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(Journal of Leukocyte Biology. 2006;80:994-1000.)
© 2006 by Society for Leukocyte Biology

Role of gp120 in dendritic cell dysfunction in HIV infection

Claire Chougnet* and Sandra Gessani{dagger},1

* Division of Molecular Immunology, Cincinnati Children’s Hospital Research Foundation and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; and
{dagger} Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy

1 Correspondence: Istituto Superiore di Sanità, Department of Cell Biology and Neurosciences, Viale Regina Elena 299, Via Castro Laurenziano 10, Rome, Rome 00161, Italy. E-mail: sandra.gessani{at}iss.it


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ABSTRACT
 
Only a limited fraction of circulating virions are demonstrably infectious; therefore, exposure to inactivated viruses may mimic the most frequent type of CD4-HIV interactions that occur in vivo. Several studies have recently underscored the crucial role that those noninfectious viruses could play in defective immune function in HIV-infected individuals and in particular, in the dysregulation of dendritic cell (DC) function. In this review, we discuss how interactions between DC and HIV gp120 or inactivated virus, which harbor intact surface gp120, lead to impaired DC function through direct (direct contact) or indirect mechanisms (as a consequence of primary CD4+ T cell dysregulation, followed by defective CD4-DC interactions). It is important that these functionally impaired DCs fail to give optimal signal to T cells but appear to favor the emergence of regulatory T cells. gp120-mediated impairment of DC function could therefore play an important role in the pathogenesis of HIV disease.

Key Words: T cells • AIDS pathogenesis • immune regulation


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DENDRITIC CELLS AND THEIR ROLE IN AIDS PATHOGENESIS
 
Dendritic cells (DCs) play a pivotal role in linking innate and adaptive immunity by their ability to induce appropriate immune responses upon recognition of invading pathogens [1 ]. Because of their central role in the induction of immune responses, modulation of DC function represents thus a strategic mechanism for a pathogen to evade immune surveillance. Supporting this theory, there is growing experimental evidence of the capacity of some viruses, including HIV-1, to affect DC biology [2 , 3 ]. DCs are among the first cellular targets of HIV-1 [4 5 6 7 ], and their migratory nature makes them strong candidates for viral spreading and transmission, either as directly infected cells or by passively transporting viruses sequestered in endosomal compartments [4 , 7 , 8 ]. Finally, DCs in lymphoid tissues may serve as reservoirs of HIV-1 that continually contribute to infection of newly recruited T cells [9 ]. It is now becoming clear that HIV-1 exploits multiple stages of the intercellular processes involved in the generation and regulation of the adaptive immune response to gain access to its main target cell population, the CD4+ T cells [10 ]. Thus, the central role of DCs in stimulating T cells not only provides a route for viral transmission, but also represents a vulnerable point at which HIV-1 can interfere with the initiation of T cell-mediated immunity.

HIV infection is associated with a gradual loss of immune competence, leading to an increased susceptibility to infection and cancer. While HIV infection is associated with abnormalities in most compartments of the immune system, defects in cell-mediated immunity appear to be of the greatest clinical importance. Impaired APC function is thought to be a critical component of HIV-associated immunodeficiency, and a variety of functional defects have been reported in macrophages and DCs isolated from HIV-infected patients [11 , 12 ]. It is interesting that defects in the number [13 14 15 16 ] and function [14 , 17 ] of DCs have been observed during disease progression, although the extent of this impairment remains controversial [18 , 19 ]. However, the mechanisms underlying DC defects have not been clearly delineated. In particular, it is not well established whether these defects are directly due to infection of DCs by HIV, or to their exposure to HIV products independently of viral infection. Alternatively, they could occur as a consequence of HIV-mediated dysregulation of CD4+ T cells. Because the extent of DC infection is quite limited in vivo, it can be predicted that indirect mechanisms will play a central role in DC dysfunction.

