Along with recognition of the antigen-major histocompatibility complex (MHC) by the T-cell receptor (TCR) and costimulation, the two components of the two-signal model for T-cell activation [1], a third signal given by inflammatory cytokines is required to induce productive responses [2]. TCR-mediated stimulation in the absence of signal 2 (costimulation) or signal 3 (inflammatory cytokines) may result in T-cell anergy, cell death and/or tolerance induction [2, 3]. In this review, we will discuss the importance of the costimulatory and co-inhibitory molecules of the tumor necrosis factor receptor super-family (TNFRSF) and the B7 super-family.
Members of the TNFRSF of costimulatory molecules can be divided into two classes. Receptors that contain a cytoplasmic death domain (DD) (e.g. Fas, DR4) can convey an apoptotic signal and can regulate cell proliferation, inflammatory responses and tumor progression, whereas receptors that contain a TNFR associated factor (TRAF) binding domain (e.g. CD27, CD40, 4-1BB, OX40) regulate diverse immunological processes including enhancement of
*Address correspondence to this author at the Laboratory of
Molecular and Cellular Therapy, Medical School of the Vrije Universiteit Brussel, Laarbeeklaan 103, room E 206, 1090 Brussels, Belgium; Tel: 32-2-477.45.69; Fax: 32-2-477.45.68;
proliferation, survival, generation of effector T cells, amplification of inflammatory responses and migration [4, 5]. TNFSF/TNFRSF interactions can stimulate both T cells and antigen-presenting cells (APCs) and can mediate communication between CD4
+ and CD8
+ T
cells [6]. TNF receptors can signal through association with various TRAF family members. TRAFs can allow activation of both the canonical and the non-canonical NF- B signaling pathways, which are known to be important for cell survival [6].
The ‘prototypic’ costimulatory receptor of the B7 super-family is CD28. Upon interaction with one of its ligands, CD80 or CD86, CD28 induces up-regulation of survival genes in naïve T cells, facilitates cell cycle progression and enhances IL-2 production [7]. However, another member of this family, the CD28 homolog CTLA-4, was found to be a higher affinity partner for CD80 and CD86 [8]. Mice studies revealed a critical inhibitory function for CTLA-4 [9]. Other members of the B7 family of costimulatory molecules are ICOS and PD-1. The ICOS/ICOS ligand pathway has critical roles in stimulating effector T-cell responses and T-cell dependent B-cell responses and in regulating T-cell tolerance [10]. Interactions between the inhibitory receptor PD-1 and one of its ligands, PD-L1 or PD-L2, can regulate both the induction and maintenance of peripheral T-cell tolerance [10] and can exert critical inhibitory functions in the setting of chronic antigen expression, as observed during chronic viral infections or in cancer patients [11].
2 Current Molecular Medicine, 2011, Vol. 11, No. 3 De Keersmaecker et al.
When studying interactions between costimulatory/co-inhibitory receptors and their ligands, it is important to keep in mind that the costimulatory/co-inhibitory ligands of both the TNFSF and B7 super-family, including CD80, CD86 [12], PD-L1 [13] and GITRL [14], can mediate ‘reverse signaling’ in cells expressing these molecules, thus potentially providing feedback mechanisms to APCs. This reverse signaling is often associated with immunesuppressive effects, as described for PD-L1 [13] and GITRL [14]. Furthermore, a number of these ligands, including CD70, CD80 and PD-L1, have also been found on T cells and may therefore not only modulate APC function, but also T-cell function. Additionally, some receptors share the same ligands. Thus, CD28 and CTLA-4 both interact with CD80. Some receptors can bind more than one ligand, for instance, PD-1 can bind to both PD-L1 and to PD-L2. Finally, some receptors/ligands may have an as yet unidentified ligand/receptor (for example CD83). Thus, the degree of expression of these ligands and receptors on APCs and T cells will determine the quality of the T-cell stimulation. These arguments illustrate the complexity of the crosstalk between immunoregulatory pathways and the importance of further investigation.
During HIV infection, costimulatory molecules could be exploited as a way to ‘boost’ anti-HIV cytotoxic T lymphocyte (CTL) responses or to reduce inhibitory pathways. For example, blocking of the PD-1/PD-L1 pathway or triggering of the 4-1BB receptor on CD8
+ T
cells could enhance HIV-specific CTL responses [15, 16]. On the other hand, chronic immune (over)activation is directly associated with HIV-1 disease progression [17]. The expression patterns of costimulatory and co-inhibitory receptors and their ligands are often impaired in HIV-infected patients compared to healthy individuals (Table 1). Another hallmark of HIV infection is a massive CD4
+ T-cell loss
early after infection, especially in the gut, which could be partially explained by the induction of cell death pathways, mediated by HIV proteins [18-21]. In this review, we give an overview of the features of some of the most intensively investigated receptor/ligand pairs of the TNF and the B7 super-family, we discuss the expression patterns of different costimulatory and co-inhibitory receptors and their ligands during HIV infection and we explore how interventions that mimic or block receptor/ligand interactions can be applied to enhance anti-HIV immunity.
TUMOR NECROSIS FACTORY SUPER-FAMILY
TNF Receptors with a Cytoplasmic Death Domain
Fas/FasL
Activation of Fas (CD95, APO-1) on T cells can either result in T-cell proliferation, T-cell apoptosis or in the silencing of T-cell activation [22, 23], depending on the signal, cell type and cellular context. Its ligand, FasL (CD178), is predominantly expressed on T cells and NK cells, but was also detected on human
immature dendritic cells (DCs) and monocytes [24]. Fas is widely expressed and its ligation by FasL triggers apoptosis. Therefore, the expression of FasL should be tightly regulated to prevent unintentional killing of healthy cells [25, 26].
The Fas/FasL pathway is induced during HIV disease and has been proposed to play a role in HIV-associated lymphocyte anergy and programmed death [22]. Fas is over-expressed on T and B cells in HIV-infected patients and a positive correlation was found between Fas expression on CD4
+ T cells and plasma
viral load [22, 27]. Apart from the Fas over-expression, the increased level of immune activation during HIV infection may contribute to the increased number of apoptotic cells in HIV-infected patients, since Fas
+
resting T cells are resistant to apoptosis [28-30]. Fas expression decreases on CD8
+ T cells during
combined antiretroviral therapy (cART), but the mean frequency of Fas
+ CD8
+ T cells remains higher
compared to healthy individuals [27]. Moreover, it has been suggested that cART reduces the sensitivity of CD4
+ T cells to Fas-mediated apoptosis [31]. These
observations are in accordance with the fact that cART decreases the number of apoptotic T cells in the lymphoid tissue [31, 32].
Elevated levels of FasL are detected in the plasma of HIV-infected patients at the time of maximum plasma viral load [33]. Moreover, HIV infection induces FasL expression in macrophages and DCs, thereby suppressing T-cell activation and survival [23,34]. FasL levels are also up-regulated on CD4
+ T cells [35] after
they are exposed to soluble HIV Nef, gp120 or Tat proteins [36-37]. The FasL overexpression on circulating CD4
+ T cells of HIV-infected patients is
normalized during cART treatment [38]. In contrast to T and B cells, monocytes from HIV-infected individuals express less FasL compared to monocytes from healthy persons [39]. One of the mechanisms responsible for the B-cell and CD4
+ T-cell apoptosis in
HIV infection could be the interaction between the over-expressed FasL on APCs and Fas on B cells and CD4
+
T cells [40-42].
Given the severe effects of Fas/FasL signaling on HIV immunity, blocking this receptor/ligand interaction could be an interesting therapeutic approach. It has been shown that ex vivo IL-12 treatment inhibits Fas-mediated apoptosis in CD4
+ T cells from HIV-infected
patients [43]. In a pilot study, Fas/FasL signaling was blocked by administering a recombinant humanized anti-FasL antibody (Ab) to rhesus macaques. The efficacy of this treatment as a prophylactic anti-SIV treatment was evaluated. There was no effect of anti-FasL on plasma viral load, but an increased virus-specific immunity and a delayed disease progression were found in treated animals [44]. In a comparable study with larger animal groups, it was shown that antigen-specific memory T-cell responses after SIV infection were preserved in the immunized macaques and that there was an association with decreased levels of regulatory T-cell (Treg) numbers. Humoral SIV
HIV and Costimulation Current Molecular Medicine, 2011, Vol. 11, No. 3 3
Table 1. Expression Patterns of Costimulatory and –Inhibitory Molecules in HIV-Infected Patients
Molecule Cells Expression in HIV-infected patients Reference(s)
4 Current Molecular Medicine, 2011, Vol. 11, No. 3 De Keersmaecker et al.
(Table 1). Contd…..
Molecule Cells Expression in HIV-infected patients Reference(s)
B7 superfamily
Naïve CD4+ T cells (after TCR
engagement) Down-regulated [71] CD28
CD8+ T cells Down-regulated [124,248]
T cells Up-regulated [254] CD80
APCs Down-regulated [145-146,255]
T cells Up-regulated [65,245] CD86
APCs Down-regulated [145-146, 255,258]
CD4+ T cells (HIV-specific) Up-regulated [284-287]
Tregs Up-regulated [288]
CTLA-4
CD8+ T cells Up-regulated [285]
CD4+ T cells (HIV-specific) Up-regulated [287,308,314]
CD4+ T cells (infected) Down-regulated [315]
CD8+ T cells Up-regulated [305-306]
Monocytes Up-regulated [317]
PD-1
NKT cells (CD4+ cells) Up-regulated [318]
T cells Up-regulated [317,319-320, 322]
B cells Up-regulated [319]
Monocytes Up-regulated [319,322]
PD-L1
mDCs Up-regulated [321]
Expression levels of costimulatory and –inhibitory molecules molecules that differ in HIV-infected patients compared to healthy individuals are indicated in the table. Expression levels were determined on resting cells isolated from treatment naïve patients, unless otherwise indicated.
specific immune responses were not altered by anti-FasL treatment [45]. On the other hand, two reports conclude that the Fas/FasL pathway is not involved in activation-induced apoptosis because apoptosis still occurs when this pathway is blocked [40, 43].
To conclude, the over-expression of Fas on T and B cells and of its ligand on APCs results in massive immune cell apoptosis during HIV infection. Further research will have to clarify whether blocking of this pathway could be a promising therapeutic approach.
TRAIL/DR4 DR5
TRAIL induces apoptosis by binding to its death receptors, DR4 (TRAIL R1) or DR5 (TRAIL R2), thereby activating caspase 3 on target cells [46, 47]. However, two other TRAIL receptors, decoy receptor 1 (DcR1) and DcR2, were shown to block TRAIL signal transduction [47].
Soluble TRAIL (sTRAIL) levels are elevated in the plasma of HIV-infected patients, before plasma viral loads peak, resulting in a mean peak of plasma TRAIL levels that fall within the biologically relevant concentration range for the induction of cell death. These observations implicate that TRAIL is an early mediator of cell death in acute HIV infection [33]. HIV induces TRAIL [38,48,49] and DR4 [49] expression on CD4
+ T cells, leading to apoptosis in vitro and in vivo.
TRAIL expression is regulated by HIV gp120 induced IFN- production by monocytes and plasmacytoid DCs
(pDCs) [50,51]. Furthermore, it was shown that pDCs up-regulate surface TRAIL expression upon TLR7 stimulation, which could be provided by HIV motifs [52]. The expression of TRAIL on pDCs correlates positively with HIV viral loads and TRAIL-expressing pDCs are able to kill DR4
+ CD4
+ T cells from HIV-
infected patients. Thus, over-expression of TRAIL on pDCs may contribute to the CD4
+ T-cell loss during HIV
infection [49]. CD4+ T cells from HIV-infected patients
were shown to be more susceptible to TRAIL-induced apoptosis compared to uninfected CD4
+ T cells in vitro
[53] and these observations were confirmed in vivo in a human peripheral blood lymphocyte (PBL)-transplanted non-obese diabetic (NOD)-severe combined immunodeficient (SCID) (hu-PBL-NOD-SCID) mouse model. This hu-PBL-NOD-SCID mouse model allowed to see extensive infection with HIV-1. Massive apoptosis was predominantly observed in virus-uninfected CD4
+ T cells in the spleens of HIV-1–
infected mice. The apoptotic cells were frequently found in conjugation with TRAIL
+ CD4
+ human T cells,
suggesting that a large number of HIV-1–uninfected CD4
+ T cells undergo TRAIL-mediated apoptosis in
HIV-infected lymphoid organs [54]. cART therapy leads to an up-regulation of the apoptosis-inhibiting DcR2 receptor on CD4
+ T cells, which subsequently become
resistant to pDC-mediated apoptosis [49], and to a reduction of TRAIL levels in the blood and in the lymph nodes [38]. However, the DR expression on CD4
HIV and Costimulation Current Molecular Medicine, 2011, Vol. 11, No. 3 5
cells in the lymph nodes remains elevated upon cART [38].
It has been shown that administration of an anti-TRAIL Ab to HIV-infected hu-PBL-NOD-SCID mice markedly reduces CD4
+ T-cell apoptosis [54]. By
performing in vitro experiments, Stary et al. demonstrated that pre-incubation of pDCs from a HIV-infected patient with anti-TRAIL and anti-IFN- Abs can essentially abolish pDC-mediated cytotoxicity against the CD4
+ T cells [49].
In summary, the TRAIL/DR signaling pathway results in enhanced cell death. However, in contrast to FasL, TRAIL can also bind to apoptosis-inhibiting receptors. Promising results have been obtained when the TRAIL/DR pathway was blocked using several different approaches. Keeping these encouraging results in mind, it is surprising that the number of studies evaluating the potential role of this pathway during HIV infection remain so limited.
TNF Receptors that Contain a TRAF Binding Domain
CD27/CD70
CD27 is primarily expressed on naïve CD4+ and
CD8+ T cells, as well as on memory B cells and natural
killer (NK)-cell subsets [55, 56]. The expression of CD27 is increased upon T-cell activation, but is down-regulated after several rounds of division [57]. The ligand for CD27, CD70 (CD27L), is expressed on activated T cells, B cells and DCs [58, 59] and can function as a signal transducing receptor itself. CD70 costimulates T-cell activation via CD27 through the activation of both canonical and non-canonical NF- B pathways [60] and can sensitize naïve CD4
+ T cells for
IL-12-induced Th1 development [61]. Moreover, CD27 ligation induces an up-regulation of the pro-survival molecule Bcl-xL [61].
Serum levels of soluble CD27 (sCD27) are elevated in HIV-infected patients, especially in patients that develop AIDS-associated non-Hodgkin’s lymphoma (AIDS-NHL) [62]. High levels of sCD27 correlate directly with HIV-viremia and inversely with CD4
+ T-cell
counts [63]. sCD27 is a potential blocker of CD70 action, suggesting that HIV infection can impair CD70 function [64]. cART induces a significant reduction, but not a normalization, of plasma sCD27 levels [63].
In HIV-infected patients, CD27 expression is decreased on total CD8
+ T cells [65]. However, in
contrast to CMV- and EBV-specific T cells, HIV-specific T cells are characterized by a persistent CD27 expression, which correlates with lower cytokine production and perforin levels [66, 67]. In accordance, higher numbers of HIV-specific CD27
- CD8
+ T cells
have been associated with delayed disease progression [67]. It is possible that CD27
+ HIV-specific
T cells are arrested in an immature and functionally impaired stage due to a lack of CD4
+ T-cell help [68].
Ochsenbein et al. used CD27+ and CD27
- T-cells
derived from a clone of CD27+ CD8
+ T-cells from a
HIV-infected patient to study the effects of CD27-expression and signaling on T-cell survival and functionality. In contrast to the studies mentioned above, they found that CD27
+ T cells actually have a
higher proliferative capacity upon HIV-specific stimulation compared to CD27
- T cells. Moreover, they
show that signaling through CD27 results in reduced apoptosis and increased IL-2 production. After transfer back into the patient, the autologous HIV-specific CD27
- T cells rapidly disappear, whereas the CD27
+ T
cells persist at high frequency, suggesting that HIV-specific CD27
+ CD8
+ T cells have a survival advantage
in vivo and that the transfer of CD27+ T cells may
permit a strong persistent response in HIV-infected patients [69]. These results suggest that the predominance of CD27
+ CD8
+ HIV-specific T cells may
not reflect an abnormality in differentiation, but rather an appropriate compensation because of the survival and proliferative advantages of such cells after target recognition, particularly in a CD4
+ T-cell deficient
environment [69]. Furthermore, expression levels of CD27 on total PBMC correlate positively with CD4
+ T-
cell counts [70].
In contrast to the CD8+ T cells, the CD27 induction
upon TCR stimulation of naïve CD4+ T cells from HIV-
infected patients is impaired. This mechanism could explain the failure of the CD4
+ T cells to expand during
HIV infection [71]. The proportion of circulating CD27+
B cells is also substantially reduced and correlates with the CD4
+ T-cell number in HIV-infected patients
[41,62,72].
The expression of CD70 on B and T cells is higher in HIV-infected patients compared to healthy subjects. The higher CD70 expression on T cells contributes to their APC-like properties in vitro [65]. An enhanced stimulatory potential of these ‘non-professional APCs’ may contribute to persistently high levels of immune activation during HIV infection [73]. Indeed, the expression levels of CD70 on T cells correlate inversely with the CD4
+ T-cell counts during HIV infection [41].
The increased expression of both CD27 and CD70 is also observed on NK cells from HIV-infected patients, and this phenomenon is more pronounced during chronic infection [74].
Wang et al. made use of monocytes that over-express CD70 and found that CD70 is efficacious in stimulating influenza-specific CTL, but that it does not rescue the expansion of HIV-specific CD8
+ T cells from
HIV-infected donors [15].
To conclude, the expression patterns of CD27 and CD70 are clearly disrupted during HIV infection. However, the debate about the role of CD27 expression and triggering on CD8
+ T-cells for the
induction of functional anti-HIV CTL responses is still unresolved.
