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Originally published online as doi:10.1189/jlb.0403178 on July 22, 2003

Published online before print July 22, 2003
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(Journal of Leukocyte Biology. 2003;74:683-690.)
© 2003 by Society for Leukocyte Biology

Immunodeficiency virus exploitation of dendritic cells in the early steps of infection

Natalia Teleshova, Ines Frank and Melissa Pope1

Center for Biomedical Research, Population Council, New York, New York

1Correspondence: Center for Biomedical Research, Population Council, 1230 York Avenue, New York, NY 10021. E-mail: mpope{at}popcbr.rockefeller.edu


   ABSTRACT
TOP
 ABSTRACT
THE DENDRITIC CELL (DC)...
 DC-MEDIATED SPREAD OF...
 AVERSION OF EFFECTIVE IMMUNE...
 SUMMARY AND FUTURE DIRECTIONS
 REFERENCES
 
The unique capacity of dendritic cells (DCs) to capture and process pathogens for presentation to the immune system, combined with their capacity to express costimulatory and adhesion molecules as well as cytokines and chemokines, renders them powerful antigen-presenting cells. However, immunodeficiency viruses hijack DCs to facilitate virus dissemination while subverting effective immune activation. Depending on the activation level of the DC subset, human immunodeficiency virus can use different receptors (CD4, chemokine, and C-type lectin receptors) to bind to DCs. These aspects likely impact whether a DC is productively infected by or simply carries virus for transmission to more permissive targets. DCs efficiently transmit virus to CD4+ T cells, driving virus growth as well as providing signals to trigger virus expansion in virus-bearing CD4+ T cells. There is accumulating evidence that viral determinants (nef, tat) selectively modulate immature DC biology, fostering DC–T cell interactions and virus replication without up-regulating costimulatory molecules for effective immune function. In addition, virus-loaded, immature DCs activate CD4+ virus-specific T cells, and mature DCs stimulate CD4+ and CD8+ T cells. Thus, even if immature DCs entrap virus as it crosses the mucosae and initiate a CD4+ T cell response, this is likely insufficient to control infection. Appreciating how virus modulates DC function and what determines whether virus is processed for immune stimulation or transmitted between cells will unveil the exact role of these cells in the onset of infection and advance preventative microbicide and vaccine/therapeutic approaches.

Key Words: antigen-presenting cells • T cells • CD4+ • HIV • SIV


   THE DENDRITIC CELL (DC) SYSTEM
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 ABSTRACT
 THE DENDRITIC CELL (DC)...
DC-MEDIATED SPREAD OF...
 AVERSION OF EFFECTIVE IMMUNE...
 SUMMARY AND FUTURE DIRECTIONS
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DC biology is becoming increasingly complex and has recently been detailed in several reviews [1 2 3 4 5 6 7 8 ]. A summary of classical DC features and those most relevant to human immunodeficiency virus (HIV) biology is provided in Table 1 . The DC system comprises two major subsets, MDCs and PDCs [1 , 2 , 10 ]. Each has distinct characteristics that may contribute uniquely to orchestrate immune activation but also to HIV infection. PDCs represent a more-recently defined population found predominantly in blood, cerebrospinal fluid (CSF), and lymphoid tissues and are distinguished from MDCs by the expression of CD123 and BDCA-2 and the absence of classical myeloid markers [10 , 11 ]. Moreover, they are distinct from MDCs in that they produce high levels of type 1 interferons (IFNs) in response to microbial stimuli [1 , 2 , 12 ]. Several different subsets of DCs make up the MDC pool, including circulating MDCs (blood and CSF), IDCs in the T cell areas and germinal center DCs of the B cell areas of lymphoid tissues, DCs in the dermis or submucosal tissues, LCs in the epidermis or outer epithelial tissues of the mucosae, and those generated in vitro from blood moDCs or bone marrow (BM) precursors. Recent work suggests that up to five subsets of phenotypically distinct DCs have been identified in blood [13 ].


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  		Table 1. DC Membrane Phenotypes–Molecules Involved in HIV-Capture/Infection and Characteristic Markers Commonly Monitored in DC Biology

 
DCs are motile cells, migrating continuously around the body even under steady-state conditions, and directed migration in response to inflammatory cytokines and chemokines is enhanced in the face of inflammation [14 15 16 17 18 19 ]. DCs are BM-derived cells that are typically re-seeding tissues from progenitors circulating in the blood. It is interesting that a recent report suggested that although the re-seeding of skin upon LC migration in response to inflammatory signals involves blood-borne cell precursors, the steady-state maintenance of LCs in the skin involves cells coming from a non-BM source, possibly through low-level proliferation of a resident population [20 ]. This finding may have important implications for the LC subsets involved in the earliest stages of infection after exposure to HIV, which crosses healthy resting versus inflamed mucosal surfaces (as may occur as a result of tissue damage or coinfection). The motility of DCs likely allows virus that has been captured by them to rapidly move to lymphoid tissues, where virus can be efficiently amplified upon encountering permissive target cells, e.g., CD4+ T cells and macrophages.