An important aspect of HIV pathogenesis is the concept of affected "bystander" cells. These are cells of the immune system that become functionally impaired via exposure to viral gene products, and not via direct infection. In this respect, interactions of gp120 with immune cells, independently of productive infection, can profoundly influence cellular functions in vivo, contributing to the progressive immune suppression observed in AIDS patients [20 , 21 ]. gp120 is present in tissues [22 ] and in the blood of HIV-infected donors [23 , 24 ] on the surface of virions both infectious and non-infectious and as a free protein. Of note, only a limited fraction ({approx}0.1%) of circulating virions are demonstrably infectious [25 , 26 ], therefore exposure to inactivated viruses may mimic the most frequent type of CD4-HIV interactions that occurs in vivo.

The following sections will examine the mechanisms underlying the capacity of HIV-1 to dysregulate DC functions, discussing the direct and indirect effects of gp120 on these cells, and how they contribute toward the overall immunodeficiency of HIV infection. It should be noted however, that HIV infection of DC is also enhancing the spread of the virus, which we will not review herein.


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EXPOSURE OF DCs TO HIV-1 ENVELOPE ALTERS THEIR DIFFERENTIATION/MATURATION PROGRAM
 
Exposure of DCs to HIV-1 initiates an aberrant pathway of maturation, which is associated with a profound impairment of functions critically important for the generation of protective immunity. Initial ex vivo studies carried out with blood DCs isolated from HIV-infected patients revealed that plasmacytoid (PDCs) and myeloid (MDCs) DCs exhibit high expression of the maturation markers CD86 and CD40 [15 , 27 ]. In addition, PDCs in chronically-infected individuals exhibit an impairment of virus-induced production of type I IFN, possibly because they have been previously activated [14 , 28 ]. Likewise, it has been observed that in vivo maturation of circulating MDCs is impaired in HIV-infected individuals, likely following the blunted up-regulation of CD40 Ligand (CD40L) expression on activated CD4+ T cells [29 ]. Since functional maturation of DCs is essential for activation and expansion of effector T cells, decreased expression of costimulatory molecules is expected to have negative effects on antigen presentation and activation of T cell responses.

In vitro studies showed PDC maturation following direct exposure to HIV-1 [30 , 31 ]. It is interesting that although MDCs were not directly affected by exposure to HIV-1, the cytokines secreted by HIV-activated PDCs could induce MDC maturation [30 ]. HIV-induced PDC maturation was also associated with high levels of CCR7 expression and migration toward CCL19 [30 , 32 ]. This effect could explain the accumulation of DCs in lymphoid tissues during primary HIV infection when the viral load is high [33 ]. In contrast with these studies, Smed-Sorensen and colleagues [34 ] reported that while exposure of MDCs and PDCs to HIV-1 alone resulted in only weak maturation of both DC subsets, TLR7/8 ligation induced full maturation in both infected and non infected cells. The different effects of HIV exposure on DC maturation appears to be a consequence of virus dose and length of virus exposure [34 ].

HIV infection of DCs generated from monocytic precursors (monocyte-derived DCs, MDDCs), isolated from both HIV-uninfected and infected individuals, leads to profound alteration of their properties. Although MDDCs infected in vitro with R5 HIV-1 up-regulate the expression of costimulatory molecules, their production of effector cytokines in response to CD40L is skewed as compared with uninfected cells [35 ]. Granelli-Piperno and colleagues also demonstrated that infected DCs specifically fail to mature in response to different stimuli [36 ]. Moreover, after in vitro super-infection, DCs from HIV-infected patients produce IL-10 in response to T cell mediated stimulus, whereas uninfected DCs from the same patients do not [36 ]. Likewise, although HIV-1 was reported to affect DC migration by triggering cell-specific signaling machinery, it did not induce their full maturation [37 ].