OX40/OX40L
OX40 (CD134) is expressed on activated T cells [75] and its triggering results in an enhanced
6 Current Molecular Medicine, 2011, Vol. 11, No. 3 De Keersmaecker et al.
proliferation, cytokine production and survival of antigen-specific T cells [75-77]. OX40 is also involved in T-cell migration and OX40-mediated costimulation of CD4
+ T cells by OX40L stimulates the production of
both Th1 and Th2 cytokines [78, 79]. Under certain conditions, OX40 can also contribute to CD8
+ T-cell
responses [80,81], probably because OX40 stimulation leads to a sustained expression of the pro-survival molecule Bcl-xL in activated CD8
+ T cells [82]. Human
Tregs express OX40 upon stimulation [83]. OX40 stimulation turns off their immunosuppressive effects and causes CD4
+ CD25
- effector T cells to become
resistant to the immunosuppressive effects of Tregs in mice [84]. OX40L (gp34, CD134 ligand) is expressed on mature DCs [85] and activated B cells [86] and can be up-regulated on T cells after their activation [87]. Reverse signaling through OX40L enhances DC maturation and induces elevated humoral immunity [88].
OX40 is up-regulated on resting CD4+ T cells during
HIV infection, but the expression is normalized upon cART treatment [27,89]. On the other hand, the expression of OX40 on activated CD4
+ T cells is
decreased during HIV infection [90]. Resting CD8+ T
cells from HIV-infected individuals also express low levels of OX40, which is not observed in healthy donors [89]. OX40L expression on monocytes is elevated during HIV infection [91].
In a mouse model, the immune stimulatory effect of a HIV-1 canarypox vaccine on CD8
+ T cell-responses
was enhanced by co-administration of OX40L, but humoral responses were not altered [92]. Furthermore, proliferation of HIV-specific CD4
+ T cells is enhanced
upon coculture with monocytes infected with OX40L-expressing adenovirus [89]. HIV-specific CD8
+ T-cell
responses are also enhanced in the presence of OX40L-adenovirus infected monocytes, be it in a CD4
+
T-cell dependent way [89,93].
An important issue to keep in mind when considering to exploit the OX40/OX40L pathway as a therapeutic target in HIV-infected patients is that stimulation of HIV-infected CD4
+ T cells through OX40
by OX40L transfected cells significantly enhances HIV expression in these cells and induces apoptosis in vitro [94]. Furthermore, the DC-mediated up-regulation of CXCR4 on CD4
+ T cells, rendering them susceptible to
infection with X4 HIV strains, is at least partially mediated by the interaction of OX40 with its ligand [95]. On the other hand, OX40 stimulation suppresses the infection of primary activated PBMC with R5 HIV-1 strains via enhanced production of the R5 HIV-1 suppressing -chemokines RANTES, MIP-1 and MIP-1 [96]. Furthermore, potential side effects of OX40L therapy could be overcome by providing OX40L treatment in combination with cART, so that a possible enhancement of HIV replication can be neutralized. Moreover, Takahashi et al. observed that costimulation of OX40
+ HIV-infected T cell lines via OX40L and TNF-
leads to a marked reduction of HIV-production [97].
Thus, although interference with the OX40/OX40L signaling pathway has shown some positive results in vitro, knowledge about the expression of this costimulatory receptor/ligand pair in HIV-infected patients remains limited, and therefore, further investigation is warranted.
4-1BB/4-1BBL
4-1BB (CD137, ILA) mediates T-cell costimulation through NF- B activation [98,99], which in turn can regulate the expression of the pro-survival molecule Bcl-xL [100]. Another downstream effect of 4-1BB ligation is the inhibition of the expression of the pro-apoptotic molecule Bim [20,101]. 4-1BB is expressed on activated T cells, NK cells and NKT cells [102] and is constitutively expressed on monocytes, neutrophils and DCs [103-105]. Costimulation through 4-1BB can enhance proliferation, cytokine production and cytotoxic activity of CD8
+ T cells [100,106] and
enhances CD8+ T-cell survival, particularly late in the
primary immune response, thus contributing to a larger CD8
+ memory T-cell pool [81,107,108]. 4-1BB
costimulation was also shown to improve proliferation, cytokine production and survival of human CD4
+ T cells
in vitro [109-111] and in vivo [112,113]. However, other studies reported only limited effects of 4-1BB signaling on CD4
+ T-cells [107] and in some murine in vivo
models, the enhanced IFN- production upon anti-4-1BB Ab treatment leads to suppression of CD4
+ T-cell
responses via TGF- and the induction of indoleamine 2,3-dioxygenase (IDO) in macrophages and DCs [114]. As many other costimulatory receptor/ligand pairs, the 4-1BB/4-1BBL system can signal in a bidirectional manner in cells that express both molecules, for example DCs and human B cells. 4-1BB ligation on DCs can enhance activation and antigen uptake [115] and controls the immunogenicity and duration of DC-T-cell interactions [116]. 4-1BB stimulation of human B cells leads to enhanced proliferation, survival, cytokine secretion and Ig production and cytokine secretion [117,118]. Human 4-1BB inhibits NK cell reactivity against acute myeloid leukemia cells, while activating signals are transduced by its counterpart on NK cells in mice [119]. 4-1BB has been shown to turn off the immunosuppressive effects of Tregs in mice [120] and humans [83, our unpublished results].
4-1BB is expressed at a lower level on HIV- compared to CMV-specific cytokine producing CD4
+ T-
cells. 4-1BB expression on CD4+ T cells is inversely
correlated with HIV viral load. Moreover, IL-2 production in response to Gag stimulation, which is associated with a good prognosis during HIV infection, is higher in CD4
+ T cells that express 4-1BB, compared
to CD4+ T cells that lack 4-1BB expression [91]. 4-
1BBL expression on monocytes from HIV-infected patients is higher than on monocytes derived from healthy individuals [91].
A recombinant poxvirus expressing HIV antigens and 4-1BBL was tested for its immunogenicity in mice. When included in the boost phase of a prime-boost vaccination strategy, 4-1BBL significantly enhanced
HIV and Costimulation Current Molecular Medicine, 2011, Vol. 11, No. 3 7
HIV-specific T-cell responses. Using this vaccination strategy, 4-1BBL was neither capable of modulating the CD4
+ T-cell response, nor the humoral responses
[121]. In another murine model, Gag-specific cellular immune responses elicited by plasmid DNA immunizations were enhanced by an anti-4-1BB agonistic Ab as well as by 4-1BBL encoding DNA vectors, but the agonistic Ab suppressed humoral immunity to Gag whereas 4-1BBL DNA enhanced vaccine-induced Gag-specific IgG responses. The expression of Gag and 4-1BBL from the same plasmid was critical for this adjuvant activity [122]. CD8
+ T cells
from HIV-infected patients can respond to 4-1BBL costimulation in the absence of CD4
+ T-helper cells or
exogenously added IL-2 [123]. In addition, 4-1BBL can costimulate human CD28
- T cells [106], which is
promising since loss of CD4+ T-helper cells, IL-2 and
CD28 expression are characteristic for HIV infection [124, see below]. Furthermore, Wang et al. showed that, regardless of the PD-1 status of the T cells, 4-1BBL is able to expand a population of CD8
+ T cells
that express multiple markers of effector function [15]. It is important to note that cross-linking of 4-1BB with an agonistic Ab significantly enhances HIV-replication in CD4
+ T-cells in the presence of anti-CD3 Ab [125].
Thus, given the strong costimulatory effects of 4-1BB signaling in CD8
+ T cells, irrespective of the level
of IL-2, PD-1 and CD28, which are all disrupted during HIV infection (see below), exploiting this pathway could be very promising as a therapeutic anti-HIV intervention, as suggested by several studies.
CD40L/CD40
CD40L (CD154) is expressed on activated T cells, eosinophils, basophils and NK cells [126, 127]. Its receptor, CD40, is expressed on DCs and B cells. CD40L-expressing CD4
+ T cells are generally required
for the generation of functional CTL responses. CD40/CD40L interactions lower the threshold of antigen required to activate primary T-cell responses and can augment the survival of activated T cells [128]. Ligation of the CD40 receptor, for example by interaction with CD40L expressing CD4
+ T cells,
‘licenses’ APCs to express co-stimulatory molecules, enhances their survival [129-131] and induces production of IL-12 and other cytokines and chemokines [131-134], which can in turn induce Th1 differentiation and stimulate IFN- production by NK cells. CD40 stimulation releases mouse but not human DCs from the suppressive effects of Tregs [135, 136]. Finally, CD40L promotes the differentiation of activated B cells and is required for the class switch from IgM to IgG production [137].
HIV infection is associated with elevated levels of sCD40L, which do not decline upon cART treatment [138]. sCD40L was reported to inhibit IL-12 production by stimulated monocytes [138]. Furthermore, HIV-infected patients exhibit increased proportions of CD40L
+ resting CD4
+ T cells, which are reduced upon
cART [27]. However, CD40L expression on T cells from patients with advanced HIV infection is reduced
upon stimulation [90,139] and in response to opportunistic pathogens [140]. This absence of CD40L
+ T cells contributes to deficient Th1 responses
through decreased IL-12 production [139,140] and impaired development of functional memory B cells [141]. Two mechanisms have been proposed to underlie CD40L impairment. First of all, interactions between the major HIV-1 surface glycoprotein, gp120, and the CD4 receptor on the surface of CD4
+ T cells
could cause decreased CD40L expression [90,142]. Secondly, Subauste et al. described CD40 as a mediator of impaired CD40L protein expression on CD4
+ T cells of HIV-infected patients [143].
CD40 expression on monocytes and DCs from HIV-infected patients is increased in a disease stage-related fashion, but this increase disappears upon cytokine stimulation [139,144,145]. In patients with acute HIV-1 infection, an increased frequency of CD40
high cells is evident in the lymphoid tissues, but
AIDS patients show a reduced expression of CD40 in the lymphoid tissue [145]. The HIV-1 Vpr protein can down-modulate the expression of CD40 on monocyte-derived macrophages and monocyte-derived DCs [146]. Defective CD40/CD40L interactions could play a crucial role in the APC abnormalities observed during HIV infection, including decreased levels of CD80 and CD86 expression by lymph node DCs [145, see below] defective allo-stimulatory capacity [147] and decreased numbers of circulating DCs [143,148,149]. The importance of CD40 for the induction of T-cell responses in a vaccination context was shown by Nchinda et al. They observed that wild-type mice vaccinated with DC-targeted Gag showed efficient anti-Gag immune responses. However, CD40
-/- mice
developed reduced CD4+ and CD8
+ T-cell immunity
[150]. On the other hand, CD8+ T cells from HIV-
infected patients proliferate less compared to CD8+ T
cells from healthy individuals in response to cell-bound CD40, while CD4
+ T-cell responses were similar in
patients and controls upon CD40 stimulation [151].
HIV-related B-cell defects include non-specific hypergammaglobulinemia as well as impaired IgG and IgA responses to pathogens and vaccines [141]. CD40L induces immunoglobulin heavy-chain class-switch recombination through NF- B [152]. However, the HIV Nef protein renders B cells less responsive to CD4
+ T-cell help as provided by CD40L [153].
An intriguing characteristic of CD40L and CD40 is that they can both be inserted within the envelope of emerging HIV-particles [154]. CD40L-bearing viruses may promote IgG and IL-6 production by B cells in an NF- B dependent manner, show an enhanced binding of the virion to B cells and facilitates their eventual transfer to autologous CD4
+ T cells [155].
CD40 signaling can influence replication of HIV within cells and the sensitivity of various cell types to HIV infection in several ways, leading to either enhanced or decreased HIV-infectivity or -replication. First, CD40/CD40L interactions on macrophages and DCs induce the production of MIP-1 , MIP-1 and
8 Current Molecular Medicine, 2011, Vol. 11, No. 3 De Keersmaecker et al.
RANTES, chemokines that in turn enhance the replication of X4 HIV-strains in CD4
+ T cells [156], but
protect CD4+ T cells from infection by R5 HIV-strains
[134,157-159]. Second, CD40L stimulates the expression of monocyte-derived chemokines with possible anti-HIV activity and fractalkines by DCs [160-162]. Third, CD40L can cause a down-regulation of CCR5 on the DC and macrophage surface, thus protecting these cells from infection by R5 viruses [131,134,163]. However, other reports show that the addition of CD40L to macrophage and B-cell cultures can result in a significant increase of both CD4 and CCR5 expression, making the cells more susceptible to HIV infection [158,164,165]. Fourth, CD40L increases overall viral production by prolonging the life span of infected macrophages [158]. Fifth, CD40L can down-regulate the antiviral efficacy of HIV reverse-transcriptase inhibitors [158]. Sixth, macrophages that express Nef are stimulated through the CD40 receptor release a paracrine factor that renders T cells permissive to HIV infection [166]. Finally, CD40 stimulation in the presence of IL-4 and IL-2 leads to an enhanced HIV-replication in B cells [164].
Administration of a human CD40L plasmid combined with an HIV DNA vaccine caused stimulation of both Th1 and Th2 cells in mice, leading to both humoral and cellular antigen-specific immunological enhancement [167]. In addition, sCD40L in DNA/poxvirus combination enhanced both the magnitude and the breadth of HIV-specific cellular immune responses in mice. In this study, sCD40L was necessary in both prime and boost inoculation. Moreover, humoral responses were enhanced when CD40L was added to some immunization regimens, depending on the vector used [168]. Lin et al. tested vesicular stomatitis virus glycoprotein-pseudotyped replication-defective simian immunodeficiency viruses (dSIVs) as an anti-HIV vaccine and found that CD40L-dSIVs enhanced activation of rhesus macaque DCs, enhanced proliferation and IFN- secretion by naïve T cells and induced stronger humoral and cell mediated immunity in mice [169]. Importantly, the defective IL-12 production by PBMC from HIV-infected patients can be restored upon stimulation with IFN- and CD40L [139,144,170]. DCs engineered with CD40L are very potent for priming naïve anti-HIV CD8
+ T-cell
responses and enhancing pre-existing HIV-specific CD8
+ T-cell responses [128, 171]. Furthermore, CD40L
trimers can enhance HIV-specific CTL responses both in the presence and in the absence of CD4
+ T-cell help
in the majority of patients, whereas, CD40L trimers do not completely substitute for CD4
+ T-cell help in a
smaller number of patients [172]. Interestingly, addition of recombinant trimeric CD40L could reverse the functional defects exhibited by DCs co-cultured with HIV-exposed T-cells [173]. Recently, the use of autologous DCs matured with a cytokine cocktail and co-electroporated with messenger RNA encoding CD40L and the HIV-antigens Gag, Vpr, Rev and Nef as a therapeutic anti-HIV vaccine was tested in HIV-infected patients. The immunogenicity of this vaccine
was tested by a proliferation assay and in some patients, CD8
+ T-cell proliferative responses were
higher after vaccination. No evidence of autoimmunity or change in viral load was observed. However, the role of CD40L in the immune responses observed upon vaccination remains unclear since the study did not include a control arm with patients receiving DCs that were not modified with CD40L [174].
Reservoirs of latent HIV in T cells and macrophages pose one of the major obstacles that hamper final eradication of HIV. Targeting costimulatory molecules expressed on cell types harboring latent HIV to achieve reactivation may potentially provide a new approach to overcome this problem. Trimeric forms of CD40L allow for the direct reactivation of latent HIV infection and this reactivation is augmented by TNF- [175]. Another ‘pro’ argument for targeting the CD40 pathway as a therapeutic approach during HIV infection is that stimulation of cell surface CD40 with CD40L leads to an up-regulation of APOBEC3G, an intracellular innate antiviral factor that has been found to inhibit HIV infection [176, 177].
To conclude, the CD40/CD40L couple has been very extensively investigated in the context of HIV infection. These molecules influence the immune responses through various mechanisms, which makes it difficult to translate in vitro observations to the in vivo situation. CD40L can induce IL-12 secretion by APCs, making this molecule an attractive target during HIV infection, which is characterized by reduced IL-12 levels. It is therefore not surprising that this costimulatory molecule is, to our knowledge, the first that was tested in a therapeutic anti-HIV trial in humans.
RANK/RANKL
RANK (receptor activator of NF- B) is expressed on DCs and is up-regulated upon CD40L stimulation [178]. Its ligand, RANKL, also called TNF-related activation-induced cytokine (TRANCE), is expressed by activated CD4
+ and CD8
+ T cells [179, 180]. RANKL
induces IL-12 and IL-15 production by DCs [180], promotes their survival [181] and serves as a ‘back-up’ DC stimulator when CD40L is not available [64].
RANKL levels are significantly increased in the plasma of cART-naïve HIV-infected patients compared to healthy donors. In addition, RANKL plasma concentrations are positively correlated to HIV-1 viral load [182]. An association between HIV-related osteopenia/osteoporosis and the serum levels of RANKL in HIV-infected patients has been described [183]. Soluble HIV envelope gp120 and the HIV Vpr protein are able to mediate an up-regulation of RANKL in PBMC [184, 185].
Yu et al. were the first, and to our knowledge so far the only group to show that RANKL can offer limited help to virus-specific CD8
+ T-cell responses in HIV-
infected individuals [186].
The expression of RANK/RANKL and its function during HIV infection are poorly investigated, contrary to
HIV and Costimulation Current Molecular Medicine, 2011, Vol. 11, No. 3 9
its ‘brother’-pair CD40/CD40L. However, the RANKL-mediated induction of IL-12 by DCs is an interesting feature, warranting further research.
GITR/GITRL
Glucocorticoid-induced TNFRSF-related protein (GITR) is expressed on activated and antigen-specific lymphocytes and NK cells. Its ligand, GITRL, is mainly expressed on APCs, including myeloid DCs (mDCs), pDCs, B cells and monocytes [187-192]. GITR signaling enhances antigen-specific effector T-cell responses, partially by making T cells resistant to apoptosis [193, 194] and leads to NK-cell co-activation, activation of macrophages and modulation of DC function [195]. GITR is also expressed on Tregs [196, 197] and agonistic anti-GITR Abs abrogate the immunosuppressive properties of Tregs in mice [196,198], but not in humans [197].
Not much is known about the expression of GITR and its ligand during HIV infection, except the observation that CD4
+ T-cell surface expression of
GITR is higher than in uninfected individuals, but is impaired upon stimulation [199]. Interestingly, a recent report shows that HIV-patients have significantly elevated percentages of Foxp3
+ CD4
+ Tregs,
particularly in patients with lower CD4+ T-cell counts
[200]. In spite of elevated percentages of Tregs, the percentage of GITR
+ cells in the CD4
+ T-cell population
is lower in HIV-patients compared to healthy individuals [200], which may indicate the fact that GITR expression on Tregs is decreased in HIV-patients.