DCs in the circulation and peripheral tissues are normally in what is described as an immature state, expressing low levels of adhesion and costimulatory molecules that are necessary for the activation of strong T and B cell responses. In fact, immature DCs appear to be pivotal in the development and maintenance of peripheral tolerance (reviewed in refs. [3 , 21 , 22 ]), a feature that HIV may capitalize on to avoid immune activation (below). Even targeting an antigen directly to DCs in vivo did not induce active immunity (rather an unresponsive tolerogenic state) unless the DCs were coincidently activated via CD40 [23 ]. Activation of DCs through tumor necrosis factor (TNF)–TNF receptor interactions and TLRs stimulates them to express higher levels of costimulatory and adhesion molecules (Table 1) and secrete chemokines and cytokines to favor DC–T and DC–B cell interactions that drive immune activation (reviewed in refs. [4 , 24 ]). This can occur as DCs migrate to draining lymphoid tissues, where they activate adaptive immunity. In general, immature DCs express the CCRs CCR5 and CCR6, which are down-modulated on maturation. Coincidently, CCR7 and CXCR4 increase upon DC maturation, dictating the migratory pathways of these cells into the lymphoid tissues.

As a strong animal model to study HIV pathogenesis, DC biology in the macaque system has begun to be intensely investigated in the last years. Characteristic myeloid-derived DCs possessing many of the attributes described for human DCs can be identified and isolated from the tissues of healthy and simian immunodeficiency virus (SIV)-infected macaques [9 , 25 26 27 28 ] as well as being generated from blood monocytes [29 30 31 ] or BM progenitors [32 ]. CD11c+CD123-/low MDCs and CD11c-CD123+ PDCs have also been identified in the blood and lymph nodes (LNs) of macaques (N. Teleshova, Jennifer Jones, and M. Pope, in preparation; Mark Feinberg, 2003 HIV Pathogenesis Meeting, Palm Springs, CA).


   DC-MEDIATED SPREAD OF IMMUNODEFICIENCY VIRUS INFECTION
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Infection of DCs versus capture and internalization of virus by DCs
DCs express CD4, CCRs, and CLRs; however, the subset of DCs and its state of activation strongly influence which of these molecules is expressed and at what levels (Table 1) . Although these molecules usually function to facilitate normal DC activities (e.g., antigen capture, migration, DC–T cell interactions), they also play a critical role in the interactions with immunodeficiency viruses. Although it is likely never an all-or-none situation, the use of specific receptors by distinct DC subsets probably determines whether these cells get productively infected versus whole virions being captured and internalized by the cell before being transmitted to neighboring leukocytes.

CCR5-expressing, immature moDCs, LCs, MDCs, and PDCs are especially susceptible to productive infection with R5 HIV [9 , 33 34 35 36 ], yet activated moDCs or LCs (in which CCR5 expression is diminished) appear to be more resilient (reviewed in ref. [9 ]). In contrast, immature and mature DCs can capture R5 and X4 viruses, a process which is largely dependent on CLRs (and CD4), and transmit them to permissive cells to augment virus amplification. A recent report from Nguyen and Hildreth [37 ] detailed the use of the CLR macrophage mannose receptor (CD206) in capture and transmission of virus by macrophages. Studies have also highlighted the involvement of CLRs, such as DC-SIGN (CD209; reviewed in ref. [38 ]) and CD206 in virus-capture by DCs, and how the contribution of these receptors to virus-binding/uptake varies depending on the subset being examined [39 , 40 ] (Table 1) . Specifically, immature moDCs, fresh LCs, and dermal DCs from skin predominantly use CLRs to bind HIV envelope, whereas CLRs and CD4 are involved in virus-binding/uptake by matured moDCs, and emigrated skin DCs as well as PDCs and MDCs resident in tonsillar tissue or blood primarily use CD4. Thus, the selective expression of CLRs by distinct DC subsets and the contribution of additional CLR(s; and possibly non-CLRs) that are yet to be defined underscore the complex nature of CLR involvement in DC-virus interactions.

