on MHC (signal 1). These
activated T cells proliferate, express their effector functions, and
some become memory T cells. B) In adaptive immune responses,
memory T cells encounter antigen in the absence of danger, so that B7
molecules are absent from the APCs. However, T cell receptor (TCR)
stimulation (signal 1) induces memory T cells to express CD40L, which
then interacts with CD40 on the APC to engage TRAF6 directly. This
TRAF6-mediated APC stimulation again leads to B7 expression (signal 2)
and fully activates the memory T cell. In addition, chemokines produced
by CD40L-stimulated APC attract additional naive T cells that can
become activated by these APCs if they recognize the MHC-presented
antigen.
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TRAF6 knock-out mice have been constructed. Although homozygous
TRAF6-deficient mice survive for <2 weeks, macrophage cultures can be
derived from their bone marrow cells for study. As expected, the
production of nitric oxide after lipopolysaccharide (LPS) (a Tlr4
ligand) or IFN- plus IL-1ß stimulation does not occur in mice
lacking TRAF6. In addition, B cells derived from these mice fail to
activate NF-B in response to LPS, IL-1ß, or CD40 ligation [22
].
Because these TRAF6-deficient mice develop osteopetrosis as a result of
impaired functioning of osteoclasts (a monocyte-derived cell lineage)
[22
, 23
], it is likely that signaling induced by RANKL is also impaired
because RANK is needed for osteoclast activation [24
].
These studies show that a single adapter protein, TRAF6, is required
for both the innate responses to LPS and injury, with its attendant
release of IL-1 [25
], and for CD40 signaling. Janeway [26
] and
Matzinger [27
] first proposed that some type of noxious stimulus is
necessary to trigger an immune response. LPS (a Tlr4 ligand) serves as
the prototypic molecular embodiment of "danger" (Matzinger’s
term), which induces B7 molecules (CD80 and CD86) and other APC factors
needed to stimulate naive T cells. Once stimulated, a fraction of these
T cells become memory cells. As recently shown by Lanzavecchia’s
group, memory T cells are distinguished by the acquisition of the CCR7
chemokine receptor, which directs their migration out of the periphery
and toward lymph nodes and by a marked enhancement in CD40L expression
after TCR stimulation. As a consequence of this enhanced CD40L
expression, activated memory T cells are much more effective at
stimulating dendritic cells to produce IL-12 than are activated naive T
cells [28
]. Therefore, the TRAF6 pathway provides a common pathway for
APC stimulation both at the site of "danger" (leading to the
initial immune response) and at the site of a cognate interaction
between a specific memory T cell and an antigen-bearing APC (leading to
an expansion of antigen-specific responsive T cells).
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MEASUREMENT OF CD40L EXPRESSION BY ACTIVATED CD4+ T
CELLS: CD40L EXPRESSION DECLINES WITH THE DEVELOPMENT OF AIDS
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CD40L (also called CD154 or TNFSF5) is a type II transmembrane
trimeric protein that is primarily expressed on the surface of a subset
of CD4+ T cells upon cellular activation. The time course
of CD40L expression is critically dependent upon the stimulus used to
activate the T cells. Using phorbol myristate acetate (PMA) plus
calcium ionophore, CD40L appears on a majority of T cells beginning at
2 h, peaking at 6 h, and lasting for >20 h. Anti-CD3
antibody, which acts through the TCR, is a more physiological stimulus
that induces CD40L on a small subset of T cells beginning in 5 min and
lasting for only 2–6 h [29
]. A secondary effect of T cell stimulation
is the up-regulation of CD40L transcription, and concurrent CD28
stimulation stabilizes the CD40L mRNA.
The very early appearance of CD40L on the surface of activated T cells
after TCR stimulation is unusual for a T cell activation marker. It is
now recognized that CD40L pre-exists within cytoplasmic granules in a
subset of CD4+ and CD8+ T cells and that TCR
stimulation leads to the rapid exteriorization of this storage depot
[29
]. However, this phenomenon cannot be appreciated when T cells are
stimulated in mixed cultures such as PBMCs, because contact with CD40
receptor-bearing cells transmits a reverse signal that causes CD40L to
become rapidly re-internalized through a pathway that leads to its
degradation in lysosomes [30
]. Even using purified CD4+ T
cells, immobilized anti-CD3 stimulation of CD4+ T cells
from healthy individuals results in <1% of cells staining positively
for CD40L at 6 h [31
]. An additional new technique is flow
cytometric analysis of permeabilized cells that have been
intracellularly stained for CD40L, but this method has so far only been
applied to murine cells [32
, 33
].
The importance of the inducing stimulus on the dynamics of CD40L
expression complicates measurements of the expression of CD40L on T
cells from HIV-infected individuals. Using PMA and calcium ionophore to
maximally stimulate T cells, a reduction in CD40L-expressing
CD4+ T cells was found in one study [34
] but not another
[35
] (Table 2) . In contrast, Vanham et al. [36
] used the more natural TCR stimulation
provided by immobilized anti-CD3 antibody and found a severe defect in
CD40L in CD4+ T cells in AIDS but not in earlier stages of
HIV infection. These authors used Fc receptor-bearing murine P815
mastocytoma cells as a surface for the immobilization of anti-CD3
antibody, which was added to the media to gradually assemble on the
P815 cells during a convenient overnight co-culture with T cells. At
the same time this culture was set up, a fluorochrome-conjugated
anti-CD40L antibody was added to the culture media to capture CD40L as
it surfaced for subsequent detection by flow cytometry. Using
uninfected subjects, 0.1% of unstimulated CD4+ T cells
were positive for CD40L and 
50% were positive after anti-CD3
stimulation. HIV-infected subjects with >200 CD4+ T
cells/µL behaved similarly. However, for subjects with AIDS (<200
CD4+T cells/µL), only 18% of CD4+ T cells
expressed CD40L after anti-CD3 stimulation, a significant reduction
[36
]. With the development of AIDS, not only are total CD4+
T cells depleted, but also the percentage capable of expressing CD40L
is reduced. Because CD40L is a limiting factor for immune responses in
a mouse model in vivo [37
], it is likely that the reduced CD40L
expression on CD4+ T cells in AIDS plays a role in the
immunodeficiency of HIV infection.