In mice, triggering of GITR was shown to potently enhance T cell responses in disease models for cancer, parasitic, fungal and viral infections [196-197,200-202]. Initially, it was assumed that GITR triggering on Tregs reduces their suppressive effect, but Stephens et al. showed that GITR expression is required on effector T cells but not on Tregs to alleviate Treg suppression [203]. More recent studies showed that the predominant effect of GITR triggering can be attributed to a potent costimulatory effect on effector T cells [204-205]. Another recent study shows that GITR expression on CD8
+ T cells is required for optimal
responses against lethal influenza by enhancing the survival of CD8
+ T cells [206]. Furthermore,
administration of multimeric sGITRL augments CD4+ T-
cell, CD8+ T-cell and Ab-responses to Gag DNA
vaccination in mice [199]. In humans, GITR triggering reduces the expression of intracellular activated caspase-3 in HIV-specific CD4
+ T cells [201]. However,
triggering of GITR results in modestly increased HIV-specific CD4
+, but not CD8
+ T-cell cytokine secretion
and proliferation [207, our unpublished data].
Not much research has been performed to unravel the function of the GITR/GITRL pathway during HIV infection. However, GITR triggering seems to result in only limited enhancement of CD4
+, but not of CD8
+,
HIV-specific T-cell responses. Furthermore, in contrast to the promising results obtained in mice, GITR ligation does not influence Treg-mediated immune suppression
in humans. Therefore, GITR/GITRL does not seem to be the best candidate costimulatory receptor/ligand pair to target during HIV infection.
HVEM/LIGHT
Herpes virus entry mediator (HVEM) is expressed on B cells, DCs, monocytes and macrophages [208, 209]. HVEM is also constitutively expressed on naïve T cells, but is transiently down-regulated following T-cell activation [210]. One of its ligands, LIGHT, is up-regulated on activated T and B cells as well as on immature DCs [210-213]. HVEM interaction with LIGHT induces co-stimulatory signals and contributes to T-cell activation and induction of chemokine and cytokine production [214]. Cross-linking HVEM through LIGHT also stimulates B-cell proliferation and Ig production [215]. Apart from HVEM, LIGHT also binds lymphotoxin -receptor (LT R) and TNFR decoy receptor 3 (DCR3) [211, 216-218]. As described above for RANK and CD40, signaling through LT R is required for optimal DC function in mice [219]. To our knowledge, the importance of lymphotoxin receptor signaling for DC function during HIV infection has so far not been investigated.
Another HVEM ligand, lymphotoxin (LT ), a member of the TNFSF, is secreted by activated Th1 cells, fibroblasts, endothelial and epithelial cells. The binding of LT to HVEM is relatively weak [218]. Although its exact functional role in the HVEM pathway is unclear [209], LT has a role in the regulation of lymphocyte migration, and thus contributes to inflammatory responses [220]. Similar to HVEM/LIGHT interaction, binding of HVEM to LT stimulates T-cell proliferation and IFN- production [221].
HVEM is the only TNFR that is known to bind with ligands that do not belong to the TNFSF [218]: it was recently discovered that BTLA (B7 super-family member) and CD160 (Ig super-family member) bind to HVEM, resulting in a co-inhibitory signal to T-cell activation [212, 221, 222] and B-cell proliferation [223]. BTLA is expressed on naïve and activated lymphocytes [224, 225] and is up-regulated on anergic T cells, comparable with the inhibitory molecule PD-1 (see further). BTLA expression is also observed on DCs [226]. CD160 is mainly expressed on T cells, NKT cells and NK cells [227-229].
Although HVEM binding to LIGHT or LT delivers a positive signal to T-cell activation, the overall function of HVEM is inhibitory, suggesting that the negative signals mediated by BTLA and CD160 are dominant. The cysteine-rich domain 1 (CRD1) of HVEM is essential for the binding of the co-inhibitory ligands CD160 and BTLA, but not for the costimulatory ligand LIGHT. Therapies targeting the CRD1 of HVEM to block BTLA and CD160 binding may thus be promising for enhancing immune responses and vaccination efficacy [209]. However, whether this approach would be applicable in HIV-infected patients, remains to be investigated.
10 Current Molecular Medicine, 2011, Vol. 11, No. 3 De Keersmaecker et al.
THE B7 SUPER-FAMILY
Interactions between molecules from the B7 family of costimulatory and co-inhibitory molecules may play an important role not only in priming cells, but also in regulating activated T cells in both lymphoid and non-lymphoid organs in vivo. The family consists of two costimulatory receptors, CD28 and ICOS, and two co-inhibitory receptors, PD-1 and CTLA-4. CD28 and CTLA-4 share the same ligands, namely CD80 and CD86. ICOS binds with ICOSL and PD-1 interacts with PD-L1 and PD-L2. CD28 is constitutively expressed on CD4
+ T cells, but its homologue CTLA-4 is only
expressed upon T-cell activation. CD28 provides the signal required for the full activation of T cells on the engagement of the TCR, whereas CTLA-4 acts as an attenuator of T-cell activation. A decreased expression of CD28 is coupled to an up-regulation of CTLA-4 expression during HIV-1 infection. Upon TCR ligation, the relative expression of CD28 and CTLA-4 dictate the resulting T-cell response [230]. It is important to keep in mind that the avidity of CTLA-4 for CD80 and CD86 is 100-fold higher than that for CD28 [231,232].
PD-1 and CTLA-4 inhibit T-cell activation by using partially overlapping signaling pathways that converge on inhibiting of phosphorylation of the kinase Akt [233]. Both CTLA-4 and PD-1 increase the T-cell motility and override the TCR-induced stop signal that is necessary for a stable conjugate formation between T cells and APCs [234, 235]. However, despite these similarities, the regulatory roles of the CTLA-4 and PD-1 pathways are different [reviewed by 236].
CD28/CD80 & CD86
CD28 costimulatory signals regulate IL-2 production and T-cell survival, lower the threshold for T-cell activation and promote an enhancement of the T-cell metabolism, as needed for T-cell proliferation [7,237,238]. In humans, CD28 is constitutively expressed by the majority of CD4
+ and CD8
+ T cells
[239]. However, human T cells tend to lose CD28 expression with age, resulting in the appearance of CD28
- CD8
+ T cells and CD28
dim CD4
+ T cells
[240,241]. CD80 and CD86 are expressed on professional APCs, such as activated B cells, activated monocytes, macrophages and DCs as well as Langerhans cells of the skin [242-244]. Activated or in vitro stimulated T cells also express CD80 and CD86 [65,245]. Some subtle differences between the functions of CD80 and CD86 have been reported. First, CD80 mediated signaling may be associated with CD4
+
T-cell precursor commitment to a Th1 cytokine pattern whereas triggering of CD28 via CD86 may result in a Th2 cytokine pattern [246]. However, these results may reflect the use of blocking antibodies that differentially effect the T-cell differentiation due to different kinetics of expression. Second, although both CD80 and CD86 bind CTLA-4 with higher binding affinity than CD28, CD80 was suggested to interact mainly with CTLA-4 in vivo [247].
CD28 is also down-regulated on T cells during HIV infection, resulting in a similar phenotype as T cells from elderly people. The expression of CD28 on total PBMC correlates positively with CD4
+ T-cell counts
[70]. Thus, most HIV-1 infected patients accumulate CD8
+ T cells belonging to an intermediate (CD28
-
CD27+) phenotype, also characterized by low perforin
levels [66,124,248,249]. Optimal anti-HIV responses occur after triggering of the CD28 molecule on CD8
+ T
cells during stimulation. Furthermore, costimulation through CD28 improves the ability of CTL to suppress HIV-replication. This increase in CD8
+ T-cell antiviral
activity is associated with an enhanced IL-2 production and an increased expression of the IL-2 receptor on the CD8
+ T-cell surface [250]. Fortunately, the CD28
expression of CD8+ T cells is restored under cART
[251]. During HIV infection, naïve CD4+ T cells also
have an impaired induction of CD28 cell surface expression after TCR engagement [71]. This decreased CD28 expression may contribute to the impaired expansion of naïve T-cells observed during HIV-1 infection [71]. CD8
+ T cells from HIV-infected
patients show reduced proliferative potential and cytokine production upon co-activation with cell-bound CD80 or CD86 compared to CD8
+ T cells from healthy
donors, while responses from CD4+ T cells upon CD28-
mediated activation are similar in patients and healthy donors [151]. The HIV-1 proteins Nef and Vpr were suggested to be involved in the HIV-mediated decrease of CD28 expression on T cells [252, 253].
The expression of CD86 is significantly increased on both freshly isolated and in vitro stimulated CD4
+
and CD8+ T cells from HIV-infected individuals
[65,245]. T cells expressing costimulatory ligands, such as CD86, are able to induce proliferation of responder T cells, demonstrating that, during HIV infection, circulating T cells undergo a transition from a reactive to a ‘non-professional APC’ phenotype [245], as also reported for CD70
+ T cells (see above). Furthermore,
expression of CD80 or CD86 on the T-cell surface may permit direct T-T cell contact via CD28 or CTLA-4 and could result in direct transmission of HIV [254]. In contrast, on APCs, CD80 and CD86 are down-regulated during HIV infection [255]. The HIV-1 Nef protein can relocate CD80 and CD86 away from the monocyte cell surface [256]. The endocytic mechanism used for removal of CD80 and CD86 is distinct from the one used for the relocation of MHC class I [256]. On the other hand, Nef is also found as a secreted protein, which can trigger DCs, resulting in a modest up-regulation of surface CD80 and CD86 [257]. Similar to HIV-1 Nef, the Vpr protein can down-modulate the expression of CD80 and CD86 on monocyte-derived macrophages and DCs [146]. The down-regulated expression of CD80 and CD86 on monocytes and DCs during HIV infection leads to a subsequent failure to generate HIV-specific CD4
+ T-cell responses and an
impaired activation of CD8+ T cells, resulting in
inefficient suppression of HIV-1 replication [145,258]. On the other hand, lymphoid tissues from patients with acute HIV-1 infection show an up-regulation of the
HIV and Costimulation Current Molecular Medicine, 2011, Vol. 11, No. 3 11
number of CD80+ and CD86
+ DCs compared with
uninfected healthy controls. However, patients with acute EBV infection show significantly higher numbers of CD80
+ and CD86
+ DCs in the lymph nodes
compared to patients with acute HIV-1 infection [145].
Host-derived CD28, CD80 and CD86 can be present in the HIV-1 envelope, which results in an augmentation in virus infectivity when the target cells express high levels of the respective ligands and receptors [259-261]. CD80 and CD86-carrying viruses have the capacity to act synergistically with the CD3/TCR complex, which leads to the activation of NF-
B and NFAT [260,262]. However, when CTLA-4 is expressed on the T-cell surface, this HIV-1 costimulatory property is abolished [260]. Interestingly, both HIV-1 virions and microvesicles preferentially incorporate CD86 compared to CD80 [263].
CD28 costimulation of HIV-1 infected cells favors TCR-induced activation of the transcription factors NF-AT, AP1 and NF- B, which have a binding site in the HIV-1 LTR and activate HIV-1 transcription [264-267]. In contrast, other studies report that an expansion of naïve CD4
+ T cells from HIV-infected patients using
antibodies against CD3 and CD28 or through cross linking by anti-CD3 and CD80 results in a complete suppression of viral replication [268-270]. Conflicting results may be explained by a study performed by Barker et al. The authors of this study found that continuous exposure of CD4
+ T cells to anti-CD3 and
CD28 Abs following acute infection prevents HIV-virus production by the CD4
+ T cells, but the opposite was
found when CD28 costimulation is removed early after stimulation [271]. Furthermore, CD3/CD28 stimulated naïve CD4
+ T cells can inhibit CD28-mediated R5 HIV-
replication in memory CD4+ T cells [272], but also
results in an up-regulated CXCR4 expression, which may result in increased infection by X4 HIV [273].
CD28 can also act as a TCR-independent signaling unit by delivering specific signals that can induce HIV transcription and replication through the trans-activation of the HIV-1 LTR in an NF- B dependent manner [274, 275]. In contrast, it has been described that X4 and R5 HIV-1 replication can be inhibited by immobilized CD28 mAbs [276]. However, direct application of CD28 mAb mostly enhanced viral replication [276]. The strength of the costimulatory signal is critical for inhibition of HIV replication [272]. Discrepancies in several studies investigating the effects of CD28-mediated costimulaton on HIV-replication may rely on the ability of anti-CD28 Ab with distinct binding specificities to activate different signaling pathways [277].
Co-immunization with plasmid DNA encoding for HIV-1 antigens and for CD86 does not result in changed humoral responses but induces a dramatic increase in CD4
+ T-cell proliferation in mice and in
CD8+ T-cell induction in mice and chimpanzee [278-
280]. Mice co-immunized with CD86 express a higher level of MIP-1 , a potent chemo-attractant and a major HIV-suppressive factor [280]. In contrast, co-
immunization with CD80 encoding DNA resulted only in a minor enhancement of CD4
+ and CD8
+ T-cell
responses [278,280]. On the other hand, using an in vitro model with primary human cells, Bukczynski et al. found that monocytes infected with adenoviruses encoding for CD80 can enhance HIV-specific CD8
+ T-
cell expansion [123]. Interestingly, CD80 stimulation of CD8
+ T cells from chronically infected donors was
shown to be most effective in combination with 4-1BBL costimulation [15,123]. Thus, it may be that combination therapies are required for CD80 to be effective.
CTLA-4/CD80 & CD86
CTLA-4 antagonizes the positive secondary signal mediated by CD28. CTLA-4 is constitutively expressed on Tregs [230,281] and is rapidly expressed by newly activated T cells. Apart from the CTLA-4 immune suppressive effect on the cells that express CTLA-4 themselves, CTLA-4 can also mediate suppression of target cells by triggering reverse signaling through its ligands expressed on other T cells or APCs [282]. For example, CTLA-4 mediated ligation of CD80 and/or CD86 on DCs activates tryptophan catabolism, which leads to immune suppression [283].
During all stages of HIV infection, CTLA-4 expression levels are increased on HIV-specific CD4
+ T
cells, but not on CMV-specific CD4+ T cells from the
same individuals [284-287]. The frequency of CTLA-4+
Tregs is also increased in patients with chronic HIV infection and could play a role in HIV-associated immune dysfunction [288]. Leng et al. found that the proportion of CTLA-4
+ CD8
+ T cells is higher in HIV-
infected patients compared to healthy individuals and is correlated to the numbers of CTLA-4
+ CD4
+ T cells.
However, the number of CTLA-4+ CD8
+ T cells is lower
than the number of CTLA-4+ CD4
+ T cells in both HIV-
infected patients and healthy donors [285] and, in contrast to PD-1, CTLA-4 is not highly expressed on HIV-specific CTL [16]. The HIV-1 regulatory protein Vpr was suggested to play a role in the increased CTLA-4 expression on T cells during HIV infection [253]. CTLA-4 expression is positively correlated with markers of HIV-disease progression and negatively with the capacity of CD4
+ T cells to produce IL-2 in an antigen-
specific fashion [285, 286] and with the proliferation of PBMC in response to HIV-1 antigens [285]. Interestingly, HIV-specific CD4
+ T cells that produce
only IFN- express more CTLA-4 compared to IFN-+
IL-2+ HIV-specific CD4
+ T cells [286]. CTLA-4
expression is low in elite controllers and CTLA-4 expression levels are decreased but maintain elevated in chronically HIV-infected patients with viral loads suppressed by cART, suggesting that the absence of detectable viral load alone is not responsible for the low expression in elite controllers [286-287].
Just as CD28, CD80 and CD86, CTLA-4 can also be incorporated in HIV-1 virions. The infectivity of CD28
+ CTLA-4
+ HIV-1 virus particles is slightly reduced
after addition of an anti-CD28 antibody, but virus
12 Current Molecular Medicine, 2011, Vol. 11, No. 3 De Keersmaecker et al.
attachment is almost completely abolished by treatment with an anti-CTLA-4 antibody [261].
Riley et al. showed that CTLA-4 engagement counteracts the potential antiviral effects of CD28 by preventing the CD28-mediated down-regulation of CCR5 expression [289]. Therefore, the ratio of CTLA-4 to CD28 engagement could determine the susceptibility to HIV-1 infection [289]. This hypothesis is confirmed by the fact that unopposed CTLA-4 signaling due to CD28 blockade promotes vigorous HIV-1 replication [289]. Results from another study show that CTLA-4 can induce TGF- secretion [290], which can result in an increased HIV transcription [291].
Due to the over-expression of CTLA-4 during HIV infection and its immune inhibitory effects, much effort was put in the investigation of the effects of inhibiting B7-CTLA-4 interactions (and concomitant promoting B7-CD28 interactions) during HIV. CTLA-4 blockade could affect Treg function, Treg differentiation and/or co-inhibitory pathways [292]. However, one should take into account that CTLA-4 blockade could also result in autoimmunity.
In vitro blockade of CTLA-4 engagement augments HIV-specific CD4
+ T-cell proliferation and IL-2 and IFN-
production [286]. Depletion of CD25+ T cells does not
abrogate these effects, indicating that Tregs do not play a major role in the CTLA-4 mediated immune suppression observed during HIV infection [286]. In addition, CTLA-4 blockade results in a decrease in HIV-specific TGF-
+ and IL-10
+ CD8
+ T-cell responses,
and a concomitant increase in HIV-specific IFN-+ CD8
+
T-cell responses and this effect is abrogated by CD4+
T-cell depletion. These findings suggest that CTLA-4 signaling in CD4
+ T cells can regulate inhibitory
functions of HIV-specific CD8+ T cells [293].
In primary SIV-infection, CTLA-4 blockade increases T-cell activation and viral replication, particularly at mucosal sites, and paradoxically also increases the tissue expression and activity of IDO, an enzyme induced by the engagement of B7 by CTLA-4. Moreover, CTLA-4 blockade does not restore SIV-specific immune responses [294]. Furthermore, treatment of SIV-infected macaques with a blocking anti-CTLA-4 Ab leads to decreased responsiveness to cART and abrogates the ability of therapeutic T-cell vaccines to decrease the viral set point [294]. A possible mechanism could be that CTLA-4 blockade decreases the threshold for T-cell activation and may therefore provide more target cells to the virus. Thus, the fact that CTLA-4 blockade in SIV-infected macaques does not result in increased immune responses suggests a predominant role for immune activation, and a limited contribution of inhibitory mechanisms to the suppression of immune responses in vivo [294]. However, Hryniewicz et al. investigated the impact of CTLA-4 blockade in SIV-infected macaques treated with cART and found this treatment strategy resulted in a decreased expression of IDO and TGF- in tissues. Furthermore, in this study, CTLA-4 blockade was associated with a trend towards
decreased viral RNA levels in the lymph nodes and towards increased effector functions of CD4
+ and CD8
+
SIV-specific T-cell responses after interruption of cART [295].
