Originally published online as doi:10.1189/jlb.0503208 on September 2, 2003
Published online before print September 2, 2003
(Journal of Leukocyte Biology. 2003;74:710-718.)
© 2003
by Society for Leukocyte Biology
The role of dendritic cell C-type lectin receptors in HIV pathogenesis
Stuart Turville*,
John Wilkinson*,
Paul Cameron
,
Joanne Dable* and
Anthony L. Cunningham*,1
* Centre for Virus Research, Westmead Millennium Institute, Westmead, NSW 2145, Sydney, Australia;
Department of Immunopathology, ICPMR, Westmead Hospital, Westmead, NSW 2145, Sydney, Australia
1 Correspondence: Westmead Millennium Institute, P.O. Box 412 Darcy Road, Westmead, NSW 2145, Australia. E-mail: tony_cunningham{at}wmi.usyd.edu.au
 |
ABSTRACT
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Dendritic cells play a major role in HIV pathogenesis. Epithelial dendritic cells appear to be one of the first cells infected after sexual transmission and transfer of the virus to CD4 lymphocytes, simultaneously activating these cells to produce high levels of HIV replication. Such transfer may occur locally in inflamed mucosa or after dendritic cells have matured and migrated to local lymph nodes. Therefore, the mechanism of binding, internalization, infection and transfer of HIV to CD4 lymphocytes is of great interest. Recently, the role of the C-type lectin DC-SIGN as a dendritic cell receptor for HIV has been intensively studied with in vitro monocyte-derived dendritic cells. However, it is clear that other C-type lectin receptors such as Langerin on Langerhan cells and mannose receptor on dermal dendritic cells are at least equally important for gp120 binding on epithelial dendritic cells. C-type lectin receptors play a role in virus transfer to T cells, either via de novo infection ("cis transfer") or without infection ("in trans" or transinfection). Both these processes are important in vitro, and both may have a role in vivo, although the low-level infection of immature dendritic cells may be more important as it leads to R5 HIV strain selection and persistence of virus within dendritic cells for at least 24 h, sufficient for these cells to transit to lymph nodes. The exact details of these processes are currently the subject of intense study.
Key Words: Langerhans cells • monocyte derived dendrite cells • DC-SIGN • mannose receptor • Langerin • HIV receptors • HIV transmission
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The dendritic cell family
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Dendritic cells (DCs) play a key role in the defense against invasion by pathogens, the development and maintenance of innate and adaptive immunity of such pathogens and mediation of vaccine-induced immunity. However, they can be subverted by microbes, especially HIV, to transport viruses and bacteria to target organs. DCs are antigen-presenting cells, the only ones capable of initiating a primary immune response, but they are also a major source of chemokines and cytokines.
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Diversity within the DC family: DC subsets in vivo
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DC populations can be subdivided into four subsets, which include the precursor DC, plasmacytoid DC, immature DC and mature DC. Precursor DC (pre-DC) are postulated to migrate from the bone marrow to peripheral tissues in blood, where chemokine and cytokine gradients stimulate migration of pre-DC and subsequent differentiation into tissue resident DC. Pre-DC differs from classic immature and mature DC, as they can rapidly assume either the phenotype of immature or mature DC, under appropriate in vitro or in vivo conditions. Pre-DC have been traditionally identified in blood and/or lymphoid tissue as "Lineage Negative," cells defined by the lack of the surface markers CD3, CD14, CD11b, CD56, and CD19 and by the expression of CD11c and moderate to high HLA-DR [1
]. (Fig. 1
upper panel). Peripheral blood subsets such as "monocyte" populations bearing CD2, CD16, and DC-SIGN may also act as precursors to DCs [1
, 2
3
4
5
6
7
]. Some evidence for the role of monocytes as DC precursors was provided by the well-known conversion of peripheral blood monocytes to monocyte-derived dendritic cells (MDDC with IL-4 and GM-CSF), an in vitro model for immature dermal or interstitial DC [8
9
10
].
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Figure 1. Schematic representation of human DC subsets in vitro and in vivo. DC subsets are presented either as precursor, immature, or mature DCs with several representative phenotypic markers presented below each subset. DCs’ putative differentiation pathways from precursor subsets through to the final mature DC subset are present as lines linking potentially related DC subsets.
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Another "lineage-negative" blood DC population that expresses high levels of HLA-DR and also markers BDCA-2 and CD123 but not CD11c is the family of plasmacytoid DC [11
, 12
]. They are considered separate from the pre-DC as they are key cells of the innate immune response in vivo and can prime the adaptive immune response by production of high levels of type I interferons [13
], especially in response to viral (including HIV) challenge [14
].