It is not yet clear if the basis for a reduction in CD40L-expressing
CD4+ T cells in HIV infection is a result of a defect in
the signalling pathways needed for CD40L expression or whether there is
a depletion of the differentiated CD4+ T cell subset
capable of expressing CD40L. In this regard, CD27L (also called CD70 or
TNFSF7) has been reported to promote the development of
CD40L-expressing CD4+ T cells in T cell-dendritic cell
co-cultures [38
]. Because CD27L expression is greatly reduced on B
cells from HIV-infected individuals [34
], it is possible that deficient
CD27L expression leads to a cell production defect that contributes to
the reduced numbers of CD40L-expressing CD4+ T cells in
AIDS.
Similar studies have examined the effects of SIV infection upon CD40L
expression in nonhuman primates. Using PMA and calcium ionophore, Brice
et al. [39
] found no differences in CD40L expression on
CD4+ T cells from rhesus macaques at any stage of SIV
infection, consistent with a similarly performed study in humans with
HIV infection [35
]. Interestingly, however, there were significant
differences in the normal physiology of CD40L expression between rhesus
macaques, sooty mangabees (SMs), and African green monkeys (AGMs). In
SMs, CD40L is expressed on activated CD4+ T cells at almost
twice the density measured on activated rhesus CD4+ T
cells. In AGMs, CD40L is expressed mainly on a subset of activated CD8+
T cells rather than on CD4+ T cells. Only the rhesus
macaque expresses CD40L in a manner similar to humans. Because
SIV-induced AIDS develops only in rhesus macaques and not in SMs or
AGMs, it is tempting to speculate that a relative preservation of CD40L
expression contributes to the disease resistance of SIV-infected SMs
and AGMs [39
].
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CD40L EFFECTS THAT INCREASE HIV REPLICATION
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One of the most established concepts in HIV retrovirology is that
CD4+ T cell activation is required for HIV to replicate in
these cells [40
]. Consequently, it is not surprising that the first
observations on the effects of CD40L on HIV replication by Clark’s
group showed that CD40L expression by anti-CD3 activated
CD4+ T cells was needed to induce B7 molecule expression on
dendritic cells, resulting in full CD4+ T cell activation
and the enhanced growth of HIV-1 IIIB (LAI), a CXCR4-utilizing (X4)
syncytium-inducing strain of HIV-1 [41
]. Similar results were reported
by Tsunetsugu-Yokota et al. [42
]. Because CD40L induces macrophages and
dendritic cells to produce MIP-1
, MIP-1ß, and RANTES, it is
notable that these same ß-chemokines enhance the replication of X4
strains of HIV in CD4+ T cells [43
]. These factors could
explain why the peak of viremia that occurs in SIV-infected macaques 2
weeks post-infection correlates in time with a transient surge in CD40L
expression by peripheral blood CD4+ T cells [44
].
Additionally, CD40L expression is needed for retroviral replication in
MAIDS, a murine model of AIDS [45
].
CD40L also stimulates HIV production by infected dendritic cells. These
cells can become infected by CCR5-utilizing (R5) nonsyncytium-inducing
strains when they are immature, but viral reverse transcription does
not complete in these resting cells [46
]. After CD40L stimulation,
however, dendritic cells become resistant to de novo infection yet
complete reverse transcription of the viral genomes already within
them, leading to the production of infectious virions [47
]. As an
additional factor, CD40L stimulation activates NF-B, which in turn
promotes transcription from the HIV LTR [48
].
CD40L has other, less important, effects in promoting HIV replication
and disease. For a small subset of B cells, CD40L induced the
expression of both CD4 and CXCR4, making these cells susceptible to HIV
infection [49
, 50
]. Microvascular endothelial cells expressing
abnormally high levels of CD40 have been found to stimulate
CD40L-expressing B cells, favoring the development of lymphoma [51
].
Perhaps because CD40 is present on normal endothelial cells, a
proportion of Kaposi’s sarcoma tumor cells express CD40 [52
].
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CD40L EFFECTS THAT DECREASE HIV REPLICATION: CHEMOKINES
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CD40L can limit HIV replication by inducing the production of
HIV-suppressive ß-chemokines. Our studies found that contact with
CD40L-expressing cells induced monocyte-derived macrophages (MDM) to
produce copious amounts of MIP-1, MIP-1ß, and RANTES. For MIP-1
and MIP-1ß, the amount produced per cell per day exceeded that of any
nontransformed CD8+ T cell, CD4+ T cell, or NK
cell yet described. The ß-chemokine-containing supernatants from
these CD40L-stimulated macrophages protected purified CD4+
T cells from infection by the R5 strain, HIV-1-SF162, and this
protection was abrogated using a cocktail of antibodies which
neutralized these three ß-chemokines [53
]. Analogous results were
obtained using CD40L-stimulated monocyte-derived dendritic cells (DC)
[54
55
56
]. CD40L also caused the down-regulation of CCR5 from the
surface of dendritic cells [46
, 55
, 56
] and macrophages [57
],
protecting these cells from infection by R5 viruses.
In addition to inducing the CCR5-binding ß-chemokines, CD40L also
stimulates the production of other chemokines. Monocyte-derived
chemokine (MDC) is strongly induced by CD40L in DC [58
, 59
]. This may
be significant because some [60
] but not all studies have found that a
processed form of MDC has anti-HIV activity. More recently, CD40L has
been shown to stimulate fractalkine expression by dendritic cells and B
cells [61
, 62
]. Fractalkine may also have anti-HIV activity against
isolates that use the fractalkine receptor (CX3CR1) as a co-receptor
[63
]. Finally, in macaque PBMCs, CD40L induced the production of IL-16,
which suppresses SIV replication by reducing the transcription of viral
mRNA [64
]. Taken together, CD40L provides a molecular link between
antigen-specific T cell stimulation and the production of anti-HIV
chemokines by macrophages and dendritic cells.
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CD40L EFFECTS THAT DECREASE HIV REPLICATION: IL-12 AND IFN-
INDUCTION
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CD40L induces macrophages and dendritic cells to produce IL-12.