The use of viruses inactivated with Aldrithiol-2 (AT-2), a procedure that blocks infectivity without altering the conformation of the envelope [38 ], as well as the use of recombinant envelope glycoproteins, provides evidence that most of the effects observed in HIV-exposed DCs are independent of virus replication, but are directly related to gp120-mediated signaling. The major functional defects observed in DC subsets upon their exposure to HIV-1 apart from infection are summarized in Table 1 . In particular, it was shown that exposure of MDDCs to either AT-2-inactivated virus [39 ] or to recombinant gp120 [39 , 40 ], results in the acquisition of a mature phenotype, characterized by a significant up-regulation of co-stimulatory molecules and MHC antigens, as well as in the appearance of the DC maturation marker, CD83. However, despite such activated phenotype, gp120-exposed DCs were functionally impaired in terms of production of effector cytokines (i.e., IL-12 and TNF-{alpha}) and chemokines (CCL3, CCL4, CCL5) and capacity to induce T cell proliferative responses [39 ]. gp120-exposed DCs also retained a high capacity to uptake antigens [39 ]. This finding is consistent with the results from Kawamura and coworkers, showing that enriched populations of in vitro HIV-infected DCs are poor stimulators of allogeneic CD4+ T cell proliferation and IL-2 production [44 ]. It is interesting that these HIV-infected DCs secrete gp120 that, in turn, impairs CD4+ T cell function [44 ]. Functional but not phenotypic impairment of DCs is also observed when immature DCs are generated from monocytes in the presence of gp120 and then stimulated with LPS or CD40L [39 ]. However, it should be noted that, in contrast to the above-mentioned studies documenting DC impairment, Williams and colleagues reported that DC exposure to X4 gp120 results in the acquisition of an activated phenotype that correlates with increased IL-12 production and allostimulatory capacity [40 ]. These discrepancies are likely explained by the fact that different monocytic populations were used to generate DCs, as well as by the different experimental conditions used to differentiate and/or stimulate these cells.


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  		Table 1. Recombinant gp120 and Virion Inactivated-Induced, Functional Defects in DC Subsets


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ALTERED PRODUCTION OF CYTOKINES/CHEMOKINES IN HIV-1 gp120-EXPOSED DC SUBSETS
 
Several studies investigated the functional consequences of HIV exposure of different DC subsets on their capacity to release cytokines and chemokines, immunomediators that play a fundamental role in controlling the homeostasis of the immune system. As a key cell type in innate antiviral immunity, PDCs have been extensively studied in the context of HIV-1 infection. PDCs directly recognize and respond to HIV-1 infection by producing large quantities of IFN-{alpha} [30 31 32 , 34 , 42 , 43 , 45 , 46 ]. Virus-induced IFN-{alpha} contributes, at least in part, to the restriction of viral replication in PDCs themselves [31 , 45 ] and CD4+ T cells [32 ], as well as to the secondary MDC maturation [30 ] (see above). There is general consensus that gp120 is required for IFN-{alpha} induction by PDCs and that this effect is mediated through its interaction with CD4 [30 , 32 , 43 , 46 ]. However, whether gp120 is sufficient to induce IFN-{alpha} production remains controversial. We have recently studied the relative importance of HIV-1 surface components in triggering IFN production in DCs. To address this issue, we comparatively studied IFN-{alpha} production by donor-matched blood DC subsets and in vitro generated MDDCs, exposed to either recombinant gp120 or gp41 [42 ]. Both X4 and R5 gp120 were sufficient to induce IFN-{alpha} secretion by PDCs, although to a lesser extent than the whole inactivated virus. Conversely, negligible IFN-{alpha} secretion was observed upon gp41 treatment [42 ]. In contrast, neither gp120 nor gp41 induced IFN-{alpha} production by MDCs or MDDCs. However, in other studies, gp120 and gp160 preparations from different viral strains failed to induce any detectable IFN production by PDCs [32 , 43 , 46 ]. It is interesting that it was recently reported that IFN-{alpha} production by PDCs in response to HIV-1 requires at least two interactions between the virus and the cell. Initially, envelope-CD4 interactions mediate endocytosis of HIV. Subsequently, endosomally-delivered viral nucleic acids stimulates PDCs through Toll-like receptor TLR7 [46 ]. Additionally, a role for TLR9 signaling in this process was suggested by the inhibition of HIV-induced IFN production by low concentrations of chloroquine [32 ], which are known to selectively block TLR9 [47 ]. These discrepant results between studies may indicate the existence of distinct mechanisms operating at different levels, i.e., one at the level of the cellular membrane upon early DC-HIV-1 interaction, followed by another event occurring within the PDC after viral internalization. It should be noted that different approaches were used in the above-mentioned studies (notably, differences in the number of cells, in the gp120/gp160 preparations, or in the time of treatment), which may have favored one mechanism over another, providing thus an explanation for such discrepant results.