Although some virions likely fuse with the outer membrane of DCs, considerable amounts of virus are internalized by immature and mature DCs and held in distinct intracellular locations [41 ]. This virus appears to be sequestered in compartments that lack traditional endolysosomal markers [42 ] (Stuart Turville et al., submitted). Recent reports [42 , 43 ] suggested that the CD209-bound virus can be rapidly internalized and then protected from degradation to facilitate subsequent transmission to nearby CD4+ T cells over time. However, we recently observed that although some internalized virus is retained in immature and mature DCs, there is considerable degradation of virus/viral proteins with time, and this coincided with a reduction in virus transmission to T cells unless the virus was amplified in the immature DC subset (Stuart Turville et al., submitted). CD209 can contribute to virus-binding and may also be internalized by certain immature DC subsets. However, this does not account for all virus captured by DCs, as blocking with mannan and anti-CD209 monoclonal antibodies (Ab) is only partial. It also seems unlikely that CD209 contributes significantly to virus capture by mature DCs or LCs, as its surface expression is significantly reduced or nonexistent. Data from our laboratory indicate little if any colocalization of internalized virus with CD209 or CD206 within moDCs (Stuart Turville et al., submitted). If virus is internalized bound to these receptors, it is likely rapidly released from the receptor, which then recycles to the cell surface. It is interesting that gp120 binding and internalization correlated with down-modulation of CD206 expression by immature DCs, but this was not the case for CD209 (Stuart Turville et al., submitted). Alternatively, CLR-bound virus might be handed on to another receptor(s) before its internalization.

DC-mediated transmission
DCs efficiently transmit infectious virus to neighboring CD4+ T cells (reviewed in ref. [9 ]). In fact, recent work suggests that DC-mediated virus transfer occurs in two distinct phases: First, immature and mature DCs readily capture and internalize virus before transmitting it to CD4+ T cells (in the absence of DC infection), and second, after the decline of the first phase, the amplification of R5 HIV in immature DCs contributes to the spread of newly synthesized progeny virus to CD4+ T cells (Stuart Turville et al., submitted). DC-mediated transmission is particularly efficient with activated T cells but is readily observed with resting CD4+ T cells that do not need to proliferate to support virus growth [44 45 46 ]. Of note, addition of DCs to virus-loaded, resting T cells also triggered virus replication in resting cells [47 ], which occurs most rapidly with memory T cells [9 ]. Subsequent observations that resting T cells can be productively infected in situ within days after mucosal exposure [48 , 49 ] can be explained by the fact that DCs may capture and/or get infected initially [50 , 51 ] and then transmit the virus to these T cells coincident with providing the suboptimal activation signals that do not induce effective T cell proliferation but drive virus growth. In addition, DCs within the tissues can provide signals to circulating virus-carrying, resting T cells, which upon triggering, get induced to express virus.

In vivo, DC-mediated transmission was observed when subcutaneously reinjected DCs that had been loaded with SIV ex vivo readily transmitted infection to the donor macaques [52 ]. Notably, unlike cell-free virus, which resulted in infected CD4+ T cells representing >90% of the virus-producing cells in the draining LNs, the draining LNs of animals that received DC-associated virus contained between 25% and 50% virus-positive macrophages. Thus, cell-associated virus appeared to increase the involvement of macrophages in the earlier stages of infection and may have important implications for virus dissemination and immune activation. Whether this observation reflects direct DC-to-macrophage transmission versus macrophages picking up virus as a result of ingestion of (e.g., dying) reinjected DCs is unclear and requires further examination.

The exact mechanism facilitating DC-driven transmission (to T cells, macrophages, and any other permissive target cells) remains to be elucidated fully, and whether this differs when the DC is carrying R5 versus X4 viruses is not known. DC-driven transmission of HIV/SIV to T cells requires cell contact [53 54 55 ] and can be efficiently blocked using anti-envelope Ab [56 , 57 ], small molecule CCR5 inhibitors [58 , 59 ], but only partially at best with anti-CD209 Ab [42 , 53 , 60 61 62 ] (compared with virtually complete blocks of transmission by DC-SIGN-expressing transfectants). These data suggest the involvement of envelope glycoprotein interacting with receptors on the recipient T cells (some of which involves CCR5), but this process is unlikely to be heavily dependent on CD209 on the virus-bearing DC. Such transmission may involve newly produced virus budding from the cell membrane of the DC (immature DCs) and/or whole virus being released from within compartments of the DC (immature and mature DCs; Fig. 1 ).



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  		Figure 1. Possible modes of virus transmission from DCs to permissive CD4+ T cells. Immature and mature DCs internalize virions that can be released from the intracellular compartments at the DC–T cell contact points for direct transfer of whole virus to T cells. Following productive infection of the immature DCs, new progeny viruses released from the cell surface and handed over to T cells may also contribute to virus spread.