The immature DCs comprise myeloid populations acting as sentinels in various tissues where they entrap microbes and microbial antigens and convey them to local lymphoid tissue or lymph nodes for establishment of immunity (see [1
, 15
] for review). Langerhans cells (LCs) [16
] are located within the basal and suprabasal layers of the stratified squamous epithelium of skin and oral and ano-genital mucosa [17
, 18
]. They characteristically express high levels of CD1a antigen, intracellular Birbeck granules (trilaminar cytoplasmic structures visible by electron microscopy) and the C-type lectin, Langerin [19
] (Fig. 1
middle panel). The role of Langerin on LCs is yet to be determined, although it is capable of binding mannose-bearing ligands such as those on microbial glycoproteins [20
]. Introduction of Langerin into heterologous cells results in appearance of Birbeck granules [19
].
Subjacent to the epithelium are the diverse and widely distributed interstitial DCs. They differ functionally from LCs as they variably express the CD1a antigen and do not contain Birbeck granules [21
]. The interstitial DC network is present in the dermis [22
23
24
] and oral, vaginal, and colonic lamina propria [25
26
27
]. One of the most studied interstitial DC is the dermal DC. The dermal DC expresses CD1b and shows heterogenous and low-level expression of CD1a, CD1c, and CD14 expression [1
, 22
23
24
, 28
, 29
].
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Surface receptors for microbial antigens on DCs
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Surface receptors of DCs are capable of binding microbial antigens and include Fc receptors, the pattern-associated membrane proteins (PAMPs) or Toll-like receptors and C-type lectin receptors (CLRs) [30
31
32
33
34
]. DCs can take up molecules via endocytosis mediated through clathrin-coated pits or via caveolae, macropinocytosis, or phagocytosis [35
, 36
]. The latter is defined as ingestion of particles >0.5µm in size and is mediated by receptors, actin-myosin interactions, and kinase/ATP dependence. Immature DCs are phagocytic, but less than macrophages. Phagocytosis allows uptake of apoptotic cells and ‘cross priming’ of CD8 cells [37
]. Macropinocytosis is a major mechanism for fluid-phase uptake. After uptake, endocytosed molecules enter early endosomes where they may either be selectively retrieved and recycled to the plasma membrane (recycling endosomal pool) or pass into the late endosomes where the pH starts to drop (
6) and enzymatic digestion of protein antigens begins, resulting in 15-22mers which bind to MHCII molecules in an MHCII-enriched compartment. Phagocytosis follows a similar pathway with the initial formation of phagosomes to which lysosomes fuse, delivering enzymes for digestion of its contents [38
, 39
].
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Maturation and migration of DCs
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Immature MDDCs are highly endocytic but less potent immune stimulators. Maturation diminishes endocytosis but increases immunostimulatory function, especially to T-lymphocytes. This occurs via TNF-TNFR or TLR-mediated activation pathways [38
39
40
41
]. DC-T cell interactions normally trigger DC activation via the TNF family members (e.g., CD40L). Maturation results in up-regulation of DC adhesion and costimulatory molecules; help in binding to and activation of T cells; modulation of chemokine receptors, which help direct DCs to the lymphoid tissues; and the secretion of cytokines (IL-12, IL-15, IL-18) and chemokines (MDC, TARC, ELC), which stimulate DC-T cell interactions, which in turn drive CD4 and CD8 lymphocyte activation [42
]. Maturation of DCs results in decreased CCR5 and increased CXCR4 expression in slightly different patterns in LCs and MDDCs in vitro [43
].
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Interaction of HIV with DCs
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Acute SIV replication can be observed within LCs, tissue DCs, and resting T cells in the genital mucosa of macaques soon after infection [44
, 45
]. Migrating DCs are probably responsible for transport of SIV/HIV to T cell regions of draining iliac or colonic lymph nodes [46
]. Infection of an activated CD4 lymphocyte is more efficient when the virus is transferred during a DC-T cell response. During the early phase of HIV replication in vivo, this DC-T-lymphocyte synergy is likely to play a major role in initial viral replication. This view is supported by observations of highly active replication of HIV-1 within lymphoepithelia of lymphoid tissue within syncytia containing DC markers [47
, 48
]. DC-lymphocyte synergy during HIV infection is also supported by in vitro observations of HIV-infected DC-CD4 lymphocyte cocultures. HIV infection can result in syncytium formation between DC and multiple bound T-lymphocytes, leading to viral production greater than that of any individual cell population [49
, 50
]. Such HIV or SIV transfer from DC to CD4 lymphocytes probably occurs predominantly in the lymph node but may also occur within DC-T cell clusters in inflamed skin or mucosa.