PDC interaction with HIV has also been described to result in the production of a panel of chemokines. In particular, our comparative analysis of PDCs, MDCs and MDDCs from the same donor demonstrated that gp120 up-regulates the production of some inflammatory chemokines (CCL2, CCL3 and CCL4) in PDCs, whereas MDCs seem to be completely refractory [42 ]. These results are in agreement with the data showing the induction in PDCs of the pro-inflammatory cytokine TNF-{alpha} by AT-2-inactivated HIV [30 ] as well as of CCL3 and CCL5 by infectious virus [45 ]. Of note, the respective role of gp120-CD4 interactions vs. gp120-chemokine receptor in the altered production of cytokines/chemokines has only been partially explored.


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INDUCTION OF DC CHEMOTAXIS BY gp120
 
Leukocyte infiltration at the sites of infection or inflammation is a key event in host defense [48 ], and it has been recognized that gp120 or AT-2 inactivated viruses could recruit both T cells and monocytes [49 50 51 ]. Parallel studies carried out in MDDCs have shown migration toward R5 but not X4 HIV-1 strains. Furthermore, pre-exposure of MDDCs to R5 HIV-1 or its recombinant gp120 protein prevents migration toward CCR5 ligands [41 ], which is likely due to gp120-mediated internalization of a number of chemoattractant receptors, including HIV-1 fusion co-receptors. These latter results provide an explanation for the reported viral interference following initial infection, as well as for the suppression of APC-dependent inflammatory reactions.


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EXPOSURE OF DCs TO gp120 AFFECTS THEIR SURVIVAL
 
In addition to the above-described phenotypic and functional DC alterations induced by HIV, several studies reported significant changes in the number of circulating DCs (from different subsets) during the course of HIV infection. However, little is known on the underlying mechanisms and it is still debated whether such numerical changes are the result of cell loss or redistribution of DCs from the blood to other areas. In this regard, exposure of blood PDCs to AT-2-inactivated X4 and R5 HIV-1 increases the viability of these cells, which become able to survive for a few days in the absence of IL-3 [30 ]. In addition, HIV-exposed PDCs exhibit enhanced CCR7 expression [30 , 32 ], enabling them to migrate in response to the chemokine CCL19 [30 ]. Taken together, these data support the hypothesis that decreased number of circulating PDCs may in fact be due to their preferential relocation to lymphoid organs.


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INDIRECT MODEL OF HIV-MEDIATED DC DYSFUNCTION
 
An alternative mechanism to explain HIV-mediated DC dysfunction in vivo is that such defective function is in fact a functional consequence of CD4+ T cell dysregulation. In this model, infection of the affected DCs, or their direct exposure to HIV antigens, is not required. This hypothesis derives from the crucial contribution of cellular interactions between activated CD4+ T cells and DCs in optimal DC activation on one hand [52 ], and the inhibitory effect of HIV antigens, notably HIV gp120, on CD4+ T cell activation, on the other hand [11 ].

We have recently explored the hypothesis of an indirect mechanism for defective DC function, through impaired T cell activation, and we have shown that T cells exposed to AT-2 inactivated HIV-1 provide a sub-optimal activation/maturation signal to DCs [53 ]. This was evidenced by the markedly low upregulation of CD40, CD86, and CD83 expression by DCs cultured with T cells activated in presence of AT-2 HIV. These DCs also exhibited reduced secretion of IL-10 and IL-12 p40 [53 ]. The mechanism by which HIV-exposed T cells are responsible for sub-optimal DC activation likely involves defective CD40-CD40L interactions, since addition of recombinant CD40L overcame impaired DC activation [53 ]. Blunted CD40L expression on HIV-exposed T cells was shown to follow CD4-gp120 interactions, in a coreceptor-independent fashion [54 ]. Therefore, it is likely that inhibition of DC function through the indirect pathway is mainly dependent on CD4-gp120 interactions. It is interesting that IL-12 p40 production was more affected in DCs cultured with T cells exposed to AT-2-inactivated HIV-1 than the other markers of DC activation were. One potential explanation for such differential sensitivity is that IL-12 p40 production is highly dependent on IFN-{gamma}, which is also inhibited in HIV-exposed T cells [55 ]. Thus, both mechanisms (blunted CD40L expression and low IFN-{gamma} production) could have participated into the profound inhibition of IL-12 p40 production.