To conclude, CD28 and CTLA-4 play a major, but opposite role in the determination of T-cell function. The down-regulation of CD28 is associated with a concomitant up-regulation of CTLA-4 during HIV infection. Enhancement of CD28 signaling and/or blocking of CTLA-4 could therefore be a valuable approach to abrogate HIV-mediated T-cell defects. Furthermore, CTLA-4 blockade has been used in trials for metastatic melanoma without major safety concerns [296]. These resuls may pave the way for more rapid application in HIV. However, since CTLA-4 is preferentially up-regulated on virus-specific CD4
+ T
cells but not CD8+ T cells [286], CTLA-4 blockade
could preferentially expand HIV-specific CD4+ T cells
and could result in an increased CD4+ T-cell activation,
thus providing additional targets for viral infection without improvement of CTL function to dampen this effect [16]. Furthermore, inhibitory pathways, like the CTLA-4 signaling cascade, may attenuate the systemic immune hyper-activation and the ensuing immunopathogenesis [16]. However, the blockade of CTLA-4 could be applicable as a therapeutic tool, during cART treatment.
PD-1/PD-L1 PDL-2
The inhibitory receptor PD-1 (programmed cell death-1, PDCD1, CD279) has been reported to be expressed on CD4
+ and CD8
+ T cells, NK T cells, B
cells, macrophages and monocytes upon activation [282,297-299]. PD-1 expression leads to a cell survival defect in vivo and cross-talk between PD-1 and Fas is suspected since increases in both spontaneous and Fas-mediated apoptosis are found in PD-1
+ HIV-
specific CD8+ T cells [300]. PD-1 is highly expressed
on exhausted T cells during chronic viral infections. High antigen levels that persist for extended periods of time drive this over-expression of PD-1. Blockade of the PD-1-PD-L1 pathway can restore effector functions [301]. However, a potential immune-stimulatory effect of PD-L1 has also been suggested under certain experimental conditions [302, 303]. Similar to other CD28 family members, PD-1 transduces a signal when engaged in combination with TCR ligation, but does not transduce a signal when cross-linked alone [242].
PD-L1 (B7-H1, CD274) is constitutively expressed on B cells, DCs, macrophages and T cells and is further up-regulated upon activation or IFN- treatment [242,282,304]. PD-1 has a second ligand, PD-L2 (B7-DC, CD273), which is mainly expressed on macrophages and DCs, has a higher affinity for PD-1 compared to PD-L1 and can be induced by IL-4 [282]. PD-L2 is inducibly expressed on DCs and macrophages [242].
Since PD-1 is expressed on B cells and macrophages and PD-L1 is expressed on T cells, bidirectional and reverse signaling is possible [242].
HIV and Costimulation Current Molecular Medicine, 2011, Vol. 11, No. 3 13
PD-1 expression is up-regulated in HIV-infected patients, mainly on early/intermediate differentiated (CCR7
- CD27
+) HIV-specific CD8
+ T-cell subsets [305,
306], but is down-regulated during later stages of differentiation [306]. The Nef protein was shown to up-regulate PD-1 through a p38 MAPK-dependent mechanism during infection in vitro [307]. The increased PD-1 expression correlates with impaired HIV-specific CD8
+ T-cell cytokine production and
proliferation [305,308]. There is an inverse correlation between the number of HIV-specific functional (proliferating, perforin
+, TNF-
+ and/or IL-2
+) CD8
+ T
cells and the level of PD-1 expression [305,308] and a positive correlation between the sensitivity of virus-specific CD8
+ T cells to apoptosis and PD-1 expression
[300]. Long-term non progressive (LTNP) HIV-patients exhibit HIV-specific memory CD8
+ T cells with
markedly lower PD-1 expression compared to typical progressors [309]. However, since PD-1 expression on HIV-specific CD8
+ T cells of LTNPs is still higher
compared to bulk CD8+ T cells in these patients,
Salisch et al. proposed that PD-1 can be used as an indicator of low-level HIV-replication, rather than as a marker of T-cell exhaustion [310]. In HIV-infected patients, HLA-A restricted epitopes are mostly recognized by CD8
+ T cells that are unable to produce
IL-2 and do not proliferate in response to antigen. These dysfunctional CD8
+ T cells express higher levels
of PD-1 compared to HLA-B restricted polyfunctional CD8
+ T-cell populations. Moreover, a significant
negative correlation between the proportion of HIV-specific IL-2 secreting CD8
+ T cells and PD-1
expression levels was detected [311]. Advanced HIV disease is characterized by an increased number of HIV-specific IL-10
+ CD8
+ T cells. Interestingly, the level
of PD-1 expression on HIV-specific effector CD8+ T
cells is significantly increased in the presence of these IL-10
+ suppressor CD8
+ T cells. However, blocking of
PD-1 does not prevent suppression by the IL-10+ CD8
+
T cells [312]. The cellular mechanisms by which PD-1 ligation results in T-cell inhibition are not fully understood, but it has recently been reported that PD-1 ligation leads to an up-regulated expression of basic leucine transcription factor (BATF), a transcription factor of the AP-1 family, in exhausted CD8
+ T cells.
Enforced BATF expression results in impaired T-cell proliferation and cytokine secretion, whereas silencing BATF in T cells from individuals with chronic viremia rescues HIV-specific T-cell function [313].
PD-1 expression is also significantly higher on HIV-specific CD4
+ T cells compared with total or CMV-
specific CD4+ T cells in untreated HIV-infected subjects
[287,308,314]. The expression of PD-1 is higher on HIV-specific CD4
+ T cells than on CD8
+ T cells and
there is a strong positive correlation between PD-1 expression on CD4
+ and CD8
+ T cells in HIV-infected
patients [314]. Interestingly, PD-1+ CD4
+ T cells are
preferentially infected by HIV-1, probably due to their activation status. However, CD4
+ T cells that get
productively infected with the HIV virus lose PD-1 expression. These infected CD4
+ T cells are less
susceptible to apoptosis compared to uninfected CD4+
T cells in the same infected milieu. The loss of PD-1 expression in infected CD4
+ T cells is regulated by the
HIV-1 virus at the transcriptional level. Thus, the up-regulated PD-1 expression on effector CD4
+ T cells
enhances their sensitivity to apoptosis while its down-regulation on infected CD4
+ T cells results in protection
against apoptosis, thereby assisting virus production and dissemination [315]. When HIV-replication is suppressed under cART therapy, PD-1 expression on HIV-specific CD4
+ and CD8
+ T cells decreases and
there is a correlation between PD-1 expression on HIV-specific CD4
+ and CD8
+ T cells and plasma viral load,
and thus antigenemia, and CD4+ T-cell counts
[251,287,305,308,314]. Interestingly, the expression of PD-1 is significantly lower on HIV-specific CD4
+ and
CD8+ T cells in the blood compared with those in the
lymph nodes and the gut associated lymphoid tissue (GALT), the main sites of HIV replication [314,316].
PD-1 over-expression is not limited to T cells during HIV infection. Said et al. observed that the high amounts of microbial products and inflammatory cytokines in the plasma of HIV-infected individuals lead to an up-regulation of PD-1 expression on monocytes, which correlates with high plasma concentrations of IL-10 and decreased CD4
+ T-cell proliferation and
cytokine production during HIV infection [317]. The PD-1 expression is higher in monocyte subsets of untreated HIV-infected subjects compared to cART-treated HIV-infected patients [317]. Upon ligation with PD-L1, but not with PD-L2, PD-1
+ monocytes were
triggered to produce IL-10 [317]. HIV-specific CD4+ T
cells express elevated amounts of PD-L1 and are thus more prone to trigger IL-10 production in PD-1
+
monocytes [317]. HIV-1 infection is also associated with an elevated expression of PD-1 on the CD4
-
subset of NKT cells. However, functional defects observed in NKT cells from HIV-infected patients are largely PD-1 independent. The elevated PD-1 expression on the NKT cells is not restored by cART [318].
During HIV infection, PD-L1 expression is increased on mDCs, monocytes, B cells and CD4
+ and CD8
+ T
cells. This higher PD-L1 expression is associated with an increased production of IL-10 and correlates directly with plasma viral load and inversely with CD4
+ T-cell
counts [319-320]. PD-L1+ mDCs are associated with
disease progression and are maintained at a relatively low level in LTNP [321]. However, PD-L1 expression on mDCs is decreased upon successful immune reconstitution after cART treatment [321]. Reverse signaling through ligation of PD-L1 with soluble PD-1 reduces maturation of, and IL-12 production by mDCs and results in increased mDC apoptosis and IL-10 production [321]. Monocytes and CCR5
+ T cells from
HIV-uninfected persons up-regulate PD-L1, but not PD-L2, upon in vitro exposure to HIV, through a mechanism involving IFN- [322]. Another mechanism for the increased expression of PD-L1 during HIV infection could be the presence of HIV-derived TLR 7/8 ligands [323]. CD14
14 Current Molecular Medicine, 2011, Vol. 11, No. 3 De Keersmaecker et al.
node express PD-L1 and PD-L2 at higher levels than those in the blood, suggesting that the PD-1 pathway is more active in the lymph node [314].
Since the similarities between PD-1 and CTLA-4 function and the promising results obtained by blocking CTLA-4 signaling, similar approaches have been tested for the PD-1/PD-L1 pathway. Indeed, blockade of the PD-1 pathway enhances HIV-specific CD4
+ and CD8
+
T-cell responses, resulting in increased cytokine production, elevated numbers of granzyme B
+ CD8
+ T
cells and enhanced T-cell proliferation [305, 308, 309, 314]. Moreover, the increased PD-1-mediated IL-10 production in monocytes from untreated HIV-infected patients is inhibited by the addition of an antibody to PD-L1 [317]. Thus, PD-1 blockade can influence T-cell functionality and IL-10 production by monocytes, but furthermore, it can influence the CD8
+ T-cell cycle; it is
known that an increase in both telomere length and telomerase activity of antigen-specific CD8
+ T cells is
associated with control of HIV-1 infection. Telomere length and telomerase activity are both increased in HIV-progressors by exposing antigen-stimulated T cells to antibodies that block the PD-1/PD-L1 pathway. In this way, blockade of the PD-1 pathway fundamentally alters the life expectancy and the ability of HIV-specific CD8
+ T-cell clones to persist, self-renew and expand
during the course of infection [324]. In addition, in vitro blockade of PD-L1 enhances the allo-stimulatory capacity of mDCs and results in an increased IL-12 production [321].
Velu et al. reported the first in vivo study showing an enhancement of SIV-specific immune responses through PD-1 blockade using an anti-PD-1 antibody in a macaque model. Their results show an expansion of virus-specific, polyfunctional CD8
+ T cells, both in the
peripheral blood and in the GALT. Furthermore, PD-1 blockade also resulted in an increase in virus-specific CD4
+ T cells and memory B cells and elevated
numbers of envelope-specific Ab. These enhanced immunologic responses correspond with reduced plasma viral load and prolonged survival. No evidence of autoimmune disease was observed [325].
When blocking PD-1/PD-L1 interactions, one should consider the effect of the blockade on Tregs [326]. PD-L1 negatively regulates Treg proliferation in persons chronically infected with HCV [327]. Therefore, it remains possible that blockade of PD-1 will not only increase anti-viral function of CD8
+ T cells, but may
also enhance the function of antigen-specific Tregs, which can suppress the antiviral response [326]. On the other hand, a risk of PD-1 blockade is the induction of unwanted autoimmunity by over-enhancement of T effector activity. However, if PD-1 blockade also enhances the function of Tregs, this may counter effector T-cell responses and help to achieve an effective antiviral response [328].
CD8+ T-cell exhaustion is mediated by multiple
inhibitory receptors. Therefore, it is not clear whether blockade of either PD-1 or CTLA-4 will be enough to reverse T-cell exhaustion [326]. Apart from PD-1 and
CTLA-4, TIM-3 and LAG-3 have also been shown to inhibit T-cell function. The expression of the glycoprotein TIM-3 was shown to be increased in HIV-infected individuals. Levels of TIM-3 expression on T cells from HIV-infected individuals correlate positively with HIV-1 viral load and inversely with CD4
+ T-cell
counts. During progressive HIV infection, TIM-3 expression is up-regulated on HIV-specific CD8
+ T
cells, which fail to produce cytokines or to proliferate. Blockade of the TIM-3 pathway can restore HIV-specific T-cell functionality [329]. Jin et al. found that co-expression of TIM-3 and PD-1 is associated with more severe CD8
+ T-cell exhaustion in terms of
proliferation and secretion of effector cytokines (IFN- , TNF- and IL-2). Furthermore, CD8
+ T cells expressing
both inhibitory receptors also produce the suppressive cytokine IL-10. Combined blockade of TIM-3 and PD-1 synergistically improved CD8
+ T-cell responses and
viral control in vivo in mice during chronic lymphocytic choriomeningitis virus (LCMV) infection [330]. Kaufmann et al. found that most HIV-specific CD4
+ T
cells from patients with progressive disease co-express CTLA-4 and PD-1, whereas individual HIV-specific CD4
+ T cells from elite controllers have more
heterogeneous patterns of PD-1 and CTLA-4 expression [286]. Furthermore, Kassu et al. reported that more than 30% of the HIV-specific CD4
+ T cells
from untreated subjects co-express PD-1, CTLA-4 and Tim-3, whereas <2% of CMV-specific CD4
+ T cells
express all three receptors. The simultaneous expression of these three inhibitory markers on HIV-specific CD4
+ T cells correlates more strongly with
plasma HIV viral load than the individual expression of these molecules [287] and there is a significant positive correlation between the expression of PD-1 and CTLA-4 on HIV-specific IFN- producing CD4
+ T cells [287].
The over-expression of PD-1 and PD-L1 during HIV infection and the associated T-cell anergy prompted scientists to investigate the effects of blocking this pathway. Blockade of the PD-1/PD-L1 interaction has beneficial effects on CD8
+ T-effector functions and
monocytes. However, the role of PD-L2 during HIV infection remains a subject for further investigation.
ICOS/ICOSL
Inducible costimulator (ICOS) transmits positive signals following interactions with its ligand (ICOSL, B7RP1). ICOS expression peaks during early stages of HIV-1 infection, drops in the asyptomatic phase and increases as AIDS develops [331]. HIV-1 gp120 induces transient ICOS expression in naïve T cells [331].
Ligation of ICOS suppresses the early stages of both X4 and R5 HIV-1 replication in PHA-stimulated CD4
+ T cells. ICOS stimulation may render uninfected
T cells resistant to HIV-1 replication and suppresses HIV-1 expression in persistently infected cells, be it in a less efficient manner [276].
The costimulatory effects of ICOS ligation and its suppressive effects on HIV-1 replication indicate a
HIV and Costimulation Current Molecular Medicine, 2011, Vol. 11, No. 3 15
potential beneficial effect of targeting this costimulatory pathway during HIV infection. However, the number of studies investigating ICOS/ICOSL during HIV infection remains very limited.
COMBINING COSTIMULATORY/INHIBITORY MOLECULES AS A THERAPEUTIC TOOL
Since triggering or blocking of costimulatory and co-inhibitory molecules like 4-1BB, CD28 or PD-1 can result in potent enhancement of HIV-specific CD4
+
and/or CD8+ T-cell responses, simultaneous
stimulation or blockade of those molecules could provide even stronger immune responses. For example, dual costimulation by OX40L in combination with 4-1BBL leads to improved expansion and effector function in CTL compared to costimulation with either of the individual molecules [93]. RANKL may enhance the effect of CD40L on CTL responses in some HIV-infected patients by increasing the survival of CD40L-stimulated DCs [186]. Wang et al. made use of monocytes infected with adenovirus encoding for costimulatory molecules to show that 4-1BBL combined with CD70 leads to enhanced CD8
+ T-cell responses
compared to stimulation with 4-1BBL alone. Over-expression of 4-1BBL in combination with CD70 resulted in a population of HIV-specific T cells exhibiting key features of functional restoration [15]. Using a similar approach, Bukczynski et al. showed that dual costimulation with 4-1BBL and CD80 results an enhancement of T-cell responses in long-term HIV-infected patients to a similar level of the responses obtained with T cells from patients early in HIV infection [123]. However, in cultures from early HIV-infected patients, additive effects of dual (4-1BBL and CD80) costimulation are observed for cytokine secretion while cultures form most chronic HIV-infected patients accumulate minimal amounts of cytokines, even in the presence of both 4-1BBL and CD80 costimulation [123]. We found that a combination of 4-1BBL and CD40L stimulation leads to synergistic increase in HIV-specific T-cell responses [our unpublished data]. Although several combinations of costimulatory molecules result in additive or synergistic enhancement of HIV-specific T-cell responses, some combinations do not provide additional benefit: OX40L combined with CD40L was not superior to OX40L alone in helping a HIV canarypox vaccine-induced CD8 T-cell responses in mice [92]. Gag DNA vaccination with both GITRL- and CD40L-encoding plasmids elicits fewer CD8
+ T-cell
responses compared to CD40L alone in mice [207].
There is a direct correlation between increased HIV-specific CD4
+ T-cell proliferation after blockade of PD-
L1 and that after blockade of CTLA-4. Intriguingly, there is heterogeneity in responses, with subjects responding to blockade of both CTLA-4 and PD-L1, to blockade of either molecules or to none [286].
Kassu et al. demonstrated that a high percentage of HIV-specific CD4
+ T cells that express PD-1, CTLA-4
or TIM-3 also co-express CD28, whereas co-expression of these 4 molecules on CMV-specific CD4
+
T cells is not remarkable. A combination of in vitro blockade of PD-1 together with costimulation through CD28 increases HIV-specific CD4
+ T-cell proliferation
in a synergistic way [287].
In the absence of CD28, ICOS can cooperate with 4-1BB to allow influenza-specific CD8
+ T-cell
expansion in a mouse model [332]. Given the increased frequency of CD28
- T cells in HIV-infected
patients, ICOS-L and 4-1BBL could be a good costimulation duet to include in therapeutic anti-HIV vaccines [333].