IL-12 promotes the production of IFN-, Th1 T cell differentiation,
and CTL activity. CD40L also induces IL-18 mRNA in dendritic cells [10
]
and MDM (unpublished results). Although IL-18 is molecularly unrelated
to IL-12, IL-18’s biological activities overlap with IL-12 and the two
molecules synergize to stimulate IFN- production [65
].
Staphylococcus aureus Cowan strain (SAC) has been used as a
stimulant to uncover the severe IL-12 production defect that occurs in
AIDS (1% of normal levels) [66
, 67
]. Chougnet et al. [68
]
confirmed this result and used anti-CD40L antibodies to
determine that 60% of the IL-12 response to SAC in semi-purified
monocytes is a result of SAC-induced CD40L expression. The addition of
soluble CD40L and IFN- to monocyte cultures from HIV-infected
subjects restored SAC-induced IL-12 production to normal [68
].
Therefore, as the crucial T cell molecule needed for IL-12 production
by macrophages and dendritic cells, CD40L is important for the
immunological production of IFN-, which in turn strongly protects
macrophages from HIV infection [69
70
71
].
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EVIDENCE THAT HIV ACTIVELY SUPPRESSES CD40L EXPRESSION
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Given the CD40L-dependent anti-HIV activities described above, it
is not surprising that HIV-1 has evolved a means to suppress CD40L
expression. In a pioneering study, Chirmule et al. [72
] found that
purified gp120 suppressed the expression of CD40L on
anti-CD3-stimulated CD4+ T cells, in turn preventing the
induction of B7-1 expression on B cell APCs [72
]. More recently, DNA
microarray technology (Affymetrix GeneChip) was used to detect the
mRNAs present in PBMCs from HIV-infected individuals during successful
antiretroviral therapy and after discontinuing this therapy. On
treatment when virus was undetectable, CD40L mRNA was present in PBMCs.
However, after treatment was stopped, CD40L mRNA was 1 of only 20 out
of 6,800 mRNAs that was down-regulated as the virus levels rebounded
[73
].
The mechanism whereby HIV suppresses CD40L expression likely involves
the binding of gp120 to CD4 because certain anti-CD4 antibodies also
suppress CD40L expression [72
]. This effect of anti-CD4 antibody is
relatively selective, however, and does not extend to certain other
aspects of T cell activation such as the expression of the CD69
activation marker [74
]. Of great interest, as originally shown in 1984
in Chess’s laboratory, only certain anti-CD4 antibodies suppress CD40L
expression (measured then as the ability of anti-CD3 stimulated T cells
to provide help for antibody production by B cells) [75
]. The anti-CD4
antibodies that most strongly inhibit T cell help (i.e., CD40L) are the
same clones as those that interfere with HIV infection [76
]. This
suggests that HIV interacts with the surface of CD4 that delivers a
signal to suppress CD40L expression (Fig. 2)
.
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Figure 2. HIV-1 envelope engages CD4 on T cells in a manner similar to
CD40L-down-regulating anti-CD4 antibodies. As described by Sattentau et
al. (76), certain anti-CD4 monoclonal antibodies (especially OKT4a and
OKT4e) block HIV-1 infection. In a syncytium-forming assay
(x-axis), a lower 50% inhibitory dose (ID50) for infection
indicates a more powerfully protective antibody. In entirely separate
experiments, Rogozinski et al. described the ability of these same
anti-CD4 antibodies to down-regulate the "help" provided by
anti-CD3-activated CD4+ T cells for B cell IgG production
(75), which is now known to be a result of CD40L (y-axis).
The graph indicates that those anti-CD4 antibodies that strongly block
the interaction of HIV-1 gp120 with CD4 also strongly inhibit CD40L
expression. Of the several possible ways in which HIV-1 gp120 might
interact with CD4, it interacts with the face of the CD4 molecule that
conveys a negative signal for CD40L expression.
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|
It is now understood that HIV uses a chemokine receptor as its main
cellular receptor, and that binding to CD4 is of secondary importance
[77
]. Why, then, is HIV so committed to interacting with CD4? One
explanation has been that HIV targets CD4+ cells to hide
within the immune system and produce a persistent infection. A second
explanation is that the portion of Env that binds to the chemokine
receptor needs to remain inaccessible for neutralizing antibodies and
that binding to CD4 is simply a means of inducing the conformational
change needed to expose this chemokine receptor-binding domain.
However, the suppressive effects of CD4 binding on CD40L expression
suggest an additional explanation: HIV binds to CD4 to down-modulate
CD40L expression, which in turn blunts the body’s anti-HIV
ß-chemokine and CTL responses and permits the virus to replicate more
efficiently.
No detailed information is available to indicate how much gp120 is
required for CD40L down-regulation nor where in the body this
down-regulation might be occurring. gp120 at the picomolar level
(1–100 ng/ml) has been reported in sera from patients with late-stage
HIV infection. This circulating gp120 occurs mainly as an immune
complex with anti-gp120 antibody [78
, 79
]. Complexes of gp120 bound to
CD4 have also been detected on the surfaces of circulating
CD4+ T cells [80
]. Anti-gp120 antibodies may cross-link
gp120 bound to CD4 on T cells, thereby promoting its suppressive
effects [81
, 82
]. One possibility is that the high level of gp120
present in the vicinity of an HIV-producing cell down-regulates CD40L
expression on nearby CD4+ T cells and thereby prevents them
from successfully activating APCs, creating a locally immunosuppressed
microenvironment. Such a scenario may contribute to the striking
absence of CD4+ T cells that respond to gp120 as an antigen
(in contrast to the frequent detection of CD4+ T cells that
respond to Gag or Nef antigens) [83
]. The presence of high-titer
anti-gp120 antibodies may be a result of B cell stimulation through a
CD40L-independent pathway, such as contact with membrane TNF [84
].