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INDUCTION OF REGULATORY T CELLS BY DC AFFECTED BY HIV INFECTION
 
One important consequence of dysregulated HIV-mediated DC activation, through direct or indirect mechanisms, could be that immature or partially mature DCs, following their interactions with HIV gp120, can subsequently engage additional antigen-specific CD4+ T cells and drive them to become regulatory T cells (Treg). Indeed, recent studies performed in murine models and with human cells have now clearly established that the role of DCs is not only to sense danger, but also to tolerize the immune system to antigens encountered in the absence of maturation/inflammatory stimuli [56 , 57 ]. Our results are in agreement with that hypothesis, because we have shown that naïve allogeneic T cells, following their stimulation by DCs cultured with HIV-exposed T cells, exhibit a profile reminiscent of that of Tr1-type regulatory cells, i.e., low proliferation, reduced production of IFN-{gamma}, but increased production of IL-10 [53 ]. Along the same line, after co-culture with HIV-infected immature DCs, T cells suppress proliferation of allogeneic T cells in a mixed lymphocyte reaction [36 ]. In this latter study, the degree of suppression correlated directly with the amount of IL-10 produced, although the cellular source of IL-10 was not determined. DCs exposed to whole HIV, but not DCs pulsed with the gag protein, induced this defect, underscoring a potential role of gp120 in this phenomenon [36 ]. Finally, strongly supporting the hypothesis that HIV-induced changes in DCs play a role in Treg induction, it was recently reported that the DCs purified from the lymph nodes of untreated HIV-infected subjects stimulate allogeneic CD4+ T cells to express FOXP3, the most reliable marker of Treg function, whereas lymph node DCs from uninfected control subjects do not [58 ].

Taken together, the results from these recent studies support a model in which HIV-mediated DC dysregulation not only impairs activation of effector T cells, but also promotes Treg emergence in the lymphoid tissues, where HIV concentrates. This latter effect would be predicted to have long-lasting detrimental consequences on the capacity of the immune system to control HIV replication. Moreover, because Treg-mediated suppression appears to be largely antigen non-specific, the resulting Treg may also suppress effective T cell responses to other pathogens, as might occur in subjects progressing to AIDS.


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CONCLUDING REMARKS
 
Despite the extensive research on DC biology over the last decade, we are still in the early stages of understanding all aspects of HIV interaction with DCs. As summarized here, recent findings show that HIV-1 exerts immunomodulatory effects on DCs, as it affects maturation, cytokine profile production, T cell stimulatory function, and migration. It has become increasingly evident that these effects can result from the effects exerted by gp120, locally released at the sites of active viral replication, or by non-infectious viruses harboring conformationally-intact envelope glycoproteins. In addition, DC biology can be indirectly affected as a functional consequence of CD4+ T cell dysregulation. Thus, HIV-1 targeting of DC function may represent a pivotal mechanism exploited by HIV-1 to subvert the host immune system. In this model (Fig. 1 ), gp120 affects the biology and function of uninfected DCs by acting at several levels: i) on DC precursors (blood monocytes) to generate DCs that exhibit a canonical phenotype but do not undergo full activation upon maturation induction; ii) on iDCs, inducing a partially mature phenotype; iii) on PDCs, inducing IFN-{alpha} and CC-chemokine production, thus favoring the recruitment of new targets susceptible to viral infection and to immune dysregulation; and finally, iv) on the level of activation of T cells, consequently impairing the process of DC maturation induced by their interactions with activated T cells. Thus, understanding how HIV subverts DC biology is crucial to design strategies biasing the DC system toward the activation of protective immune responses instead of facilitating virus spread.


Figure 1
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  		Figure 1. Model showing how HIV-1 may succeed in evading the host immune response through gp120-mediated direct and indirect bystander effects.


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ACKNOWLEDGEMENTS
 
These studies were supported by research grants from the National Institutes of Health to S. G. (AI054215) and C. C. (AI056927). The authors thank Dr. G. M. Shearer for critical reading of this review and Cinzia Gasparrini for her excellent editorial assistance.

Received March 3, 2006; revised May 16, 2006; accepted May 17, 2006.


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