CONCLUDING REMARKS
It is clear that several costimulatory and co-inhibitory pathways are disrupted or over-active during HIV infection. Furthermore, an enhancement and/or blockade of signaling through costimulatory and/or co-inhibitory molecules could be a powerful method to enhance anti-HIV responses. However, we should keep in mind that most of the costimulatory and co-inhibitory receptor/ligand pairs can signal in a bidirectional way and that the timing, context, intensity and target cell type of costimulatory signals may determine the functional consequence of their activity [73]. For example, HVEM and CD27 play an important role in the early phase of the T-cell response, next to CD28, while OX40 and 4-1BB play a role in later stages of the responses [73]. Furthermore, interfering with costimulatory/co-inhibitory interactions may cause auto-immunity or immune dysregulation and pathology in conditions of chronic immune activation, as observed during HIV infection [73]. Unexpected results could be obtained; for instance, strong costimulation can lead to the production of cytokines at levels sufficient to limit immune responses, as described for costimulation provided through 4-1BB and CD27 [123,334-336]. More localized rather than systemic delivery of agonistic antibodies or costimulatory ligands may be beneficial and treatment with costimulatory ligands may be the safest alternative compared to agonistic antibodies [337]. Furthermore, stimulation or blocking of certain pathways may lead to an activation and increased proliferation of the CD4
+ T-cell pool, which
could result in an enhanced HIV expression. On the other hand, under certain conditions, costimulation could result in reactivation of latent HIV infection, which could be a promising subject for further research.
When translating results obtained with mouse models, one should be aware that there are differences in the expression patterns of certain costimulatory/co-inhibitory molecules in mice and humans. For example, human, but not murine, B cells express 4-1BB following antigen encounter [118]. Moreover, as summarized in this review, the expression patterns of costimulatory/co-inhibitory receptor/ligand pairs is different in HIV-infected patients compared to those observed in healthy individuals. Therefore, mouse models may not be ideal to study effects of costimulation during HIV infection. In addition, several examples of conflicting results are mentioned in this
16 Current Molecular Medicine, 2011, Vol. 11, No. 3 De Keersmaecker et al.
review. Explanations for opposite observations can be bidirectional signaling and the potential existence of until now unknow costimulatory/co-inhibitory receptors and/or ligands.
One should take into account that costimulatory pathways may not only influence APCs and effector T cells, but may also have an effect on regulatory T cells. Tregs could exert opposite effects during HIV infection: they may limit viral replication by decreasing immune activation or they may increase viral replication by suppressing virus-specific immune responses [288,338-340]. Several costimulatory receptors, including GITR, OX40 and 4-1BB, are expressed by Tregs. However, the effects of manipulating those receptors in order to modulate Treg-mediated inhibition of immune responses have not yet been investigated in a HIV setting. This may be an interesting avenue for future research.
ACKNOWLEDGEMENTS
This work was supported by the DC-THERA network, by the Cancer Immunology and Immunotherapy Research Project (EU254) and by the Institute for Science and Technology (IWT, IWT-TBM 60511 project) and by the University Research Fund (OZR1801). JLA is a postdoctoral fellow of the FWO (Fund for Scientific Research Flanders).
ABBREVIATIONS
Ab = antibody
AIDS-NHL = AIDS-associated non-Hodgkin’s lymphoma
APC = antigen-presenting cell
BATF = basic leucine zipper transcription factor
cART = combined antiretroviral therapy
CRD1 = cysteine-rich domain 1
CTL = cytotoxic T cell
DC = dendritic cell
DcR = decoy receptor
DD = death domain
GALT = gut associated lymphoid tissue
GITR = glucocorticoid-induced TNFRSF-related protein
REFERENCES [1] Bretscher P, Cohn M. A theory of self-nonself discrimination.
Science 1970; 169(950): 1042-9.
[2] Curtsinger J, Mescher M. Inflammatory cytokines as a third signal for T cell activation. Curr Opin Immunol 2010; 22(3): 333-40.
[3] Jenkins M, Chen C, Jung G, Mueller D, Schwartz R. Inhibition of antigen-specific proliferation of type 1 murine T cell clones after stimulation with immobilized anti-CD3
monoclonal antibody. J Immunol 1990; 144(1): 16-22. [4] Gravestein L, Borst J. Tumor necrosis factor receptor family
members in the immune system. Semin Immunol 1998;
10(6): 423-34. [5] Screaton G, Xu X. T cell life and death signalling via TNF-
receptor family members. Curr Opin Immunol 2000; 12(3):
316-22. [6] Croft M. The role of TNF superfamily members in T-cell
function and diseases. Nat Rev Immunol 2009; 9(4): 271-85.
[7] Sharpe A, Freeman G. The B7-CD28 superfamily. Nat Rev Immunol 2002; 2(2): 116-26.
[8] Linsley P, Brady W, Urnes M, Grosmaire L, Damle N,
Ledbetter J. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 1991; 174(3): 561-9.
[9] Waterhouse P, Penninger J, Timms E, Wakeham A,
Shahinian A, Lee K, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 1995; 270(5238): 985-8.
[10] Nurieva R, Liu X, Dong C. Yin-Yang of costimulation: crucial controls of immune tolerance and function. Immunol Rev 2009; 229(1): 88-100.
[11] Pentcheva-Hoang T, Corse E, Allison J. Negative regulators of T-cell activation: potential targets for therapeutic intervention in cancer, autoimmune disease, and persistent
infections. Immunol Rev 2009; 229(1): 67-87. [12] Orabona C, Grohmann U, Belladonna M, Fallarino F, Vacca
C, Bianchi R, et al. CD28 induces immunostimulatory signals
in dendritic cells via CD80 and CD86. Nat Immunol 2004; 5(11): 1134-42.
[13] Kuipers H, Muskens F, Willart M, et al. Contribution of the
PD-1 ligands/PD-1 signaling pathway to dendritic cell-mediated CD4+ T cell activation. Eur J Immunol 2006; 36(9): 2472-82.
[14] Grohmann U, Volpi C, Fallarino F, et al. Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nat Med 2007; 13(5): 579-86.
[15] Wang C, Wen T, Routy J, Bernard N, Sekaly R, Watts T. 4-1BBL induces TNF receptor-associated factor 1-dependent Bim modulation in human T cells and is a critical component
in the costimulation-dependent rescue of functionally impaired HIV-specific CD8 T cells. J Immunol 2007; 179(12): 8252-63.
[16] Kaufmann D, Walker B. PD-1 and CTLA-4 inhibitory cosignaling pathways in HIV infection and the potential for therapeutic intervention. J Immunol 2009; 182(10): 5891-7.
HIV and Costimulation Current Molecular Medicine, 2011, Vol. 11, No. 3 17
[17] Appay V, Sauce D. Immune activation and inflammation in
HIV-1 infection: causes and consequences. J Pathol 2008; 214(2): 231-41.
[18] Xu X, Screaton G, Gotch F, et al. Evasion of cytotoxic T
lymphocyte (CTL) responses by nef-dependent induction of Fas ligand (CD95L) expression on simian immunodeficiency virus-infected cells. J Exp Med 1997; 186(1): 7-16.
[19] Badley A, Pilon A, Landay A, Lynch D. Mechanisms of HIV-associated lymphocyte apoptosis. Blood 2000; 96(9): 2951-64.
[20] Yang Y, Tikhonov I, Ruckwardt T, et al. Monocytes treated with human immunodeficiency virus Tat kill uninfected CD4(+) cells by a tumor necrosis factor-related apoptosis-
[22] Katsikis P, Wunderlich E, Smith C, Herzenberg L. Fas
antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virus-infected individuals. J Exp Med 1995; 181(6): 2029-36.
[23] Strauss G, Lindquist J, Arhel N, et al. CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling. J Exp Med 2009; 206(6): 1379-93.
[24] Lu G, Janjic B, Janjic J, Whiteside T, Storkus W, Vujanovic N. Innate direct anticancer effector function of human immature dendritic cells. II. Role of TNF, lymphotoxin-alpha(1)beta(2), Fas ligand, and TNF-related apoptosis-
inducing ligand. J Immunol 2002; 168(4): 1831-9. [25] Trambas C, Griffiths G. Delivering the kiss of death. Nat
Immunol 2003; 4(5): 399-403.
[26] Schulte M, Reiss K, Lettau M, et al. ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death. Cell Death
Differ 2007; 14(5): 1040-9. [27] Sousa A, Chaves A, Doroana M, Antunes F, Victorino R.
Early reduction of the over-expression of CD40L, OX40 and
Fas on T cells in HIV-1 infection during triple anti-retroviral therapy: possible implications for lymphocyte traffic and functional recovery. Clin Exp Immunol 1999; 116(2): 307-15.
[28] Meyaard L, Otto S, Jonker R, Mijnster M, Keet R, Miedema F. Programmed death of T cells in HIV-1 infection. Science 1992; 257(5067): 217-9.
[29] Boise L, Thompson C. Hierarchical control of lymphocyte survival. Science 1996; 274(5284): 67-8.
[30] Giri M, Nebozyhn M, Raymond A, et al. Circulating
monocytes in HIV-1-infected viremic subjects exhibit an antiapoptosis gene signature and virus- and host-mediated apoptosis resistance. J Immunol 2009; 182(7): 4459-70.
[31] Badley A, Dockrell D, Algeciras A, et al. In vivo analysis of Fas/FasL interactions in HIV-infected patients. J Clin Invest 1998; 102(1): 79-87.
[32] Dyrhol-Riise A, Stent G, Røsok B, Voltersvik P, Olofsson J, Asjö B. The Fas/FasL system and T cell apoptosis in HIV-1-infected lymphoid tissue during highly active antiretroviral
therapy. Clin Immunol 2001; 101(2): 169-79. [33] Gasper-Smith N, Crossman D, Whitesides J, et al. Induction
of plasma (TRAIL), TNFR-2, Fas ligand, and plasma
microparticles after human immunodeficiency virus type 1 (HIV-1) transmission: implications for HIV-1 vaccine design. J Virol 2008; 82(15): 7700-10.
[34] Quaranta M, Mattioli B, Giordani L, Viora M. HIV-1 Nef equips dendritic cells to reduce survival and function of CD8+ T cells: a mechanism of immune evasion. FASEB J 2004;
18(12): 1459-61. [35] Mitra D, Steiner M, Lynch D, Staiano-Coico L, Laurence J.
HIV-1 upregulates Fas ligand expression in CD4+ T cells in
vitro and in vivo: association with Fas-mediated apoptosis and modulation by aurintricarboxylic acid. Immunology 1996; 87(4): 581-5.
[36] Westendorp M, Frank R, Ochsenbauer C, et al. Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature 1995; 375(6531): 497-500.
[37] Xu X, Laffert B, Screaton G, et al. Induction of Fas ligand
expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J Exp Med 1999; 189(9): 1489-96.
[38] Herbeuval J, Nilsson J, Boasso A, et al. HAART reduces
death ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infected macaques. AIDS 2009; 23(1): 35-40.
[39] Badley A, Dockrell D, Simpson M, et al. Macrophage-dependent apoptosis of CD4+ T lymphocytes from HIV-infected individuals is mediated by FasL and tumor necrosis
factor. J Exp Med 1997; 185(1): 55-64. [40] Oyaizu N, Adachi Y, Hashimoto F, et al. Monocytes express
Fas ligand upon CD4 cross-linking and induce CD4+ T cells
apoptosis: a possible mechanism of bystander cell death in HIV infection. J Immunol 1997; 158(5): 2456-63.
[41] De Milito A, Mörch C, Sönnerborg A, Chiodi F. Loss of
memory (CD27) B lymphocytes in HIV-1 infection. AIDS 2001; 15(8): 957-64.
[42] Moir S, Malaspina A, Pickeral O, et al. Decreased survival of
B cells of HIV-viremic patients mediated by altered expression of receptors of the TNF superfamily. J Exp Med 2004; 200(7): 587-99.
[43] Estaquier J, Idziorek T, Zou W, et al. T helper type 1/T helper type 2 cytokines and T cell death: preventive effect of interleukin 12 on activation-induced and CD95 (FAS/APO-1)-
mediated apoptosis of CD4+ T cells from human immunodeficiency virus-infected persons. J Exp Med 1995; 182(6): 1759-67.
[44] Salvato M, Yin C, Yagita H, et al. Attenuated disease in SIV-
infected macaques treated with a monoclonal antibody against FasL. Clin Dev Immunol 2007; 2007: 93462.
C. Treatment with anti-FasL antibody preserves memory lymphocytes and virus-specific cellular immunity in macaques challenged with simian immunodeficiency virus.
Blood 2009; 114(6): 1196-204. [46] Sheridan J, Marsters S, Pitti R, et al. Control of TRAIL-
induced apoptosis by a family of signaling and decoy
[49] Stary G, Klein I, Kohlhofer S, et al. Plasmacytoid dendritic
cells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patients. Blood 2009; 114(18): 3854-63.
[50] Herbeuval J, Hardy A, Boasso A, et al. Regulation of TNF-
related apoptosis-inducing ligand on primary CD4+ T cells by HIV-1: role of type I IFN-producing plasmacytoid dendritic cells. Proc Natl Acad Sci USA 2005; 102(39): 13974-9.
[51] Fitzgerald-Bocarsly P, Jacobs E. Plasmacytoid dendritic cells in HIV infection: striking a delicate balance. J Leukoc Biol 2010; 87(4): 609-20.
[52] Chaperot L, Blum A, Manches O, et al. Virus or TLR agonists induce TRAIL-mediated cytotoxic activity of plasmacytoid dendritic cells. J Immunol 2006; 176(1): 248-55.
[53] Lichtner M, Marañón C, Vidalain P, et al. HIV type 1-infected dendritic cells induce apoptotic death in infected and uninfected primary CD4 T lymphocytes. AIDS Res Hum
Retroviruses 2004; 20(2): 175-82. [54] Miura Y, Misawa N, Maeda N, et al. Critical contribution of
(TRAIL) to apoptosis of human CD4+ T cells in HIV-1-infected hu-PBL-NOD-SCID mice. J Exp Med 2001; 193(5): 651-60.
[55] Gravestein L, Amsen D, Boes M, Calvo C, Kruisbeek A, Borst J. The TNF receptor family member CD27 signals to Jun N-terminal kinase via Traf-2. Eur J Immunol 1998; 28(7):
Atsuta M, et al. CD27, a member of the tumor necrosis factor
18 Current Molecular Medicine, 2011, Vol. 11, No. 3 De Keersmaecker et al.
receptor superfamily, activates NF-kappaB and stress-
activated protein kinase/c-Jun N-terminal kinase via TRAF2, TRAF5, and NF-kappaB-inducing kinase. J Biol Chem 1998; 273(21): 13353-8.
[57] de Jong R, Loenen W, Brouwer M, et al. Regulation of expression of CD27, a T cell-specific member of a novel family of membrane receptors. J Immunol 1991; 146(8):
2488-94. [58] Bowman M, Crimmins M, Yetz-Aldape J, Kriz R, Kelleher K,
Herrmann S. The cloning of CD70 and its identification as the
ligand for CD27. J Immunol 1994; 152(4): 756-61. [59] Tesselaar K, Gravestein L, van Schijndel G, Borst J, van Lier
R. Characterization of murine CD70, the ligand of the TNF
receptor family member CD27. J Immunol 1997; 159(10): 4959-65.
[60] Ramakrishnan P, Wang W, Wallach D. Receptor-specific
signaling for both the alternative and the canonical NF-kappaB activation pathways by NF-kappaB-inducing kinase. Immunity 2004; 21(4): 477-89.
[61] van Oosterwijk M, Juwana H, Arens R, et al. CD27-CD70 interactions sensitise naive CD4+ T cells for IL-12-induced Th1 cell development. Int Immunol 2007; 19(6): 713-8.
[62] Widney D, Gundapp G, Said J, et al. Aberrant expression of CD27 and soluble CD27 (sCD27) in HIV infection and in AIDS-associated lymphoma. Clin Immunol 1999; 93(2): 114-
23. [63] De Milito A, Aleman S, Marenzi R, et al. Plasma levels of
soluble CD27: a simple marker to monitor immune activation during potent antiretroviral therapy in HIV-1-infected
subjects. Clin Exp Immunol 2002; 127(3): 486-94. [64] Kornbluth R. An expanding role for CD40L and other tumor
necrosis factor superfamily ligands in HIV infection. J
Hematother Stem Cell Res 2002; 11(5): 787-801. [65] Wolthers K, Otto S, Lens S, et al. Increased expression of
CD80, CD86 and CD70 on T cells from HIV-infected
individuals upon activation in vitro: regulation by CD4+ T cells. Eur J Immunol 1996; 26(8): 1700-6.
[66] Appay V, Nixon D, Donahoe S, Gillespie G, Dong T, King A,
et al. HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J Exp Med 2000; 192(1): 63-75.
[67] van Baarle D, Kostense S, Hovenkamp E, et al. Lack of Epstein-Barr virus- and HIV-specific CD27- CD8+ T cells is associated with progression to viral disease in HIV-infection.
AIDS 2002; 16(15): 2001-11. [68] Kalams S, Walker B. The critical need for CD4 help in
maintaining effective cytotoxic T lymphocyte responses. J
Exp Med 1998; 188(12): 2199-204. [69] Ochsenbein A, Riddell S, Brown M, et al. CD27 expression
promotes long-term survival of functional effector-memory
CD8+ cytotoxic T lymphocytes in HIV-infected patients. J Exp Med 2004; 200(11): 1407-17.
[70] Wu J, Dyer W, Chrisp J, Belov L, Wang B, Saksena N.
Longitudinal microarray analysis of cell surface antigens on peripheral blood mononuclear cells from HIV+ individuals on highly active antiretroviral therapy. Retrovirology 2008; 5: 24.
[71] Luciano A, Lederman M, Valentin-Torres A, Bazdar D, Sieg S. Impaired induction of CD27 and CD28 predicts naive CD4 T cell proliferation defects in HIV disease. J Immunol 2007;
179(6): 3543-9. [72] Nagase H, Agematsu K, Kitano K, T et al. Mechanism of
hypergammaglobulinemia by HIV infection: circulating
memory B-cell reduction with plasmacytosis. Clin Immunol 2001; 100(2): 250-9.
[73] Nolte M, van Olffen R, van Gisbergen K, van Lier R. Timing
and tuning of CD27-CD70 interactions: the impact of signal strength in setting the balance between adaptive responses and immunopathology. Immunol Rev 2009; 229(1): 216-31.
[74] Titanji K, Sammicheli S, De Milito A, et al. Altered distribution of natural killer cell subsets identified by CD56, CD27 and CD70 in primary and chronic human immunodeficiency virus-
1 infection. Immunology 2008; 123(2): 164-70.