It is conceivable that this gp120 suppression of CD40L expression
defeats some crucial aspect of the immune response against HIV,
accounting for the incomplete control of viral replication and the
eventual viral conquest of the immune system. Experiments in
LCMV-infected mice showed an expansion of proliferating MHC class I
tetramer-positive CD8+ T cells, yet these LCMV-specific
CD8+ T cells were unable to function [85
]. Similarly
nonfunctional HIV-specific CD8+ T cells have been
identified in HIV-infected patients [86
, 87
]. This situation is similar
to experiments in which transgenic T cells were adoptively transferred
into tumor-bearing mice. Although all of the transgenic T cells were
able to recognize a tumor antigen, the tumor was not rejected. However,
if CD40 stimulation was provided, the tumor was rapidly eliminated
[88
]. By analogy, deficient CD40L expression may contribute to the
functional deficiencies of HIV-specific CD8+ T cells, which
may underlie the incomplete control of HIV replication by the immune
system.
|
CONSEQUENCES OF IMPAIRED CD40L EXPRESSION FOR SUSCEPTIBILITY TO
OPPORTUNISTIC INFECTIONS
|
|---|
Although the above concepts provide a rationale for believing that
HIV has specifically evolved a means to down-regulate CD40L expression
by CD4+ T cells, a susceptibility to AIDS-defining
opportunistic infections may be another consequence of deficient CD40L
expression. Children born with inactivating mutations in the CD40L gene
have the X-linked HyperIgM syndrome (X-HIM). Despite adequate
CD4+ T cell numbers, X-HIM patients have a high incidence
of Pneumocysts carinii pneumonia (PCP), mycobacterial
infections, cryptosporidiosis, cryptococcal meningitis,
post-transfusion CMV, and other infections.
For PCP, a common infection in AIDS, elegant studies in mice have shown
that CD40L is essential to activate immune cells (probably macrophages)
to eliminate this organism [89
, 90
]. The role of CD40L in mycobacterial
infections is more controversial. Out of 57 patients in the
international X-HIM registry, 2 contracted BCGosis after inadvertent
BCG vaccination, 2 developed infection with M. bovis, and 2
developed tuberculosis (1 case was limited to the lung and the other
case was disseminated) [91
] (L. Notarangelo, personal communication).
Although this suggests that CD40L is needed to resist mycobacterial
diseases, CD40L knock-out mice differed very little from wild-type mice
in their ability to control M. tuberculosis infection [92
].
However, a study of M. avium infection in mice injected with
anti-CD40L antibody showed that CD40L plays a role in the containment
of this organism. In addition, CD40L treatment of human macrophages in
vitro induces mycobacteriostatic activity against M. avium
[93
], M. bovis BCG, and M. tuberculosis
(unpublished results). Because tuberculosis is the major opportunistic
infection and cause of death in HIV-infected persons on a worldwide
basis, this opportunistic infection may be the most serious consequence
of the suppressive effects of HIV upon CD40L expression.
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CD40L EFFECTS RELEVANT TO AN HIV VACCINE
|
|---|
CD40L is important for antiviral immunity. Studies of CD40L
knock-out mice and humans with X-HIM have shown that CD40L is critical
for the production of anti-viral IgG and IgA antibodies.
CD8+ T cells are also important defenses against viruses.
In macaques, the depletion of CD8+ T cells by anti-CD8
antibody revealed an essential role for CD8+ T cells in
limiting SIV replication [94
, 95
], and it is likely that
CD8+ T cells are equally important in anti-HIV immunity
[96
]. Because CD40L is essential for CD8+ CTL activities
against allogeneic transplants and vaccine-induced CTLs against tumor
cells [5
], it would seem obvious that CD40L is necessary for antiviral
CD8+ T cells as well. However, this assumption has been
challenged by studies showing that CD40L is not required for the
generation of early antiviral CTLs against LCMV, pichinde virus, and
VSV [97
98
99
]. These findings were interpreted to show that, unlike
other microbial pathogens, "viruses know the trick" for stimulating
early CD8+ CTL without CD4+ T cell help,
probably because these inflammatory viruses directly induce the
expression of costimulatory molecules on dendritic cells [100
].
However, CD40L appears to be required for the generation of memory
CD8+ T cells [97
98
99
] and CD40L is important to the outcome
of viral infection in vivo. In studies on macrophage-tropic strains of
LCMV, which produce a more chronic viremia, Ahmed’s group found that
CD40L was absolutely required for the eventual clearance of LCMV from
the blood [32
]. Similarly, a study of VSV infection in mice showed 50%
mortality in CD40L knock-out mice versus no mortality in wild-type
controls [101
]. Using tetramer analysis, mice lacking the CD40 receptor
and challenged with VSV developed only 10% of the normal number of
anti-VSV mucosal CD8+ T cells in their intestinal lamina
propria [102
].
CD40L stimulation also induces other TNFSF molecules that support
cellular immune responses, such as OX40L and 4-1BBL. For OX40L, studies
using knock-out mice [103
, 104
] or an agonistic anti-OX40 antibody
[105
] demonstrated that an OX40L/OX40 interaction is necessary to
maintain a large population of antigen-specific CD4+ T
cells. Because CD40- stimulation induces the appearance of OX40L on
dendritic cells [103
] and B cells [106
], OX40L may mediate some of the
supportive effects of CD40L on CD4+ T cell responses.
Similarly, 4-1BBL has been shown to be important for maintaining strong
CD8+ T cell responses. 4-1BBL knock-out mice have impaired
generation of CTLs [107
] and, conversely, an agonistic anti-4-1BB
antibody enhanced the development of CD8+ T cells [108
, 109
]. Because CD40-stimulated B cells and mature dendritic cells
(formed after CD40L stimulation) both express 4-1BBL [110
], this is
another pathway through which CD40L promotes cellular immunity.
For HIV, CD4+ T cell help is thought to be essential for
anti-HIV CD8+ T cell activity [111
112
113
114
]. Because CD40L
provides the molecular basis for CD4+ T cell help [115
], it
seems very likely that CD40L is important for both the humoral and
cellular aspects of anti-HIV immunity. Recently, a study in mice showed
that the co-injection of a CD40L expression plasmid along with a
plasmid for the HIV p55 Gag protein led to a marked enhancement in
antibody and CTL responses [116
]. This suggests that CD40L could be a
useful component in an anti-HIV vaccine.