 
Recent work visualized the movement of virus from DCs to the recipient T cells [55 ] (Stuart Turville et al., submitted). Virus carried by immature or mature DCs moved rapidly to the contact point between the DC and CD4+ T cells, much like as it has been described for human T cell lymphotropic virus 1 [63 ]. This was true for resting and activated T cells, and virus protein accumulation at the contact point was even detected during the second phase of transfer from virus-producing, immature DCs (Stuart Turville et al., submitted). Such rapid and directed movement of virus to the DC–T cell synapse and subsequent handing-over of virus to the T cells suggest an efficient mode of DC-driven virus spread to T cells as may occur in vivo. Moreover, this resembles the directed, tubular movement of major histocompatibility complex (MHC)-II peptide complexes in DCs to contact points with peptide-specific T cells [64 , 65 ], which may be exploited by the virus to facilitate its spread to T cells, especially virus-specific CD4+ T cells [66 ].


   AVERSION OF EFFECTIVE IMMUNE ACTIVATION BY THE VIRUS TO ENCOURAGE INFECTION
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 THE DENDRITIC CELL (DC)...
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DCs promote virus replication, particularly in concert with CD4+ T cells, but in their role as potent antigen-presenting cells (APCs), DCs are bound to also activate virus-specific responses during infection. However, these responses are undoubtedly inept in controlling virus spread. Specifically, at the time of infection, virus dissemination is likely to be more rapid than the establishment of effective antiviral immunity [67 ]. A major contributing factor is that unlike other pathogens, immunodeficiency viruses do not activate DCs, as is necessary to augment their immunostimulatory function for the induction of effective antiviral immunity (reviewed in ref. [5 ]). Also, gp120 expressed by HIV-infected, immature moDCs impaired normal CD4+ T cell responses in vitro [68 ], suggesting an additional mechanism through which HIV-specific responses may be impeded.

Innate and adaptive immunity
Recent studies using conformationally intact yet noninfectious viruses confirmed that DCs can capture virus, process it, and present viral antigens to virus-specific T cells [31 , 69 70 71 72 ]. Initial in vivo studies also suggest that DCs carrying inactivated viruses can activate SIV-specific responses [73 , 74 ]. It is interesting that direct comparison of virus-carrying immature and mature DCs in vitro revealed that, although immature DCs activated virus-specific CD4+ T cells, mature DCs were able to stimulate CD4+ and CD8+ T cell responses [71 , 72 ]. This has important implications for DC-targeted immune therapies or vaccinations (reviewed in ref. [8 ]) as well as emphasizing how virus may take advantage of immature DCs that they encounter during mucosal transmission. Specifically, by only stimulating CD4+ T cells, this could exacerbate virus spread from immature DCs to the virus-specific (as well as nonspecific) T cells in the absence of any killing from CD8+ T cells. Even if mature DCs are encountered (as may occur in inflamed tissues), they will spread virus to nearby CD4+ T cells more rapidly than any virus-specific T (or B) cell response could be initiated. In chronic infection, virus-carrying DCs that may meet circulating CD4+ T cells would continue to foster virus growth, most notably in virus-specific cells. Hence, it is critical to dissect what drives virus spread over immune activation in the DC–T cell milieu.

Interactions of HIV with CLRs on DCs may also influence DC function to discourage the activation of immune responses needed for effective viral clearance [75 ]. Recent investigations revealed how the binding of Mycobacteria to CD209 actually resulted in inhibition of immunostimulatory activity by blocking Mycobacterium-induced DC maturation and inducing interleukin (IL)-10 production [76 ]. Furthermore, ligation of the CLR, BDCA-2, on PDCs suppressed IFN-{alpha}/ß production by PDCs [77 ], inferring ways in which pathogens binding this molecule (and related molecules) might be able to thwart innate and adaptive PDC functions.