[75] Croft M, So T, Duan W, Soroosh P. The significance of OX40
and OX40L to T-cell biology and immune disease. Immunol Rev 2009; 229(1): 173-91.
[76] Godfrey W, Fagnoni F, Harara M, Buck D, Engleman E.
Identification of a human OX-40 ligand, a costimulator of CD4+ T cells with homology to tumor necrosis factor. J Exp Med 1994; 180(2): 757-62.
[77] Flynn S, Toellner K, Raykundalia C, Goodall M, Lane P. CD4 T cell cytokine differentiation: the B cell activation molecule, OX40 ligand, instructs CD4 T cells to express interleukin 4
and upregulates expression of the chemokine receptor, Blr-1. J Exp Med 1998; 188(2): 297-304.
[78] Ito T, Amakawa R, Inaba M, et al. Plasmacytoid dendritic
cells regulate Th cell responses through OX40 ligand and type I IFNs. J Immunol 2004; 172(7): 4253-9.
[79] Burrell B, Lu G, Li X, Bishop D. OX40 costimulation prevents
[80] Bansal-Pakala P, Halteman B, Cheng M, Croft M.
Costimulation of CD8 T cell responses by OX40. J Immunol 2004; 172(8): 4821-5.
[81] Hendriks J, Xiao Y, Rossen J, et al. During viral infection of
the respiratory tract, CD27, 4-1BB, and OX40 collectively determine formation of CD8+ memory T cells and their capacity for secondary expansion. J Immunol 2005; 175(3):
1665-76. [82] Song A, Tang X, Harms K, Croft M. OX40 and Bcl-xL
promote the persistence of CD8 T cells to recall tumor-associated antigen. J Immunol 2005; 175(6): 3534-41.
[83] Nagar M, Jacob-Hirsch J, Vernitsky H, et al. TNF Activates a NF-{kappa}B-Regulated Cellular Program in Human CD45RA- Regulatory T Cells that Modulates Their
Suppressive Function. J Immunol 2010; 184(7): 3570-81. [84] Valzasina B, Guiducci C, Dislich H, Killeen N, Weinberg A,
Colombo M. Triggering of OX40 (CD134) on CD4(+)CD25+ T
cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR. Blood 2005; 105(7): 2845-51.
[85] Brocker T, Gulbranson-Judge A, Flynn S, Riedinger M, Raykundalia C, Lane P. CD4 T cell traffic control: in vivo evidence that ligation of OX40 on CD4 T cells by OX40-
ligand expressed on dendritic cells leads to the accumulation of CD4 T cells in B follicles. Eur J Immunol 1999; 29(5): 1610-6.
[86] Stüber E, Neurath M, Calderhead D, Fell H, Strober W. Cross-linking of OX40 ligand, a member of the TNF/NGF cytokine family, induces proliferation and differentiation in
murine splenic B cells. Immunity 1995; 2(5): 507-21. [87] Kondo K, Okuma K, Tanaka R, et al. Requirements for the
functional expression of OX40 ligand on human activated
CD4+ and CD8+ T cells. Hum Immunol 2007; 68(7): 563-71. [88] Stüber E, Strober W. The T cell-B cell interaction via OX40-
OX40L is necessary for the T cell-dependent humoral
immune response. J Exp Med 1996; 183(3): 979-89. [89] Yu Q, Yue F, Gu X, Schwartz H, Kovacs C, Ostrowski M.
OX40 ligation of CD4+ T cells enhances virus-specific CD8+
T cell memory responses independently of IL-2 and CD4+ T regulatory cell inhibition. J Immunol 2006; 176(4): 2486-95.
CD40 ligand dysregulation in HIV infection: HIV glycoprotein 120 inhibits signaling cascades upstream of CD40 ligand transcription. J Immunol 2004; 172(4): 2678-86.
[91] Kassu A, D'Souza M, O'Connor B, et al. Decreased 4-1BB expression on HIV-specific CD4+ T cells is associated with sustained viral replication and reduced IL-2 production. Clin
Immunol 2009; 132(2): 234-45. [92] Liu J, Ngai N, Stone G, Yue F, Ostrowski M. The adjuvancy
of OX40 ligand (CD252) on an HIV-1 canarypox vaccine.
Vaccine 2009; 27(37): 5077-84. [93] Serghides L, Bukczynski J, Wen T, et al. Evaluation of OX40
ligand as a costimulator of human antiviral memory CD8 T
cell responses: comparison with B7.1 and 4-1BBL. J Immunol 2005; 175(10): 6368-77.
HIV and Costimulation Current Molecular Medicine, 2011, Vol. 11, No. 3 19
[94] Takahashi Y, Tanaka Y, Yamashita A, Koyanagi Y,
Nakamura M, Yamamoto N. OX40 stimulation by gp34/OX40 ligand enhances productive human immunodeficiency virus type 1 infection. J Virol 2001; 75(15): 6748-57.
[95] Jourdan P, Vendrell J, Huguet M, et al. Cytokines and cell surface molecules independently induce CXCR4 expression on CD4+ CCR7+ human memory T cells. J Immunol 2000;
165(2): 716-24. [96] Tanaka R, Takahashi Y, Kodama A, Saito M, Ansari A,
Tanaka Y. Suppression of CCR5-tropic HIV type 1 infection
by OX40 stimulation via enhanced production of -chemokines. AIDS Res Hum Retroviruses 2010; 26(10): 1147-54.
[97] Takahashi Y, Tanaka R, Yamamoto N, Tanaka Y. Enhancement of OX40-induced apoptosis by TNF coactivation in OX40-expressing T cell lines in vitro leading
to decreased targets for HIV type 1 production. AIDS Res Hum Retroviruses 2008; 24(3): 423-35.
[98] Arch R, Thompson C. 4-1BB and Ox40 are members of a
558-65. [99] Jang I, Lee Z, Kim Y, Kim S, Kwon B. Human 4-1BB
(CD137) signals are mediated by TRAF2 and activate
nuclear factor-kappa B. Biochem Biophys Res Commun 1998; 242(3): 613-20.
[100] Lee H, Park S, Choi B, Kim H, Nam K, Kwon B. 4-1BB promotes the survival of CD8+ T lymphocytes by increasing
expression of Bcl-xL and Bfl-1. J Immunol 2002; 169(9): 4882-8.
[101] Sabbagh L, Pulle G, Liu Y, Tsitsikov E, Watts T. ERK-
dependent Bim modulation downstream of the 4-1BB-TRAF1 signaling axis is a critical mediator of CD8 T cell survival in vivo. J Immunol 2008; 180(12): 8093-101.
[102] Kwon B, Lee H, Kwon B. New insights into the role of 4-1BB in immune responses: beyond CD8+ T cells. Trends Immunol 2002; 23(8): 378-80.
[103] Heinisch I, Daigle I, Knöpfli B, Simon H. CD137 activation abrogates granulocyte-macrophage colony-stimulating factor-mediated anti-apoptosis in neutrophils. Eur J Immunol
2000; 30(12): 3441-6. [104] Huang Q, Liu D, Majewski P, et al. The plasticity of dendritic
cell responses to pathogens and their components. Science
2001; 294(5543): 870-5. [105] Futagawa T, Akiba H, Kodama T, et al. Expression and
function of 4-1BB and 4-1BB ligand on murine dendritic cells.
Int Immunol 2002; 14(3): 275-86. [106] Bukczynski J, Wen T, Watts T. Costimulation of human
CD28- T cells by 4-1BB ligand. Eur J Immunol 2003; 33(2):
446-54. [107] Bertram E, Lau P, Watts T. Temporal segregation of 4-1BB
versus CD28-mediated costimulation: 4-1BB ligand
influences T cell numbers late in the primary response and regulates the size of the T cell memory response following influenza infection. J Immunol 2002; 168(8): 3777-85.
[108] Dawicki W, Bertram E, Sharpe A, Watts T. 4-1BB and OX40 act independently to facilitate robust CD8 and CD4 recall responses. J Immunol 2004; 173(10): 5944-51.
[109] Gramaglia I, Cooper D, Miner K, Kwon B, Croft M. Co-stimulation of antigen-specific CD4 T cells by 4-1BB ligand. Eur J Immunol 2000; 30(2): 392-402.
[110] Cannons J, Lau P, Ghumman B, et al. 4-1BB ligand induces cell division, sustains survival, and enhances effector function of CD4 and CD8 T cells with similar efficacy. J
costimulation of human T cells induces CD4 and CD8 T cell
expansion, cytokine production, and the development of cytolytic effector function. J Immunol 2002; 168(10): 4897-906.
[112] Bansal-Pakala P, Croft M. Defective T cell priming associated with aging can be rescued by signaling through 4-1BB (CD137). J Immunol 2002; 169(9): 5005-9.
[113] Dawicki W, Watts T. Expression and function of 4-1BB during
CD4 versus CD8 T cell responses in vivo. Eur J Immunol 2004; 34(3): 743-51.
[114] Kim Y, Choi B, Kang W, et al. IFN-gamma-indoleamine-2,3
dioxygenase acts as a major suppressive factor in 4-1BB-mediated immune suppression in vivo. J Leukoc Biol 2009; 85(5): 817-25.
[115] Sharma R, Elpek K, Yolcu E, et al. Costimulation as a platform for the development of vaccines: a peptide-based vaccine containing a novel form of 4-1BB ligand eradicates
established tumors. Cancer Res 2009; 69(10): 4319-26. [116] Choi B, Kim Y, Kwon P, Lee S, Kang S, Kim M, et al. 4-1BB
functions as a survival factor in dendritic cells. J Immunol
2009; 182(7): 4107-15. [117] Pauly S, Broll K, Wittmann M, Giegerich G, Schwarz H.
CD137 is expressed by follicular dendritic cells and
costimulates B lymphocyte activation in germinal centers. J Leukoc Biol 2002; 72(1): 35-42.
[118] Zhang X, Voskens C, Sallin M, et al. CD137 promotes
proliferation and survival of human B cells. J Immunol 2010; 184(2): 787-95.
mediates opposite effects in human and mouse NK cells and impairs NK cell reactivity against human acute myeloid leukemia cells Blood 2009; 115(15): 3058-69
[120] Choi B, Bae J, Choi E, et al. 4-1BB-dependent inhibition of immunosuppression by activated CD4+CD25+ T cells. J Leukoc Biol 2004; 75(5): 785-91.
[121] Harrison J, Bertram E, Boyle D, Coupar B, Ranasinghe C,
Ramshaw I. 4-1BBL coexpression enhances HIV-specific CD8 T cell memory in a poxvirus prime-boost vaccine. Vaccine 2006; 24(47-48): 6867-74.
[122] Ganguly S, Liu J, Pillai V, Mittler R, Amara R. Adjuvantive effects of anti-4-1BB agonist Ab and 4-1BBL DNA for a HIV-1 Gag DNA vaccine: different effects on cellular and humoral
immunity. Vaccine 2010; 28(5): 1300-9. [123] Bukczynski J, Wen T, Wang C, et al. Enhancement of HIV-
specific CD8 T cell responses by dual costimulation with
CD80 and CD137L. J Immunol 2005; 175(10): 6378-89. [124] Brinchmann J, Dobloug J, Heger B, Haaheim L, Sannes M,
Egeland T. Expression of costimulatory molecule CD28 on T
cells in human immunodeficiency virus type 1 infection: functional and clinical correlations. J Infect Dis 1994; 169(4): 730-8.
[125] Wang S, Kim Y, Bick C, Kim S, Kwon B. The potential roles of 4-1BB costimulation in HIV type 1 infection. AIDS Res Hum Retroviruses 1998; 14(3): 223-31.
[126] Schönbeck U, Mach F, Libby P. CD154 (CD40 ligand). Int J Biochem Cell Biol 2000; 32(7): 687-93.
[127] van Kooten C, Banchereau J. CD40-CD40 ligand. J Leukoc
Biol 2000; 67(1): 2-17. [128] Huang X, Fan Z, Zheng L, et al. Priming of human
immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cell
responses by dendritic cells loaded with HIV-1 proteins. J Infect Dis 2003; 187(2): 315-9.
[129] Caux C, Massacrier C, Vanbervliet B, et al. Activation of
human dendritic cells through CD40 cross-linking. J Exp Med 1994; 180(4): 1263-72.
[130] Brossart P, Grünebach F, Stuhler G, et al. Generation of
functional human dendritic cells from adherent peripheral blood monocytes by CD40 ligation in the absence of granulocyte-macrophage colony-stimulating factor. Blood
1998; 92(11): 4238-47. [131] Chougnet C, Cohen S, Kawamura T, et al. Normal immune
function of monocyte-derived dendritic cells from HIV-
infected individuals: implications for immunotherapy. J Immunol 1999; 163(3): 1666-73.
[132] Cella M, Scheidegger D, Palmer-Lehmann K, Lane P,
Lanzavecchia A, Alber G. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC
activation. J Exp Med 1996; 184(2): 747-52. [133] Kuniyoshi J, Kuniyoshi C, Lim A, et al. Dendritic cell
secretion of IL-15 is induced by recombinant huCD40LT and
20 Current Molecular Medicine, 2011, Vol. 11, No. 3 De Keersmaecker et al.
augments the stimulation of antigen-specific cytolytic T cells.
Cell Immunol 1999; 193(1): 48-58. [134] di Marzio P, Mariani R, Lui R, Thomas E, Landau N. Soluble
CD40 ligand induces beta-chemokine production by
macrophages and resistance to HIV-1 entry. Cytokine 2000; 12(10): 1489-95.
[135] Serra P, Amrani A, Yamanouchi J, et al. CD40 ligation
releases immature dendritic cells from the control of regulatory CD4+CD25+ T cells. Immunity 2003; 19(6): 877-89.
[136] Misra N, Bayry J, Lacroix-Desmazes S, Kazatchkine M, Kaveri S. Cutting edge: human CD4+CD25+ T cells restrain the maturation and antigen-presenting function of dendritic
cells. J Immunol 2004; 172(8): 4676-80. [137] Kornbluth R. The emerging role of CD40 ligand in HIV
infection. J Leukoc Biol 2000; 68(3): 373-82.
[138] Sipsas N, Sfikakis P, Kontos A, Kordossis T. Levels of soluble CD40 ligand (CD154) in serum are increased in human immunodeficiency virus type 1-infected patients and
ligand induction in CD4 T cells and dysregulated IL-12 production during HIV infection. Clin Exp Immunol 1999; 117(2): 335-42.
[140] Subauste C, Wessendarp M, Portilllo J, et al. Pathogen-specific induction of CD154 is impaired in CD4+ T cells from human immunodeficiency virus-infected patients. J Infect Dis 2004; 189(1): 61-70.
[141] Müller F, Aukrust P, Nordoy I, Froland S. Possible role of interleukin-10 (IL-10) and CD40 ligand expression in the pathogenesis of hypergammaglobulinemia in human
immunodeficiency virus infection: modulation of IL-10 and Ig production after intravenous Ig infusion. Blood 1998; 92(10): 3721-9.
[142] Chirmule N, McCloskey T, Hu R, Kalyanaraman V, Pahwa S. HIV gp120 inhibits T cell activation by interfering with expression of costimulatory molecules CD40 ligand and
CD80 (B71). J Immunol 1995; 155(2): 917-24. [143] Subauste C, Subauste A, Wessendarp M. Role of CD40-
dependent down-regulation of CD154 in impaired induction
of CD154 in CD4(+) T cells from HIV-1-infected patients. J Immunol 2007; 178(3): 1645-53.
[144] Chougnet C, Thomas E, Landay A, et al. CD40 ligand and
IFN-gamma synergistically restore IL-12 production in HIV-infected patients. Eur J Immunol 1998; 28(2): 646-56.
[145] Loré K, Sönnerborg A, Broström C, et al. Accumulation of
DC-SIGN+CD40+ dendritic cells with reduced CD80 and CD86 expression in lymphoid tissue during acute HIV-1 infection. AIDS 2002; 16(5): 683-92.
[146] Muthumani K, Hwang D, Choo A, et al. HIV-1 Vpr inhibits the maturation and activation of macrophages and dendritic cells in vitro. Int Immunol 2005; 17(2): 103-16.
[147] Donaghy H, Gazzard B, Gotch F, Patterson S. Dysfunction and infection of freshly isolated blood myeloid and plasmacytoid dendritic cells in patients infected with HIV-1.
Blood 2003; 101(11): 4505-11. [148] Donaghy H, Pozniak A, Gazzard B, et al. Loss of blood
CD11c(+) myeloid and CD11c(-) plasmacytoid dendritic cells
in patients with HIV-1 infection correlates with HIV-1 RNA virus load. Blood 2001; 98(8): 2574-6.
in blood plasmacytoid dendritic cell number and function despite effective highly active antiretroviral therapy and increased blood myeloid dendritic cells in HIV-infected
[153] Qiao X, He B, Chiu A, Knowles D, Chadburn A, Cerutti A. Human immunodeficiency virus 1 Nef suppresses CD40-dependent immunoglobulin class switching in bystander B
cells. Nat Immunol 2006; 7(3): 302-10. [154] Martin G, Tremblay M. HLA-DR, ICAM-1, CD40, CD40L, and
CD86 are incorporated to a similar degree into clinical human
immunodeficiency virus type 1 variants expanded in natural reservoirs such as peripheral blood mononuclear cells and human lymphoid tissue cultured ex vivo. Clin Immunol 2004;
111(3): 275-85. [155] Martin G, Roy J, Barat C, Ouellet M, Gilbert C, Tremblay M.
Human immunodeficiency virus type 1-associated CD40
ligand transactivates B lymphocytes and promotes infection of CD4+ T cells. J Virol 2007; 81(11): 5872-81.
[156] Kinter A, Catanzaro A, Monaco J, et al. 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 1998; 95(20): 11880-5.
[157] Kornbluth R, Kee K, Richman D. CD40 ligand (CD154) stimulation of macrophages to produce HIV-1-suppressive beta-chemokines. Proc Natl Acad Sci USA 1998; 95(9):
5205-10. [158] Bergamini A, Bolacchi F, Pesce C, et al. Increased CD4 and
CCR5 expression and human immunodeficiency virus type 1 entry in CD40 ligand-stimulated macrophages. J Infect Dis
C. Identification of a strongly activating human anti-CD40
antibody that suppresses HIV type 1 infection. AIDS Res Hum Retroviruses 2008; 24(3): 367-73.