|
CONCLUSIONS
|
|---|
CD40L is established as a crucial regulator of cellular as well as
humoral immunity. The activation of T cells to express CD40L leads to
effects on APCs that both protect CD4+ T cells from HIV
infection (e.g., through ß-chemokine production) and activate these
cells for enhanced HIV replication. CD40L stimulation can also both
protect dendritic cells and macrophages from HIV infection and activate
already infected dendritic cells to express HIV. With the development
of AIDS, CD40L-expressing CD4+ T cells are
disproportionately reduced, perhaps as a result of CD40L
down-regulation secondary to gp120 interactions with CD4. Because CD40L
is needed for strong cellular immunity, the reduced expression of CD40L
on CD4+ T cells may be a factor in the progression of HIV
infection. Similarly, by creating an acquired CD40L deficiency, HIV
infection may predispose the host to those opportunistic infections for
which CD40L expression confers protection. These considerations suggest
that therapies designed to prevent or reverse the decline in
CD40L-expression by CD4+ T cells might be useful in HIV
infection. In addition, the effectiveness of an HIV vaccine may depend
upon its ability to generate CD4+ T cells capable of
expressing CD40L in response to HIV antigens.
|
ACKNOWLEDGEMENTS
|
|---|
Supported by grants from the Elizabeth Glaser Pediatric AIDS
Foundation (50944-PG-24), the National Institutes of Health (HL57911),
the UCSD Center for AIDS Research (supported by NIH grant AI36214), the
Department of Veterans Affairs, and the Research Center on AIDS and HIV
Infection of the VA San Diego Healthcare System.
|
REFERENCES
|
|---|
-
Noelle, R. J. (1996) CD40 and its ligand in host defense Immunity 4,415-419[Medline]
-
Foy, T. M., Aruffo, A., Bajorath, J., Buhlmann, J. E., Noelle, R. J. (1996) Immune regulation by CD40 and its ligand GP39 Annu. Rev. Immunol. 14,591-617[Medline]
-
Grewal, I. S., Flavell, R. A. (1997) The CD40 ligand: at the center of the immune universe? Immunol. Res. 16,59-70[Medline]
-
van Kooten, C., Banchereau, J. (2000) CD40-CD40 ligand J. Leukoc. Biol. 67,2-17[Abstract]
-
Mackey, M. F., Barth, R. J., Jr, Noelle, R. J. (1998) The role of CD40/CD154 interactions in the priming, differentiation, and effector function of helper and cytotoxic T cells J. Leukoc. Biol. 63,418-428[Abstract]
-
Lanzavecchia, A. (1998) Immunology: licence to kill [news; comment] Nature 393,413-414[Medline]
-
Calderhead, D. M., Kosaka, Y., Manning, E. M., Noelle, R. J. (2000) CD40-CD154 interactions in B-cell signaling Curr. Top. Microbiol. Immunol. 245,73-99[Medline]
-
Beg, A. A., Baltimore, D. (1996) An essential role for NF-kappaB in preventing TNF- alpha-induced cell death [see comments] Science 274,782-784[Abstract/Free Full Text]
-
Suttles, J., Evans, M., Miller, R. W., Poe, J. C., Stout, R. D., Wahl, L. M. (1996) T cell rescue of monocytes from apoptosis: role of the CD40-CD40L interaction and requirement for CD40-mediated induction of protein tyrosine kinase activity J. Leukoc. Biol. 60,651-657[Abstract]
-
Brossart, P., Grünebach, F., Stuhler, G., Reichardt, V. L., Möhle, R., Kanz, L., Brugger, W. (1998) Generation of functional human dendritic cells from adherent peripheral blood monocytes by CD40 ligation in the absence of granulocyte-macrophage colony-stimulating factor Blood 92,4238-4247[Abstract/Free Full Text]
-
Cao, Z., Xiong, J., Takeuchi, M., Kurama, T., Goeddel, D. V. (1996) TRAF6 is a signal transducer for interleukin-1 Nature 383,443-446[Medline]
-
Wong, B. R., Josien, R., Choi, Y. (1999) TRANCE is a TNF family member that regulates dendritic cell and osteoclast function J. Leukoc. Biol. 65,715-724[Abstract]
-
Darnay, B. G., Ni, J., Moore, P. A., Aggarwal, B.B. (1999) Activation of NF-kappaB by RANK requires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF- kappaB-inducing kinase. Identification of a novel TRAF6 interaction motif J. Biol. Chem./TITLE> 274,7724-7731[Abstract/Free Full Text]
-
Khursigara, G., Orlinick, J. R., Chao, M. V. (1999) Association of the p75 neurotrophin receptor with TRAF6 J. Biol. Chem. 274,2597-2600[Abstract/Free Full Text]
-
Ye, X., Mehlen, P., Rabizadeh, S., VanArsdale, T., Zhang, H., Shin, H., Wang, J. J., Leo, E., Zapata, J., Hauser, C. A., Reed, J. C., Bredesen, D. E. (1999) TRAF family proteins interact with the common neurotrophin receptor and modulate apoptosis induction J. Biol. Chem. 274,30202-30208[Abstract/Free Full Text]
-
Wong, B. R., Josien, R., Lee, S. Y., Vologodskaia, M., Steinman, R. M., Choi, Y. (1998) The TRAF family of signal transducers mediates NF-kappaB activation by the TRANCE receptor J. Biol. Chem. 273,28355-28359[Abstract/Free Full Text]
-
Galibert, L., Tometsko, M. E., Anderson, D. M., Cosman, D., Dougall, W. C. (1998) The involvement of multiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-kappaB, a member of the TNFR superfamily J. Biol. Chem. 273,34120-34127[Abstract/Free Full Text]
-