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HIV binding to DC receptors
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Viral attachment to DCs independent of CD4 and coreceptors can be followed by internalization and/or transfer to permissive T cells [51
, 52
]. Transfer of virus to these permissive T cells without de novo infection of DCs has been termed "trans"- infection or infection "in trans" (Fig. 2A
). The conventional cell membrane receptors, CD4 and CCR5, as well as CLRs and perhaps heparin sulfates are responsible for initial viral binding. The cooperation of CLRs and CD4/CCR5 in enhancing de novo infection of DCs has been termed "cis infection." Fig. 2B
). Binding mechanisms to HIV binding are often cell-type specific: Heparin sulfates may contribute on macrophages, but play a lesser role in particular DC subsets. CLR expression is diverse and abundant on epithelial DCs and MDDCs but only as mannose receptor (MR) on macrophages [33
].
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Figure 2. Role of C-type lectin receptors in enhancement of DC infection and viral transfer from DC to CD4 lymphocytes. (A) "Cis," enhancement of DC infection. In (A(i), initial viral attachment occurs predominantly via C-type lectins and then (ii) HIV is transferred to CD4 for CD4/CCR5-dependent viral fusion ("Cis" enhancement). In (B) "Trans" enhancement of CD4 lymphocyte infection through DC and their C-type lectins. In (B)(i),attachment and subsequent endosomal delivery occurs through C-type lectins. Subsequent contact with a CD4 lymphocyte bearing CD4/CCR5 in (B)(ii) results in viral regurgitation at the DC-lymphocyte interface.
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There has been mounting interest and controversy surrounding the role of CLRs expressed by DCs in binding HIV. DC-SIGN was initially suggested to play a key role in HIV dissemination by DC in vivo based on experiments with transfected cell lines and MDDCs [53
, 54
]. However on certain DC subsets in vivo other CLRs, such as Langerin (on LCs) and MR (on dermal DCs) must be more relevant. Therefore, DC-SIGN, although important, may represent only one of several CLRs on DCs that are able to interact with HIV in vivo. Nevertheless, the extensive studies of DC-SIGN documented in the literature provide important paradigms for functions of CLRs in general.
CLRs such as DC-SIGN and MR bind via their carbohydrate recognition domains to multiple high mannose but not complex oligosaccharides on gp120 via trimannose or single mannose-branched structures, respectively [55
56
57
58
].
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Dendritic cells express a diversity of HIV-binding C-type lectin receptors in vivo
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Like most biological systems, the interplay between HIV and DCs is complex. The first level of complexity is that not all DCs are similar (Fig. 1)
. One of the difficulties in DC HIV research has been the isolation of intact DCs from either tissue or blood and/or the change in phenotype during the process of isolation. Therefore, in vitro models, especially MDDCs derived from stimulation of monocyte precursors with IL-4/GM-CSF for a week, have been widely used. However, it is unclear which DCs in vivo the MDDCs resemble. They do share markers with dermal DCs [33
, 59
], yet after 6 days of cytokine stimulation, their phenotype is unique, with a complement of DC markers that cannot be attributed to one particular DC subset. For instance immature MDDCs express high levels of MR, DC-SIGN, CD1a, and little or no CD14. The only dermal DC subset in vivo that expresses both of the lectins DC-SIGN and MR expresses CD1a at low levels and significant amounts of CD14 [33
]. Therefore, although MDDC are very important as a model for several aspects of DC and HIV biology, caution must be taken when extrapolating to in vivo DC subsets. Other DC subpopulations lack CLRs like MR or DC-SIGN, but they can still play similar roles, for example, blood plasmacytoid DCs play a major role in the innate immune response to HIV, being infectable and secreting large amounts of type I interferons [14
, 60
61
62
63
64
65
66
67
]. LCs that express Langerin and not DC-SIGN or MR may be as important as lamina propria or dermal DC for SIV/HIV transmission through the stratified squamous genital epithelium. In particular, LCs may be important in viral infection of nontraumatized epithelium. They have a remarkable capacity to bind a large amount of the HIV envelope via Langerin and other CLRs [33
, 34
]. Conversely, dermal lamina propria DC may have a key role in HIV infection of inflamed or traumatized squamous epithelium or of columnar epithelium.