[160] Mueller C, Rissoan M, Salinas B, et al. Polymerase chain
reaction selects a novel disintegrin proteinase from CD40-activated germinal center dendritic cells. J Exp Med 1997; 186(5): 655-63.
[161] Papadopoulos E, Sassetti C, Saeki H, et al. Fractalkine, a CX3C chemokine, is expressed by dendritic cells and is up-regulated upon dendritic cell maturation. Eur J Immunol
1999; 29(8): 2551-9. [162] Pal R, Garzino-Demo A, Markham P, et al. Inhibition of HIV-1
infection by the beta-chemokine MDC. Science 1997;
278(5338): 695-8. [163] McDyer J, Dybul M, Goletz T, et al. 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 1999; 162(6): 3711-7.
[164] Gras G, Legendre C, Krzysiek R, Dormont D, Galanaud P, Richard Y. CD40/CD40L interactions and cytokines regulate HIV replication in B cells in vitro. Virology 1996; 220(2): 309-
19. [165] Moir S, Lapointe R, Malaspina A, et al. 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 1999; 73(10): 7972-80.
[166] Swingler S, Brichacek B, Jacque J, Ulich C, Zhou J, Stevenson M. HIV-1 Nef intersects the macrophage CD40L signalling pathway to promote resting-cell infection. Nature
2003; 424(6945): 213-9. [167] Ihata A, Watabe S, Sasaki S, et al. Immunomodulatory effect
of a plasmid expressing CD40 ligand on DNA vaccination
against human immunodeficiency virus type-1. Immunology 1999; 98(3): 436-42.
Multimeric soluble CD40 ligand (sCD40L) efficiently enhances HIV specific cellular immune responses during DNA prime and boost with attenuated poxvirus vectors MVA
and NYVAC expressing HIV antigens. Vaccine 2009; 27(24): 3165-74.
HIV and Costimulation Current Molecular Medicine, 2011, Vol. 11, No. 3 21
[169] Lin F, Peng Y, Jones L, Verardi P, Yilma T. Incorporation of
CD40 ligand into the envelope of pseudotyped single-cycle Simian immunodeficiency viruses enhances immunogenicity. J Virol 2009; 83(3): 1216-27.
[170] Smed-Sörensen A, Loré K, Walther-Jallow L, Andersson J, Spetz A. HIV-1-infected dendritic cells up-regulate cell surface markers but fail to produce IL-12 p70 in response to
CD40 ligand stimulation. Blood 2004; 104(9): 2810-7. [171] Huang X, Fan Z, Borowski L, Rinaldo C. Maturation of
dendritic cells for enhanced activation of anti-HIV-1 CD8(+) T
cell immunity. J Leukoc Biol 2008; 83(6): 1530-40. [172] Ostrowski M, Justement S, Ehler L, et al. The role of CD4+ T
cell help and CD40 ligand in the in vitro expansion of HIV-1-
specific memory cytotoxic CD8+ T cell responses. J Immunol 2000; 165(11): 6133-41.
[173] Zhang R, Lifson J, Chougnet C. Failure of HIV-exposed
CD4+ T cells to activate dendritic cells is reversed by restoration of CD40/CD154 interactions. Blood 2006; 107(5): 1989-95.
[174] Routy J, Boulassel M, Yassine-Diab et al. Immunologic activity and safety of autologous HIV RNA-electroporated dendritic cells in HIV-1 infected patients receiving
antiretroviral therapy. Clin Immunol 2010; 134(2): 140-7. [175] Kutsch O, Levy D, Kosloff B, Shaw G, Benveniste E. CD154-
CD40-induced reactivation of latent HIV-1 infection. Virology
Greene W. Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells. Nature 2005; 435(7038): 108-14.
[177] Pido-Lopez J, Whittall T, Wang Y, et al. Stimulation of cell surface CCR5 and CD40 molecules by their ligands or by HSP70 up-regulates APOBEC3G expression in CD4(+) T
cells and dendritic cells. J Immunol 2007; 178(3): 1671-9. [178] Anderson D, Maraskovsky E, Billingsley W, et al. A
homologue of the TNF receptor and its ligand enhance T-cell
growth and dendritic-cell function. Nature 1997; 390(6656): 175-9.
[179] Bachmann M, Wong B, Josien R, Steinman R, Oxenius A,
Choi Y. TRANCE, a tumor necrosis factor family member critical for CD40 ligand-independent T helper cell activation. J Exp Med 1999; 189(7): 1025-31.
[180] Josien R, Wong B, Li H, Steinman R, Choi Y. TRANCE, a TNF family member, is differentially expressed on T cell subsets and induces cytokine production in dendritic cells. J
Immunol 1999; 162(5): 2562-8. [181] Wong B, Josien R, Lee S, et al. TRANCE (tumor necrosis
factor [TNF]-related activation-induced cytokine), a new TNF
family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. J Exp Med 1997; 186(12): 2075-80.
[182] Gibellini D, Borderi M, De Crignis E, et al. RANKL/OPG/TRAIL plasma levels and bone mass loss evaluation in antiretroviral naive HIV-1-positive men. J Med
Virol 2007; 79(10): 1446-54. [183] Konishi M, Takahashi K, Yoshimoto E, Uno K, Kasahara K,
Mikasa K. Association between osteopenia/osteoporosis and
the serum RANKL in HIV-infected patients. AIDS 2005; 19(11): 1240-1.
[184] Fakruddin J, Laurence J. HIV envelope gp120-mediated
regulation of osteoclastogenesis via receptor activator of nuclear factor kappa B ligand (RANKL) secretion and its modulation by certain HIV protease inhibitors through
[185] Fakruddin J, Laurence J. HIV-1 Vpr enhances production of
receptor of activated NF-kappaB ligand (RANKL) via potentiation of glucocorticoid receptor activity. Arch Virol 2005; 150(1): 67-78.
[186] Yu Q, Gu J, Kovacs C, Freedman J, Thomas E, Ostrowski M. Cooperation of TNF family members CD40 ligand, receptor activator of NF-kappa B ligand, and TNF-alpha in the
activation of dendritic cells and the expansion of viral specific CD8+ T cell memory responses in HIV-1-infected and HIV-1-uninfected individuals. J Immunol 2003; 170(4): 1797-805.
[187] Kwon B, Yu K, Ni J, et al. Identification of a novel activation-
inducible protein of the tumor necrosis factor receptor superfamily and its ligand. J Biol Chem 1999; 274(10): 6056-61.
[188] Kim J, Choi B, Bae J, et al. Cloning and characterization of GITR ligand. Genes Immun 2003; 4(8): 564-9.
[189] Tone M, Tone Y, Adams E, et al. Mouse glucocorticoid-
induced tumor necrosis factor receptor ligand is costimulatory for T cells. Proc Natl Acad Sci USA 2003; 100(25): 15059-64.
[190] Yu K, Kim H, Song S, Min S, Jeong J, Youn B. Identification of a ligand for glucocorticoid-induced tumor necrosis factor receptor constitutively expressed in dendritic cells. Biochem
Biophys Res Commun 2003; 310(2): 433-8. [191] Hanabuchi S, Watanabe N, Wang Y, Ito T, Shaw J, Cao W,
et al. Human plasmacytoid predendritic cells activate NK
[192] Shin H, Kim S, Lee M, Suh J, Kwon B, Choi H. Soluble
glucocorticoid-induced TNF receptor (sGITR) induces inflammation in mice. Exp Mol Med 2003; 35(5): 358-64.
[193] Zhan Y, Funda D, Every A, et al. TCR-mediated activation
promotes GITR upregulation in T cells and resistance to glucocorticoid-induced death. Int Immunol 2004; 16(9): 1315-21.
[194] Nocentini G, Riccardi C. GITR: a multifaceted regulator of immunity belonging to the tumor necrosis factor receptor superfamily. Eur J Immunol 2005; 35(4): 1016-22.
[195] Nocentini G, Riccardi C. GITR: A Modulator of Immune
Response and Inflammation. Adv Exp Med Biol 2009; 647: 156-73.
[196] McHugh R, Whitters M, Piccirillo C, et al. CD4(+)CD25(+)
immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 2002; 16(2): 311-23.
[197] Tuyaerts S, Van Meirvenne S, Bonehill A, et al. Expression of human GITRL on myeloid dendritic cells enhances their immunostimulatory function but does not abrogate the
suppressive effect of CD4+CD25+ regulatory T cells. J Leukoc Biol 2007; 82(1): 93-105.
[198] Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S.
Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 2002; 3(2): 135-42.
[199] Stone G, Barzee S, Snarsky V, Kee K, Spina C, Yu X, et al. Multimeric soluble CD40 ligand and GITR ligand as adjuvants for human immunodeficiency virus DNA vaccines.
J Virol 2006; 80(4): 1762-72. [200] Suchard MS, Mayne E, Green VA, et al. FOXP3 expression
is upregulated in CD4T cells in progressive HIV-1 infection
and is a marker of disease severity. PLoS One 2010; 5(7): e11762.
[201] Stephens GL, McHugh RS, Whitters MJ, et al. Engagement
of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells. J Immunol 2004;
173(8): 5008-20. [202] Moreira AP, Cavassani KA, Massafera Tristão FS, et al.
CCR5-dependent regulatory T cell migration mediates fungal
survival and severe immunosuppression. J Immunol 2008; 180(5): 3049-56.
[203] D'Elia R, Behnke JM, Bradley JE, Else KJ. Regulatory T
cells: a role in the control of helminth-driven intestinal pathology and worm survival. J Immunol 2009; 182(4): 2340-8.
[204] Ramirez-Montagut T, Chow A, Hirschhorn-Cymerman D, et al. Glucocorticoid-induced TNF receptor family related gene activation overcomes tolerance/ignorance to melanoma
[205] Côté AL, Zhang P, O'Sullivan JA, et al. Stimulation of the
Glucocorticoid-Induced TNF Receptor Family-Related Receptor on CD8 T Cells Induces Protective and High-
22 Current Molecular Medicine, 2011, Vol. 11, No. 3 De Keersmaecker et al.
Avidity T Cell Responses to Tumor-Specific Antigens. J
Immunol 2011; 186(1): 275-83. [206] Snell LM, McPherson AJ, Lin GH, et al. CD8 T cell-intrinsic
GITR is required for T cell clonal expansion and mouse
survival following severe influenza infection. J Immunol 2010; 185(12): 7223-34.
[207] Lahey T, Loisel S, Wieland-Alter W. Glucocorticoid-induced
tumor necrosis factor receptor family-related protein triggering enhances HIV-specific CD4+ T cell cytokine secretion and protects HIV-specific CD4+ T cells from
apoptosis. J Infect Dis 2007; 196(1): 43-9. [208] De Trez C, Schneider K, Potter K, et al. The inhibitory
HVEM-BTLA pathway counter regulates lymphotoxin
receptor signaling to achieve homeostasis of dendritic cells. J Immunol 2008; 180(1): 238-48.
[209] Cai G, Freeman G. The CD160, BTLA, LIGHT/HVEM
[210] Morel Y, Schiano de Colella J, et al. Reciprocal expression of
the TNF family receptor herpes virus entry mediator and its ligand LIGHT on activated T cells: LIGHT down-regulates its own receptor. J Immunol 2000; 165(8): 4397-404.
[211] Mauri D, Ebner R, Montgomery R, et al. LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Immunity 1998; 8(1):
21-30. [212] Sedy J, Gavrieli M, Potter K, et al. B and T lymphocyte
attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat Immunol 2005; 6(1): 90-8.
[213] Tamada K, Shimozaki K, Chapoval A, et al. LIGHT, a TNF-like molecule, costimulates T cell proliferation and is required for dendritic cell-mediated allogeneic T cell response. J
Immunol 2000; 164(8): 4105-10. [214] Wang J, Fu Y. The role of LIGHT in T cell-mediated
immunity. Immunol Res 2004; 30(2): 201-14.
[215] Duhen T, Pasero C, Mallet F, Barbarat B, Olive D, Costello R. LIGHT costimulates CD40 triggering and induces immunoglobulin secretion; a novel key partner in T cell-
[216] Yu K, Kwon B, Ni J, Zhai Y, Ebner R, Kwon B. A newly
identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis. J Biol Chem 1999; 274(20): 13733-6.
[217] Schneider K, Potter K, Ware C. Lymphotoxin and LIGHT signaling pathways and target genes. Immunol Rev 2004; 202: 49-66.
[218] Steinberg M, Shui J, Ware C, Kronenberg M. Regulating the mucosal immune system: the contrasting roles of LIGHT, HVEM, and their various partners. Semin Immunopathol
2009; 31(2): 207-21. [219] Summers-DeLuca LE, McCarthy DD, Cosovic B, et al.
Expression of lymphotoxin-alphabeta on antigen-specific T
cells is required for DC function. J Exp Med 2007; 204(5): 1071-81.
[220] McCarthy D, Summers-Deluca L, Vu F, Chiu S, Gao Y,
Gommerman J. The lymphotoxin pathway: beyond lymph node development. Immunol Res 2006; 35(1-2): 41-54.
[221] Harrop J, McDonnell P, Brigham-Burke M, et al. Herpesvirus
entry mediator ligand (HVEM-L), a novel ligand for HVEM/TR2, stimulates proliferation of T cells and inhibits HT29 cell growth. J Biol Chem 1998; 273(42): 27548-56.
[222] Cai G, Anumanthan A, Brown J, Greenfield E, Zhu B, Freeman G. CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator. Nat
Immunol 2008; 9(2): 176-85. [223] Vendel A, Calemine-Fenaux J, Izrael-Tomasevic A, Chauhan
V, Arnott D, Eaton D. B and T lymphocyte attenuator
regulates B cell receptor signaling by targeting Syk and BLNK. J Immunol 2009; 182(3): 1509-17.
[224] Han P, Goularte O, Rufner K, Wilkinson B, Kaye J. An
inhibitory Ig superfamily protein expressed by lymphocytes and APCs is also an early marker of thymocyte positive selection. J Immunol 2004; 172(10): 5931-9.
[225] Hurchla M, Sedy J, Gavrieli M, et al. B and T lymphocyte
attenuator exhibits structural and expression polymorphisms and is highly Induced in anergic CD4+ T cells. J Immunol 2005; 174(6): 3377-85.
[226] Ware C. Targeting lymphocyte activation through the lymphotoxin and LIGHT pathways. Immunol Rev 2008; 223: 186-201.
[227] Maïza H, Leca G, Mansur I, Schiavon V, Boumsell L, Bensussan A. A novel 80-kD cell surface structure identifies human circulating lymphocytes with natural killer activity. J
Exp Med 1993; 178(3): 1121-6. [228] Bensussan A, Gluckman E, el Marsafy S, et al. BY55
monoclonal antibody delineates within human cord blood and
bone marrow lymphocytes distinct cell subsets mediating cytotoxic activity. Proc Natl Acad Sci USA 1994; 91(19): 9136-40.
[229] Anumanthan A, Bensussan A, Boumsell L, et al. Cloning of BY55, a novel Ig superfamily member expressed on NK cells, CTL, and intestinal intraepithelial lymphocytes. J
Immunol 1998; 161(6): 2780-90. [230] Sperling A, Bluestone J. The complexities of T-cell co-
stimulation: CD28 and beyond. Immunol Rev 1996; 153: 155-
of human CTLA-4 and delineation of a CD80/CD86 binding
site conserved in CD28. Nat Struct Biol 1997; 4(7): 527-31. [232] van der Merwe P, Bodian D, Daenke S, Linsley P, Davis S.
CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. J Exp Med 1997; 185(3): 393-403.
[233] Parry R, Chemnitz J, Frauwirth K, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005; 25(21): 9543-53.
[234] Schneider H, Downey J, Smith A, Zinselmeyer B, Rush C, Brewer J, et al. Reversal of the TCR stop signal by CTLA-4. Science 2006; 313(5795): 1972-5.
[235] Fife B, Pauken K, Eagar T, et al. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol 2009; 10(11): 1185-92.
[236] Fife B, Bluestone J. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev 2008; 224: 166-82.
[237] Lenschow D, Walunas T, Bluestone J. CD28/B7 system of T cell costimulation. Annu Rev Immunol 1996; 14: 233-58.
[238] Frauwirth K, Riley J, Harris M, et al. The CD28 signaling
[239] Azuma M, Phillips J, Lanier L. CD28- T lymphocytes.
Antigenic and functional properties. J Immunol 1993; 150(4): 1147-59.
[240] Fagnoni FF, Vescovini R, Mazzola M, et al. Expansion of
cytotoxic CD8+ CD28- T cells in healthy ageing people, including centenarians. Immunology 1996; 88(4): 501-7.
[241] Czesnikiewicz-Guzik M, Lee WW, Cui D, et al. T cell subset-
specific susceptibility to aging. Clin Immunol 2008; 127(1): 107-18.
[242] Freeman G, Wherry E, Ahmed R, Sharpe A. Reinvigorating
exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade. J Exp Med 2006; 203(10): 2223-7.
[243] Larsen C, Ritchie S, Hendrix R, et al. Regulation of
immunostimulatory function and costimulatory molecule (B7-1 and B7-2) expression on murine dendritic cells. J Immunol 1994; 152(11): 5208-19.
[244] Rattis F, Péguet-Navarro J, Staquet M, et al. Expression and function of B7-1 (CD80) and B7-2 (CD86) on human epidermal Langerhans cells. Eur J Immunol 1996; 26(2):
W. CD80 and CD86 costimulatory molecules on circulating T
cells of HIV infected individuals. Immunol Lett 1999; 65(3): 197-201.
[246] Kuchroo V, Das M, Brown J, et al. B7-1 and B7-2
costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy. Cell 1995; 80(5): 707-18.
HIV and Costimulation Current Molecular Medicine, 2011, Vol. 11, No. 3 23
[247] Sansom D, Manzotti C, Zheng Y. What's the difference
between CD80 and CD86? Trends Immunol 2003; 24(6): 314-9.
[248] Caruso A, Fiorentini S, Licenziati S, et al. Expansion of rare
CD8+ CD28- CD11b- T cells with impaired effector functions in HIV-1-infected patients. J Acquir Immune Defic Syndr 2000; 24(5): 465-74.
[249] Appay V, Dunbar P, Callan M, et al. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med 2002; 8(4): 379-85.
[250] Barker E, Bossart K, Fujimura S, Levy J. CD28 costimulation increases CD8+ cell suppression of HIV replication. J Immunol 1997; 159(10): 5123-31.