Pullen, S. S., Labadia, M. E., Ingraham, R. H., McWhirter, S. M., Everdeen, D. S., Alber, T., Crute, J. J., Kehry, M. R. (1999) High-affinity interactions of tumor necrosis factor receptor-associated factors (TRAFs) and CD40 require TRAF trimerization and CD40 multimerization Biochemistry 38,10168-10177[Medline]
-
Stout, R. D., Suttles, J. (1996) The many roles of CD40 in cell-mediated inflammatory responses Immunol. Today 17,487-492[Medline]
-
Klaus, G. G., Holman, M., Johnson-Léger, C., Christenson, J. R., Kehry, M. R. (1999) Interaction of B cells with activated T cells reduces the threshold for CD40-mediated B cell activation Int. Immunol. 11,71-79[Abstract/Free Full Text]
-
Fanslow, W. C., Srinivasan, S., Paxton, R., Gibson, M. G., Spriggs, M. K., Armitage, R. J. (1994) Structural characteristics of CD40 ligand that determine biological function Semin. Immunol. 6,267-278[Medline]
-
Lomaga, M.A., Yeh, W. C., Sarosi, I., Duncan, G. S., Furlonger, C., Ho, A., Morony, S., Capparelli, C., Van, G., Kaufman, S., van der Heiden, A., Itie, A., Wakeham, A., Khoo, W., Sasaki, T., Cao, Z., Penninger, J. M., Paige, C. J., Lacey, D. L., Dunstan, C. R., Boyle, W. J., Goeddel, D. V., Mak, T. W. (1999) TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling Genes Dev 13,1015-1024[Abstract/Free Full Text]
-
Naito, A., Azuma, S., Tanaka, S., Miyazaki, T., Takaki, S., Takatsu, K., Nakao, K., Nakamura, K., Katsuki, M., Yamamoto, T., Inoue, J. (1999) Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice Genes Cells 4,353-362[Abstract]
-
Dougall, W. C., Glaccum, M., Charrier, K., Rohrbach, K., Brasel, K., De Smedt, T., Daro, E., Smith, J., Tometsko, M. E., Maliszewski, C. R., Armstrong, A., Shen, V., Bain, S., Cosman, D., Anderson, D., Morrissey, P. J., Peschon, J. J., Schuh, J. (1999) RANK is essential for osteoclast and lymph node development Genes Dev 13,2412-2424[Abstract/Free Full Text]
-
Hogquist, K. A., Nett, M. A., Unanue, E. R., Chaplin, D. D. (1991) Interleukin 1 is processed and released during apoptosis Proc. Natl. Acad. Sci. USA 88,8485-8489[Abstract/Free Full Text]
-
Janeway, C. A., Jr (1989) Approaching the asymptote? Evolution and revolution in immunology Cold Spring Harb. Symp. Quant. Biol. 54(1),1-13
-
Matzinger, P. (1994) Tolerance, danger, and the extended family Annu. Rev. Immunol. 12,991-1045[Medline]
-
Sallusto, F., Lenig, D., Förster, R., Lipp, M., Lanzavecchia, A. (1999) Two subsets of memory T lymphocytes with distinct homing potentials and effector functions [see comments] Nature 401,708-712[Medline]
-
Casamayor-Palleja, M., Khan, M., MacLennan, I. C. (1995) A subset of CD4+ memory T cells contains preformed CD40 ligand that is rapidly but transiently expressed on their surface after activation through the T cell receptor complex J. Exp. Med. 181,1293-1301[Abstract/Free Full Text]
-
Yellin, M. J., Sippel, K., Inghirami, G., Covey, L. R., Lee, J. J., Sinning, J., Clark, E. A., Chess, L., Lederman, S. (1994) CD40 molecules induce down-modulation and endocytosis of T cell surface T cell-B cell activating molecule/CD40-L Potential role in regulating helper effector function. J. Immunol. 152,598-608
-
Balashov, K. E., Smith, D. R., Khoury, S. J., Hafler, D. A., Weiner, H. L. (1997) Increased interleukin 12 production in progressive multiple sclerosis: induction by activated CD4+ T cells via CD40 ligand Proc. Natl. Acad. Sci. USA 94,599-603[Abstract/Free Full Text]
-
Whitmire, J. K., Flavell, R. A., Grewal, I. S., Larsen, C. P., Pearson, T. C., Ahmed, R. (1999) CD40-CD40 ligand costimulation is required for generating antiviral CD4 T cell responses but is dispensable for CD8 T cell responses J. Immunol. 163,3194-3201[Abstract/Free Full Text]
-
Wykes, M., Poudrier, J., Lindstedt, R., Gray, D. (1998) Regulation of cytoplasmic, surface and soluble forms of CD40 ligand in mouse B cells Eur. J. Immunol. 28,548-559[Medline]
-
Wolthers, K. C., Otto, S. A., Lens, S. M., Van Lier, R. A., Miedema, F., Meyaard, L. (1997) Functional B cell abnormalities in HIV type 1 infection: role of CD40L and CD70 AIDS Res. Hum. Retroviruses 13,1023-1029[Medline]
-
Brugnoni, D., Prati, E., Airo, P., Castelli, F., Cattaneo, R. (1995) The ability of CD4+ cells from HIV+ individuals to express CD40 ligand after in vitro stimulation is not impaired Clin. Immunol. Immunopathol. 74,112-114[Medline]
-
Vanham, G., Penne, L., Devalck, J., Kestens, L., Colebunders, R., Bosmans, E., Thielemans, K., Ceuppens, J. L. (1999) Decreased CD40 ligand induction in CD4 T cells and dysregulated IL-12 production during HIV infection Clin. Exp. Immunol. 117,335-342[Medline]
-
Pérez-Melgosa, M., Hollenbaugh, D., Wilson, C. B. (1999) Cutting edge: CD40 ligand is a limiting factor in the humoral response to T cell-dependent antigens J. Immunol. 163,1123-1127[Abstract/Free Full Text]
-
Stuhler, G., Zobywalski, A., Grünebach, F., Brossart, P., Reichardt, V. L., Barth, H., Stevanovic, S., Brugger, W., Kanz, L., Schlossman, S. F. (1999) Immune regulatory loops determine productive interactions within human T lymphocyte-dendritic cell clusters Proc. Natl. Acad. Sci. USA 96,1532-1535[Abstract/Free Full Text]
-