Our studies show the diversity of DC receptor binding of HIV and were initially conducted with monomeric gp120 [33
, 68
]. However, we have recently shown that the patterns of binding of HIV expressing oligomeric gp120 to MDDCs are similar (unpublished data). In DCs from squamous epithelia of skin (similar to the genital mucosa, both important for HIV transmission), gp120 bound to DCs via CLRs. Distinct DC subsets in the dermis and epidermis differed in CLR expression. For instance LCs express Langerin without MR or DC-SIGN, CD1a positive dermal DCs express MR and not Langerin or DC-SIGN and CD14 positive dermal DCs express both DC-SIGN and MR but not Langerin [33
]. Thus, the MDDC in vitro model only represents one immature epithelial DC subset. Why has this functional diversity of epithelial DC subsets developed? Are there differences in microbial oligosaccharide or glycoprotein recognition or processing and ultimately in stimulation of T lymphocytes? Glycoproteins from some microbes (e.g., CMV, hepatitis C, dengue, Ebola, and mycobacteria [69
70
71
72
73
]) but not others [57
] bind to DC-SIGN. Interestingly, when dermal DCs mature and migrate out of epithelium, the CLRs are down-regulated and the cells eventually resemble DCs in blood (and tonsil), which do not usually express CLRs and bind HIV via CD4 [33
]. These observations are consistent with a role for surface CLRs on DCs as a microbial glycoprotein-trapping mechanism in the epithelium. However, inflammation of lymphoid tissue, which generates interleukin 4 can rapidly reinduce DC-SIGN on the surface of DCs (J. Anderssen, personal communication).
Among the blood DC precursors, there is a small population that expresses specifically DC-SIGN and therefore is the only subset capable of CLR-mediated attachment of HIV. The expression of CD14 on this subset and its relatively poor capacity to stimulate in allogeneic mixed leukocyte reactions suggests it may not represent the more stringently defined blood DC precursors [34
]. The other well-defined DC precursors, consisting of the lineage-negative CD1c, BDCA-3, and CD16 subsets are all negative for mannose CLRs and therefore cannot mediate HIV binding by CLR as in MDDC [74
, 33
, 34
, 75
76
77
].
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Beyond attachment: Role of C-type lectin receptors in the internalization of HIV
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Clearly, the heterogeneous distribution of CLRs on different DC subsets throughout the body will affect HIV binding and internalization. There are little data available on the physiological role of internalization of these receptors apart from MR and DC-SIGN. MR and DC-SIGN both contain dileucine (LL) and triacidic (EEE) motifs for internalization in clathrin-coated vesicles [78
]. Studies of trafficking of MR after binding may depend on its bound ligands. Mannose-BSA enters the early endosomes but appears to recycle to the plasma membrane, avoiding trafficking to lysosomes and degradation [79
, 80
]. However, lipoarabinomannan, a microbial ligand rich in oligomannose residues like gp120, colocalizes with MR in late endosomes or lysosomes [81
].
Therefore, the CLRs DC-SIGN, MR, and possibly Langerin may provide a natural route for HIV to the endolysosomal pathway in DCs, and this has been since demonstrated [51
, 82
, 83
], in contrast to initial suggestions of surface retention on THP-1 cell DC-SIGN transfectants. In our unpublished collaborative studies with Dr. Melissa Pope, HIV proteins were completely degraded by this pathway eventually colocalizing with lysosomes but whole HIV/SIV, although degraded, appears not to follow the same route. However, as shown by Lee and colleagues [84
] and lately ourselves [33
], capture of HIV by the CLRs, DC-SIGN, and MR facilitates entry of HIV into the cytoplasm by the conventional CD4/CCR5-mediated neutral membrane fusion. This process, described above is known as "cis" infection (Fig. 2A
and 2B
). Therefore, CLRs facilitate entry into two possible pathways, endocytic or neutral fusion/infection (Fig. 2A
and 2B
and Fig. 3A
and 3B
). Indeed, it can be considered that after HIV binds to its main target cells—CD4 lymphocytes, macrophages, and DCs—there is a gradation in the importance of either mode of entry. Neutral fusion of HIV (at the cell membrane) predominates in CD4 lymphocytes, and endocytic uptake predominates in DCs. The latter is clearly facilitated by the initial contact of HIV with CLRs rather than CD4. Another interesting point is whether some of the infection in DCs occurs at the earlier stages within endosomes, especially as CD4, CCR5, and CXCR4 recycle in this compartment. Frederickson et al. [85
] have demonstrated that neutralization of endosomal acidification with proton pump inhibitors like chloroquine and bafilomycin leads to an increase in infection. We have indeed observed a positive effect on DC infection after chloroquine exposure (unpublished data).