Innate-immune responses probably play an important role in the initial control of acute infection and in dampening ongoing infections to limit virus spread. Although defensins may contribute antiviral activities [78 79 80 81 ], and MDCs produce and respond to defensins [82 83 84 85 ], it is yet to be determined whether innate DC-defensin responses are involved in HIV infection. However, innate responses of PDCs against viruses have been explored in more detail. Unlike MDCs, PDCs respond to a variety of stimuli by secreting enormous amounts of type 1 IFNs [1 , 2 , 12 ]. The ability of blood cells to secrete type 1 IFNs and PDC numbers in blood reportedly decreases with HIV disease progression [86 87 88 89 ]. Moreover, PDCs produce type 1 IFNs in response to HIV (Vassili Soumelis, personal communication) [90 ] and SIV (N. Teleshova, Jennifer Jones, M. Pope, in preparation) in vitro; however, it is possible that the magnitudes and kinetics of HIV-induced responses are reduced compared with other pathogen stimuli (Vassili Soumelis, personal communication) [90 ]. What happens to PDCs in the lymphoid tissues during acute and chronic infection needs to be evaluated. PDCs poised in lymphoid follicles associated with the mucosae are in prime locations to encounter incoming virions. Whether these cells are capable of secreting type 1 IFNs as an immediate response as well as providing targets for virus amplification (as has been suggested from in vitro blood PDC studies; refs. [9 , 35 , 36 ]) also remains poorly understood. It is possible that suboptimal type 1 IFN responses, as HIV/SIV infects PDCs, would also provide minimal protection against virus spread. Whether virus can modify PDC function, as has been shown for MDCs (below), will also be critical to better appreciate PDC-virus biology.

Selective modulation of immature DC function
There is increasing evidence that immunodeficiency viruses selectively modulate immature DC function to favor virus spread (Table 2 ). This was prompted from initial studies that demonstrated virus replication in immature moDC–T cell mixtures is dependent on nef (unlike mature DC–T cell mixtures) [47 , 99 , 100 ]. Thus, immature DCs presenting nef-defective viruses do not drive rapid virus amplification and may therefore allow the activation of stronger immunity to delay the onset of disease. As wild-type (nef-containing) virus replicated well in the presence of immature DCs, studies were performed to examine the effects of nef on immature DCs.


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  		Table 2. Modulation of Immature DCs by Immunodeficiency Viruses

 
Several studies revealed that although endogenously expressed nef does not up-regulate costimulatory molecules (necessary for effective immune activation), several nef-dependent changes occurred in the immature DCs that makes them behave more like a mature DC at the level of their ability to promote virus replication. These include the release of cytokines and chemokines (IL-6, -8, -12, TNF-{alpha}, MIP-1{alpha}, -1ß, and RANTES) and increased clustering with lymphocytes, which correlated in some instances with elevated CD4+ T cell signaling and virus growth [92 93 94 95 96 97 ]. Although several different approaches were used, and there were some contradictions between studies (possibly explained by the experimental differences; Table 2 ), a consistent observation was the alteration of the cells to favor virus dissemination. Much as has been described for macrophages [101 , 102 ], nef can selectively modulate immature DCs to recruit additional leukocytes to the initial site of infection to drive virus spread in the absence of activating, potent antigen-specific CD4+ and CD8+ T cells. These observations suggest that nef expertly subverts APCs to facilitate HIV spread and amplification [103 ].

Similar observations were recently reported in response to HIV tat [98 ]. Although distinct from the effect of nef, tat reportedly activated the expression of IFN-responsive genes as well as the release of specific chemokines (IP-10, HuMIG, MCP-2, and MCP-3) to favor T cell and monocyte recruitment. Again, these events occurred in the absence of phenotypic activation of the immature DCs, further supporting virus propagation over immune activation. Therefore, to date, at least two immunodeficiency virus determinants have been shown to directly modify immature DC function to encourage virus dissemination while averting effective antigen presentation for effective T (and B) cell stimulation.


   SUMMARY AND FUTURE DIRECTIONS
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 ABSTRACT
 THE DENDRITIC CELL (DC)...
 DC-MEDIATED SPREAD OF...
 AVERSION OF EFFECTIVE IMMUNE...
 SUMMARY AND FUTURE DIRECTIONS
REFERENCES
 
DCs have a unique capacity to efficiently capture pathogens and present them to the immune system. Immunodeficiency viruses have however taken advantage of this biology to facilitate the onset of infection and their dissemination to surrounding permissive cells. Future work must identify how virus is specifically handled by distinct DC subsets and then transmitted to neighboring target cells. A complete understanding of the mechanism(s) of DC modulation by immunodeficiency viruses is also critical. An appreciation of these aspects of DC-virus biology will reveal potential targets to progress the development of preventative microbicide and vaccine strategies.


   ACKNOWLEDGEMENTS
 
M. P. is an Elizabeth Glaser Scientist of the Elizabeth Glaser Pediatric AIDS Foundation and is supported by NIH Grants R21 AI52060, R01 AI40877, P01’s HD41752, and AI52048, The Rockefeller Foundation, and the Elizabeth Glaser Pediatric AIDS Foundation. The authors thank Evan Read for assistance with the computer graphics.

Received April 24, 2003; revised June 11, 2003; accepted June 17, 2003.


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