Brice, G. T., Mayne, A. E., Leighton, K., Villinger, F., Allan, J. S., Ansari, A. A. (1999) Studies of CD40L expression by lymphoid cells from experimentally and naturally SIV-infected nonhuman primate species J. Med. Primatol. 28,49-56[Medline]
-
Zagury, D., Bernard, J., Leonard, R., Cheynier, R., Feldman, M., Sarin, P. S., Gallo, R. C. (1986) Long-term cultures of HTLV-III—infected T cells: a model of cytopathology of T-cell depletion in AIDS Science 231,850-853[Abstract/Free Full Text]
-
Pinchuk, L. M., Polacino, P. S., Agy, M. B., Klaus, S. J., Clark, E. A. (1994) The role of CD40 and CD80 accessory cell molecules in dendritic cell-dependent HIV-1 infection Immunity 1,317-325[Medline]
-
Tsunetsugu-Yokota, Y., Yasuda, S., Sugimoto, A., Yagi, T., Azuma, M., Yagita, H., Akagawa, K., Takemori, T. (1997) Efficient virus transmission from dendritic cells to CD4+ T cells in response to antigen depends on close contact through adhesion molecules Virology 239,259-268[Medline]
-
Kinter, A., Catanzaro, A., Monaco, J., Ruiz, M., Justement, J., Moir, S., Arthos, J., Oliva, A., Ehler, L., Mizell, S., Jackson, R., Ostrowski, M., Hoxie, J., Offord, R., Fauci, A. S. (1998) CC-chemokines enhance the replication of T-tropic strains of HIV-1 in CD4(+) T cells: role of signal transduction Proc. Natl. Acad. Sci. USA 95,11880-11885[Abstract/Free Full Text]
-
Giavedoni, L. D., Velasquillo, M. C., Parodi, L. M., Hubbard, G. B., Hodara, V. L. (2000) Cytokine expression, natural killer cell activation, and phenotypic changes in lymphoid cells from rhesus macaques during acute infection with pathogenic simian immunodeficiency virus J. Virol. 74,1648-1657[Abstract/Free Full Text]
-
Green, K. A., Noelle, R. J., Green, W. R. (1998) Evidence for a continued requirement for CD40/CD40 ligand (CD154) interactions in the progression of LP-BM5 retrovirus-induced murine AIDS Virology 241,260-268[Medline]
-
Canque, B., Bakri, Y., Camus, S., Yagello, M., Benjouad, A., Gluckman, J. C. (1999) The susceptibility to X4 and R5 human immunodeficiency virus-1 strains of dendritic cells derived in vitro from CD34(+) hematopoietic progenitor cells is primarily determined by their maturation stage Blood 93,3866-3875[Abstract/Free Full Text]
-
Granelli-Piperno, A., Finkel, V., Delgado, E., Steinman, R. M. (1999) Virus replication begins in dendritic cells during the transmission of HIV-1 from mature dendritic cells to T cells Curr. Biol. 9,21-29[Medline]
-
Lapointe, R., Lemieux, R., Darveau, A. (1996) HIV-1 LTR activity in human CD40-activated B lymphocytes is dependent on NF-kappaB Biochem. Biophys. Res. Commun. 229,959-964[Medline]
-
Gras, G., Legendre, C., Krzysiek, R., Dormont, D., Galanaud, P., Richard, Y. (1996) CD40/CD40L interactions and cytokines regulate HIV replication in B cells in vitro Virology 220,309-319[Medline]
-
Moir, S., Lapointe, R., Malaspina, A., Ostrowski, M., Cole, C. E., Chun, T. W., Adelsberger, J., Baseler, M., Hwu, P., Fauci, A. S. (1999) CD40-Mediated induction of CD4 and CXCR4 on B lymphocytes correlates with restricted susceptibility to human immunodeficiency virus type 1 infection: potential role of B lymphocytes as a viral reservoir J. Virol. 73,7972-7980[Abstract/Free Full Text]
-
Moses, A. V., Williams, S. E., Strussenberg, J. G., Heneveld, M. L., Ruhl, R. A., Bakke, A. C., Bagby, G. C., Nelson, J. A. (1997) HIV-1 induction of CD40 on endothelial cells promotes the outgrowth of AIDS-associated B-cell lymphomas Nat. Med. 3,1242-1249[Medline]
-
Pammer, J., Plettenberg, A., Weninger, W., Diller, B., Mildner, M., Uthman, A., Issing, W., Sturzl, M., Tschachler, E. (1996) CD40 antigen is expressed by endothelial cells and tumor cells in Kaposi’s sarcoma [see comments] Am. J. Pathol. 148,1387-1396[Abstract]
-
Kornbluth, R. S., Kee, K., Richman, D. D. (1998) CD40 ligand (CD154) stimulation of macrophages to produce HIV-1-suppressive beta-chemokines Proc. Natl. Acad. Sci. USA 95,5205-5210[Abstract/Free Full Text]
-
Caux, C., Massacrier, C., Vanbervliet, B., Dubois, B., Van Kooten, C., Durand, I., Banchereau, J. (1994) Activation of human dendritic cells through CD40 cross-linking J. Exp. Med. 180,1263-1272[Abstract/Free Full Text]
-
McDyer, J. F., Dybul, M., Goletz, T. J., Kinter, A. L., Thomas, E. K., Berzofsky, J. A., Fauci, A. S., Seder, R. A. (1999) Differential effects of CD40 ligand/trimer stimulation on the ability of dendritic cells to replicate and transmit HIV infection: evidence for CC- chemokine-dependent and -independent mechanisms J. Immunol. 162,3711-3717[Abstract/Free Full Text]
-
Chougnet, C., Cohen, S. S., Kawamura, T., Landay, A. L., Kessler, H. A., Thomas, E., Blauvelt, A., Shearer, G. M. (1999) Normal immune function of monocyte-derived dendritic cells from HIV-infected individuals: implications for immunotherapy J. Immunol. 163,1666-1673[Abstract/Free Full Text]
-
Cotter, R., Zheng, J., Thomas, E., Gendelman, H. E. (2000) CD40L activation of mononuclear phagocytes: regulation of HIV-1 replication, beta-chemokine production, and beta-chemokine receptor expression 7th Conference on Retroviruses and Opportunistic Infections ,A290 San Francisco, CA.