[251] Rehr M, Cahenzli J, Haas A, et al. Emergence of polyfunctional CD8+ T cells after prolonged suppression of human immunodeficiency virus replication by antiretroviral
therapy. J Virol 2008; 82(7): 3391-404. [252] Swigut T, Shohdy N, Skowronski J. Mechanism for down-
regulation of CD28 by Nef. EMBO J 2001; 20(7): 1593-604.
[253] Venkatachari N, Majumder B, Ayyavoo V. Human immunodeficiency virus (HIV) type 1 Vpr induces differential regulation of T cell costimulatory molecules: direct effect of
Vpr on T cell activation and immune function. Virology 2007; 358(2): 347-56.
[254] Jason J, Inge K. Increased expression of CD80 and CD86 in
in vitro-infected CD3+ cells producing cytoplasmic HIV type 1 p24. AIDS Res Hum Retroviruses 1999; 15(2): 173-81.
[255] Chaudhry A, Das S, Hussain A, et al. The Nef protein of HIV-1 induces loss of cell surface costimulatory molecules CD80
and CD86 in APCs. J Immunol 2005; 175(7): 4566-74. [256] Chaudhry A, Das S, Jameel S, et al. A two-pronged
mechanism for HIV-1 Nef-mediated endocytosis of immune
[257] Quaranta M, Tritarelli E, Giordani L, Viora M. HIV-1 Nef
induces dendritic cell differentiation: a possible mechanism of uninfected CD4(+) T cell activation. Exp Cell Res 2002; 275(2): 243-54.
[258] Kumar A, Angel J, Aucoin S, et al. Dysregulation of B7.2 (CD86) expression on monocytes of HIV-infected individuals is associated with altered production of IL-2. Clin Exp
Insertion of host-derived costimulatory molecules CD80 (B7.1) and CD86 (B7.2) into human immunodeficiency virus type 1 affects the virus life cycle. J Virol 2004; 78(12): 6222-
attachment and replication are promoted after acquisition of
host CD28 and CD152 by HIV-1. J Infect Dis 2005; 192(7): 1265-8.
[262] Bounou S, Dumais N, Tremblay M. Attachment of human
immunodeficiency virus-1 (HIV-1) particles bearing host-encoded B7-2 proteins leads to nuclear factor-kappa B- and nuclear factor of activated T cells-dependent activation of
[263] Esser M, Graham D, Coren L, et al. Differential incorporation
of CD45, CD80 (B7-1), CD86 (B7-2), and major histocompatibility complex class I and II molecules into human immunodeficiency virus type 1 virions and
microvesicles: implications for viral pathogenesis and immune regulation. J Virol 2001; 75(13): 6173-82.
[264] Li Y, Mak G, Franza BJ. In vitro study of functional
involvement of Sp1, NF-kappa B/Rel, and AP1 in phorbol 12-myristate 13-acetate-mediated HIV-1 long terminal repeat activation. J Biol Chem 1994; 269(48): 30616-9.
[265] Kinoshita S, Su L, Amano M, Timmerman L, Kaneshima H, Nolan G. The T cell activation factor NF-ATc positively
regulates HIV-1 replication and gene expression in T cells.
Immunity 1997; 6(3): 235-44. [266] Cook J, Albacker L, August A, Henderson A. CD28-
dependent HIV-1 transcription is associated with Vav, Rac,
and NF-kappa B activation. J Biol Chem 2003; 278(37): 35812-8.
[267] Roy J, Martin G, Giguère J, Bélanger D, Pétrin M, Tremblay
M. HIV type 1 can act as an APC upon acquisition from the host cell of peptide-loaded HLA-DR and CD86 molecules. J Immunol 2005; 174(8): 4779-88.
[268] Levine B, Mosca J, Riley J, et al. Antiviral effect and ex vivo CD4+ T cell proliferation in HIV-positive patients as a result of CD28 costimulation. Science 1996; 272(5270): 1939-43.
[269] Roederer M, Raju P, Mitra D, Herzenberg L. HIV does not replicate in naive CD4 T cells stimulated with CD3/CD28. J Clin Invest 1997; 99(7): 1555-64.
[270] Woods T, Roberts B, Butera S, Folks T. Loss of inducible virus in CD45RA naive cells after human immunodeficiency virus-1 entry accounts for preferential viral replication in
CD45RO memory cells. Blood 1997; 89(5): 1635-41. [271] Barker E, Bossart K, Levy J. Differential effects of CD28
costimulation on HIV production by CD4+ cells. J Immunol
1998; 161(11): 6223-7. [272] Mengozzi M, Malipatlolla M, De Rosa S, Herzenberg L,
Roederer M. Naive CD4 T cells inhibit CD28-costimulated R5
HIV replication in memory CD4 T cells. Proc Natl Acad Sci USA 2001; 98(20): 11644-9.
[273] Carroll R, Riley J, Levine B, et al. Differential regulation of HIV-1 fusion cofactor expression by CD28 costimulation of
CD4+ T cells. Science 1997; 276(5310): 273-6. [274] Asjö B, Cefai D, Debré P, Dudoit Y, Autran B. A novel mode
of human immunodeficiency virus type 1 (HIV-1) activation:
ligation of CD28 alone induces HIV-1 replication in naturally infected lymphocytes. J Virol 1993; 67(7): 4395-8.
[275] Annibaldi A, Sajeva A, Muscolini M, et al. CD28 ligation in
the absence of TCR promotes RelA/NF-kappaB recruitment and trans-activation of the HIV-1 LTR. Eur J Immunol 2008; 38(5): 1446-51.
[276] Zhou X, Kubo M, Nishitsuji H, et al. Inducible-costimulator-mediated suppression of human immunodeficiency virus type 1 replication in CD4(+) T lymphocytes. Virology 2004; 325(2):
252-63. [277] Nunès J, Klasen S, Ragueneau M, et al. CD28 mAbs with
distinct binding properties differ in their ability to induce T cell
activation: analysis of early and late activation events. Int Immunol 1993; 5(3): 311-5.
[278] Kim J, Bagarazzi M, Trivedi N, et al. Engineering of in vivo
immune responses to DNA immunization via codelivery of costimulatory molecule genes. Nat Biotechnol 1997; 15(7): 641-6.
[279] Tsuji T, Hamajima K, Ishii N, et al. Immunomodulatory effects of a plasmid expressing B7-2 on human immunodeficiency virus-1-specific cell-mediated immunity induced by a plasmid
encoding the viral antigen. Eur J Immunol 1997; 27(3): 782-7.
[280] Kim J, Nottingham L, Wilson D, et al. Engineering DNA
vaccines via co-delivery of co-stimulatory molecule genes. Vaccine 1998; 16(19): 1828-35.
[281] Egen J, Kuhns M, Allison J. CTLA-4: new insights into its
biological function and use in tumor immunotherapy. Nat Immunol 2002; 3(7): 611-8.
[282] Greenwald R, Freeman G, Sharpe A. The B7 family revisited.
Annu Rev Immunol 2005; 23: 515-48. [283] Fallarino F, Grohmann U, Hwang K, et al. Modulation of
tryptophan catabolism by regulatory T cells. Nat Immunol
2003; 4(12): 1206-12. [284] Steiner K, Waase I, Rau T, Dietrich M, Fleischer B, Bröker B.
Enhanced expression of CTLA-4 (CD152) on CD4+ T cells in
HIV infection. Clin Exp Immunol 1999; 115(3): 451-7. [285] Leng Q, Bentwich Z, Magen E, Kalinkovich A, Borkow G.
CTLA-4 upregulation during HIV infection: association with
anergy and possible target for therapeutic intervention. AIDS 2002; 16(4): 519-29.
24 Current Molecular Medicine, 2011, Vol. 11, No. 3 De Keersmaecker et al.
[286] Kaufmann D, Kavanagh D, Pereyra F, et al. Upregulation of
CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nat Immunol 2007; 8(11): 1246-54.
[287] Kassu A, Marcus R, D'Souza M, et al. Regulation of virus-specific CD4(+) T cell function by multiple costimulatory receptors during chronic HIV infection. J Immunol 2010;
185(5): 3007-18. [288] Andersson J, Boasso A, Nilsson J, et al. The prevalence of
regulatory T cells in lymphoid tissue is correlated with viral
load in HIV-infected patients. J Immunol 2005; 174(6): 3143-7.
[289] Riley J, Schlienger K, Blair P, et al. Modulation of
susceptibility to HIV-1 infection by the cytotoxic T lymphocyte antigen 4 costimulatory molecule. J Exp Med 2000; 191(11): 1987-97.
[290] Chen W, Jin W, Wahl S. Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor beta (TGF-beta) production by
murine CD4(+) T cells. J Exp Med 1998; 188(10): 1849-57. [291] Li J, Shen X, Hu P, Wang X. Transforming growth factor beta
stimulates the human immunodeficiency virus 1 enhancer
and requires NF-kappaB activity. Mol Cell Biol 1998; 18(1): 110-21.
[292] Phan G, Yang J, Sherry R, et al. Cancer regression and
autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 2003; 100(14): 8372-7.
[293] Elrefaei M, Burke C, Baker C, et al. TGF-beta and IL-10
production by HIV-specific CD8+ T cells is regulated by CTLA-4 signaling on CD4+ T cells. PLoS One 2009; 4(12): e8194.
[294] Cecchinato V, Tryniszewska E, Ma Z, et al. Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus
infection. J Immunol 2008; 180(8): 5439-47. [295] Hryniewicz A, Boasso A, Edghill-Smith Y, et al. CTLA-4
blockade decreases TGF-beta, IDO, and viral RNA
expression in tissues of SIVmac251-infected macaques. Blood 2006; 108(12): 3834-42.
[296] O'Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and
safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol 2010; 21(8): 1712-7.
[297] Agata Y, Kawasaki A, Nishimura H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 1996; 8(5): 765-72.
[298] Okazaki T, Iwai Y, Honjo T. New regulatory co-receptors: inducible co-stimulator and PD-1. Curr Opin Immunol 2002; 14(6): 779-82.
[299] Okazaki T, Honjo T. Rejuvenating exhausted T cells during chronic viral infection. Cell 2006; 124(3): 459-61.
[300] Petrovas C, Casazza J, Brenchley J, et al. PD-1 is a
regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med 2006; 203(10): 2281-92.
[301] Keir M, Francisco L, Sharpe A. PD-1 and its ligands in T-cell
immunity. Curr Opin Immunol 2007; 19(3): 309-14. [302] Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member
of the B7 family, co-stimulates T-cell proliferation and
interleukin-10 secretion. Nat Med 1999; 5(12): 1365-9. [303] Tamura H, Dong H, Zhu G, et al. B7-H1 costimulation
function. Blood 2001; 97(6): 1809-16. [304] Liu J, Hamrouni A, Wolowiec D, et al. Plasma cells from
multiple myeloma patients express B7-H1 (PD-L1) and
increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood 2007; 110(1): 296-304.
[305] Day C, Kaufmann D, Kiepiela P, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 2006; 443(7109): 350-4.
[306] Sauce D, Almeida J, Larsen M, et al. PD-1 expression on human CD8 T cells depends on both state of differentiation and activation status. AIDS 2007; 21(15): 2005-13.
[307] Muthumani K, Choo A, Shedlock D, et al. Human
immunodeficiency virus type 1 Nef induces programmed death 1 expression through a p38 mitogen-activated protein kinase-dependent mechanism. J Virol 2008; 82(23): 11536-
44. [308] Trautmann L, Janbazian L, Chomont N, et al. Upregulation of
PD-1 expression on HIV-specific CD8+ T cells leads to
reversible immune dysfunction. Nat Med 2006; 12(10): 1198-202.
[309] Zhang J, Zhang Z, Wang X, et al. PD-1 up-regulation is
correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors. Blood 2007; 109(11): 4671-8.
[310] Salisch N, Kaufmann D, Awad A, et al. Inhibitory TCR coreceptor PD-1 is a sensitive indicator of low-level replication of SIV and HIV-1. J Immunol 2010; 184(1): 476-
87. [311] Harari A, Cellerai C, Enders F, et al. Skewed association of
polyfunctional antigen-specific CD8 T cell populations with
HLA-B genotype. Proc Natl Acad Sci USA 2007; 104(41): 16233-8.
[312] Elrefaei M, Baker C, Jones N, Bangsberg D, Cao H.
Presence of suppressor HIV-specific CD8+ T cells is associated with increased PD-1 expression on effector CD8+ T cells. J Immunol 2008; 180(11): 7757-63.
[313] Quigley M, Pereyra F, Nilsson B, et al. Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat Med 2010; 16(10): 1147-51.
[314] D'Souza M, Fontenot A, Mack D, et al. Programmed death 1 expression on HIV-specific CD4+ T cells is driven by viral replication and associated with T cell dysfunction. J Immunol
2007; 179(3): 1979-87. [315] Venkatachari N, Buchanan W, Ayyavoo V. Human
downregulates PD-1 expression in infected cells and protects the cells from early apoptosis in vitro and in vivo. Virology 2008; 376(1): 140-53.
[316] Velu V, Kannanganat S, Ibegbu C, et al. Elevated expression levels of inhibitory receptor programmed death 1 on simian immunodeficiency virus-specific CD8 T cells during chronic
infection but not after vaccination. J Virol 2007; 81(11): 5819-28.
[317] Said E, Dupuy F, Trautmann L, et al. Programmed death-1-
induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat Med 2010; 16(4): 452-9.
[318] Moll M, Kuylenstierna C, Gonzalez V, et al. Severe functional impairment and elevated PD-1 expression in CD1d-restricted NKT cells retained during chronic HIV-1 infection. Eur J
Immunol 2009; 39(3): 902-11. [319] Trabattoni D, Saresella M, Biasin M, et al. B7-H1 is up-
regulated in HIV infection and is a novel surrogate marker of
disease progression. Blood 2003; 101(7): 2514-20. [320] Rosignoli G, Cranage A, Burton C, et al. Expression of PD-
L1, a marker of disease status, is not reduced by HAART in
aviraemic patients. AIDS 2007; 21(10): 1379-81. [321] Wang X, Zhang Z, Zhang S, et al. B7-H1 up-regulation
impairs myeloid DC and correlates with disease progression
in chronic HIV-1 infection. Eur J Immunol 2008; 38(11): 3226-36.
[322] Boasso A, Hardy A, Landay A, et al. PDL-1 upregulation on
monocytes and T cells by HIV via type I interferon: restricted expression of type I interferon receptor by CCR5-expressing leukocytes. Clin Immunol 2008; 129(1): 132-44.
[323] Meier A, Bagchi A, Sidhu H, et al. Upregulation of PD-L1 on monocytes and dendritic cells by HIV-1 derived TLR ligands. AIDS 2008; 22(5): 655-8.
[324] Lichterfeld M, Mou D, Cung T, et al. Telomerase activity of HIV-1-specific CD8+ T cells: constitutive up-regulation in controllers and selective increase by blockade of PD ligand 1
in progressors. Blood 2008; 112(9): 3679-87.
HIV and Costimulation Current Molecular Medicine, 2011, Vol. 11, No. 3 25
immunity in vivo by PD-1 blockade. Nature 2009; 458(7235): 206-10.
[326] Macatangay B, Rinaldo C. PD-1 blockade: A promising
immunotherapy for HIV? Cellscience 2009; 5(4): 61-5. [327] Franceschini D, Paroli M, Francavilla V, et al. PD-L1
negatively regulates CD4+CD25+Foxp3+ Tregs by limiting
STAT-5 phosphorylation in patients chronically infected with HCV. J Clin Invest 2009; 119(3): 551-64.
[328] Radziewicz H, Dunham R, Grakoui A. PD-1 tempers Tregs in
chronic HCV infection. J Clin Invest 2009; 119(3): 450-3. [329] Jones RB, Ndhlovu LC, Barbour JD, et al. Tim-3 expression
defines a novel population of dysfunctional T cells with highly
elevated frequencies in progressive HIV-1 infection. J Exp Med 2008; 205(12): 2763-79.
[330] Jin HT, Anderson AC, Tan WG, et al. Cooperation of Tim-3
and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc Natl Acad Sci USA 2010; 107(33): 14733-8.
[331] Lucia M, Buonfiglio D, Bottarel F, et al. Expression of the
novel T cell activation molecule hpH4 in HIV-infected patients: correlation with disease status. AIDS Res Hum Retroviruses 2000; 16(6): 549-57.
[332] Vidric M, Suh W, Dianzani U, Mak T, Watts T. Cooperation between 4-1BB and ICOS in the immune response to influenza virus revealed by studies of CD28/ICOS-deficient
mice. J Immunol 2005; 175(11): 7288-96. [333] Serghides L, Vidric M, Watts T. Approaches to studying
costimulation of human antiviral T cell responses: prospects for immunotherapeutic vaccines. Immunol Res 2006; 35(1-2):
137-50.
[334] Arens R, Tesselaar K, Baars P, et al. Constitutive
CD27/CD70 interaction induces expansion of effector-type T cells and results in IFNgamma-mediated B cell depletion. Immunity 2001; 15(5): 801-12.
[335] Zhu G, Flies D, Tamada K, et al. Progressive depletion of peripheral B lymphocytes in 4-1BB (CD137) ligand/I-Ealpha)-transgenic mice. J Immunol 2001; 167(5): 2671-6.
[336] Myers L, Takahashi C, Mittler R, Rossi R, Vella A. Effector CD8 T cells possess suppressor function after 4-1BB and Toll-like receptor triggering. Proc Natl Acad Sci USA 2003;
100(9): 5348-53. [337] Wang C, Lin G, McPherson A, Watts T. Immune regulation
by 4-1BB and 4-1BBL: complexities and challenges. Immunol
Carbonneil C, Levy Y. Human immunodeficiency virus-driven
expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients. Blood 2004; 104(10): 3249-56.
[339] Aandahl E, Michaëlsson J, Moretto W, Hecht F, Nixon D. Human CD4+ CD25+ regulatory T cells control T-cell responses to human immunodeficiency virus and
cytomegalovirus antigens. J Virol 2004; 78(5): 2454-9. [340] Chase A, Yang H, Zhang H, Blankson J, Siliciano R.
Preservation of FoxP3+ regulatory T cells in the peripheral
blood of human immunodeficiency virus type 1-infected elite suppressors correlates with low CD4+ T-cell activation. J Virol 2008; 82(17): 8307-15.