-
Mueller, C. G., Rissoan, M. C., Salinas, B., Ait-Yahia, S., Ravel, O., Bridon, J. M., Briere, F., Lebecque, S., Liu, Y. J. (1997) Polymerase chain reaction selects a novel disintegrin proteinase from CD40-activated germinal center dendritic cells J. Exp. Med. 186,655-663[Abstract/Free Full Text]
-
Schaniel, C., Pardali, E., Sallusto, F., Speletas, M., Ruedl, C., Shimizu, T., Seidl, T., Andersson, J., Melchers, F., Rolink, A. G., Sideras, P. (1998) Activated murine B lymphocytes and dendritic cells produce a novel CC chemokine which acts selectively on activated T cells J. Exp. Med. 188,451-463[Abstract/Free Full Text]
-
Pal, R., Garzino-Demo, A., Markham, P. D., Burns, J., Brown, M., Gallo, R. C., DeVico, A. L. (1997) Inhibition of HIV-1 infection by the beta-chemokine MDC Science 278,695-698[Abstract/Free Full Text]
-
Papadopoulos, E. J., Sassetti, C., Saeki, H., Yamada, N., Kawamura, T., Fitzhugh, D. J., Saraf, M. A., Schall, T., Blauvelt, A., Rosen, S. D., Hwang, S. T. (1999) Fractalkine, a CX3C chemokine, is expressed by dendritic cells and is up-regulated upon dendritic cell maturation Eur. J. Immunol. 29,2551-2559[Medline]
-
Foussat, A., Coulomb-L’Hermine, A., Gosling, J., Krzysiek, R., Durand-Gasselin, I., Schall, T., Balian, A., Richard, Y., Galanaud, P., Emilie, D. (2000) Fractalkine receptor expression by T lymphocyte subpopulations and in vivo production of fractalkine in human Eur. J. Immunol. 30,87-97[Medline]
-
Combadiere, C., Salzwedel, K., Smith, E. D., Tiffany, H. L., Berger, E. A., Murphy, P. M. (1998) Identification of CX3CR1. A chemotactic receptor for the human CX3C chemokine fractalkine and a fusion coreceptor for HIV-1 J. Biol. Chem. 273,23799-23804[Abstract/Free Full Text]
-
Lee, M. E., Bucur, S. Z., Gillespie, T. W., Adams, J. W., Barker, A. T., Thomas, E. K., Roback, J. D., Hillyer, C. D. (1999) Recombinant human CD40 ligand inhibits simian immunodeficiency virus replication: a role for interleukin-16 J. Med. Primatol. 28,190-194[Medline]
-
Dinarello, C. A., Novick, D., Puren, A. J., Fantuzzi, G., Shapiro, L., Mühl, H., Yoon, D. Y., Reznikov, L. L., Kim, S. H., Rubinstein, M. (1998) Overview of interleukin-18: more than an interferon-gamma inducing factor J. Leukoc. Biol. 63,658-664[Abstract]
-
Chehimi, J., Starr, S. E., Frank, I., D’Andrea, A., Ma, X., MacGregor, R. R., Sennelier, J., Trinchieri, G. (1994) Impaired interleukin 12 production in human immunodeficiency virus-infected patients J. Exp. Med. 179,1361-1366[Abstract/Free Full Text]
-
Marshall, J. D., Chehimi, J., Gri, G., Kostman, J. R., Montaner, L. J., Trinchieri, G. (1999) The interleukin-12-mediated pathway of immune events is dysfunctional in human immunodeficiency virus-infected individuals Blood 94,1003-1011[Abstract/Free Full Text]
-
Chougnet, C., Thomas, E., Landay, A. L., Kessler, H. A., Buchbinder, S., Scheer, S., Shearer, G. M. (1998) CD40 ligand and IFN-gamma synergistically restore IL-12 production in HIV-infected patients Eur. J. Immunol. 28,646-656[Medline]
-
Kornbluth, R. S., Oh, P. S., Munis, J. R., Cleveland, P. H., Richman, D. D. (1989) Interferons and bacterial lipopolysaccharide protect macrophages from productive infection by human immunodeficiency virus in vitro J. Exp. Med. 169,1137-1151[Abstract/Free Full Text]
-
Gendelman, H. E., Baca, L. M., Turpin, J. A., Kalter, D. C., Dieffenbach, C., Friedman, R. M., Meltzer, M. S. (1990) Interactions between interferon and the human immunodeficiency virus J. Exp. Pathol. 5,53-67[Medline]
-
Fan, S. X., Turpin, J. A., Aronovitz, J. R., Meltzer, M. S. (1994) Interferon-gamma protects primary monocytes against infection with human immunodeficiency virus type 1 J. Leukoc. Biol. 56,362-368[Abstract]
-
Chirmule, N., McCloskey, T. W., Hu, R., Kalyanaraman, V. S., Pahwa, S. (1995) HIV gp120 inhibits T cell activation by interfering with expression of costimulatory molecules CD40 ligand and CD80 (B71) J. Immunol. 155,917-924[Abstract]
-
Palmeri, L. D., Davey, R. T., Baseler, M. W., Stevens, R., Adelsberger, J. W., Lamberti, L., Metcal, J. A., Dewar, R., Polis, M. A., Dimitrov, D. S., Lane, H. C., Lempicki, R. A. (2000) Up-regulation of Type 1 interferon-inducible genes after HIV-1 rebound in persons terminating HAART 7th Conference on Retroviruses and Opportunistic Infections ,A450 San Francisco, CA.
-
Woods, M., Guy, R., Waldmann, H., Glennie, M., Alexander, D. R. (1998) A humanised therapeutic CD4 mAb inhibits TCR-induced IL-2, IL-4, and IL-10 secretion and expression of CD25, CD40L, and CD69 Cell. Immunol. 185,101-113[Medline]
-
Rogozinski, L., Bass, A., Glickman, E., Talle, M. A., Goldstein, G., Wang, J., Chess, L., Thomas, Y. (1984) The T4 surface antigen is involved in the induction of helper function J. Immunol. 132,735-739[Abstract]
-
Sattentau, Q. J., Dalgleish, A. G., Weiss, R. A., Beverley, P. C. (1986) Epitopes of the CD4 antigen and HIV infection Science 234,1120-1123[Abstract/Free Full Text]
-
Rizzuto, C. D., Wyatt, R., Hernandez-Ramos, N., Sun, Y., Kwong, P. D., Hendrickson, W. A., Sodroski, J. (1998) A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding [see comments] Science 280,1949-1953[Abstract/Free Full Text]
-
Oh, S. K., Cruikshank, W. W., Raina, J., Blanchard, G. C., Adler, W. H., Walker, J., Kornfeld, H. (1992) Identification of HIV-1 envelope glycoprotein in the serum of AIDS and ARC patients J. Acquir. Immune Defic. Syndr. 5,251-256
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ABSTRACT
INTRODUCTION