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Figure 3. Two possible modes of viral transfer from DC to CD4 lymphocytes in vivo (A and B). The mode of viral entry into DCs is either via endocytosis (A(i)) or CD4/chemokine receptor-dependent viral fusion followed by proviral DNA integration (B(i)). Viral transfer occurs in the short term by viral regurgitation out of vesicles (endosomes?) at the contact points with CD4 lymphocyte (A)(ii). In the long-term viral exit from the infected DC is entirely dependent on de novo viral synthesis and active budding at the DC-CD4 lymphocyte contact point (B)(ii).
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Beyond internalization: Infection of DCs and transfer of HIV or antigen to responding T-lymphocytes
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HIV can be transferred to CD4 lymphocytes from particular DC subsets without infection [42
, 66
, 67
].
Clearly, numerous observations of HIV infection of immature DCs also have been made in vivo [see 34
, 86
]. In comparison to CD4 lymphocytes and macrophages, infection of permissive DC subsets is of low productivity. However, even DC infection levels of less than 1% are more than sufficient to provide an explosive viral infection in CD4 lymphocytes [83
]. Therefore, there is still an ongoing controversy as to whether or not DC infection is needed for transfer of virus to CD4 lymphocytes; that is, it has been postulated that DCs are just cellular viral "Trojan horses", which transfer virus to permissive cell types without ever being infected themselves. Thus, Geijtenbeek and co-workers [53
] initially suggested that HIV was retained on the surface of DC-SIGN-transfected THP1 cells before transfer to T cells in a process entirely independent of DC infection. However, subsequent work by Kwon et al., McDonald et al., Nobile et al. [51
, 52
, 87
], and ourselves [82
] showed DC-SIGN-binding results in internalization by these transfected cells and that this appears similar to DC internalization prior to transfer. MR expressed by macrophages also plays a role in transfer of HIV by these cells to T cells [88
]. Whether the mechanism involves endocytosis, as probably occurs in MDDCs [82
], is unclear.
The viral transfer mechanisms from a DC subset to a naïve or activated CD4 lymphocyte can vary, depending on several key factors. These include immature vs. mature phenotype and contact phenotype, as well as the time between HIV binding to DC and the DC contacting a CD4 lymphocyte and the quantity of the virus bound.
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DC phenotype and viral transfer
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Expression of DC HIV binding receptors appears to be tightly regulated and influenced by various extracellular stimuli. As discussed above, the strong expression of the CLRs, MR, and DC-SIGN appears to be usually restricted to immature DC in peripheral tissue but can be reinduced by IL4 in lymphoid tissue [33
]. Chemokine receptor expression also varies similarly, as CCR5 clearly predominates over CXCR-4 in immature tissue DC [89
90
91
], but is down-regulated with DC maturation. Maturation also results in decreased ability to support viral replication [92
, 93
]. Recent studies suggest that the CLR expressing epithelial DC might be the only DC subsets capable of efficient capture and transfer to T cells. However, in studies by Cameron et al., direct transfer of virus from CLR-negative blood DC to CD4 lymphocytes was demonstrated [42
]. Furthermore, MDDC can transfer envelope-deficient virus similarly (McDonald, personal communication). Therefore, the mechanisms of uptake and transfer from DC to CD4 lymphocytes are enhanced by high CLR expression on DCs, but CLRs appear not to be essential. However, CLRs may be important in capture and transfer of low HIV concentrations. CLR binding affinities for HIV gp120 are only slightly higher and sometimes equal to those of CD4 [94
]. Nevertheless, higher levels of CLR expression and/or expression of multiple CLRs may provide a greater number of binding sites for HIV gp120 compared with those of CD4 alone, thus explaining the predominance of gp120 binding to CLRs rather than CD4 in MDDCs. Alternative mechanisms of HIV uptake, such as macropinocytosis, require further study.
Physical contact between the DC and the CD4 lymphocyte resulting in formation of contact regions or synapses alters transcellular HIV trafficking and transfer. When HIV-exposed DC contact CD4 lymphocytes, there is a rapid transfer of virus to the DC-CD4 lymphocyte contact points [52
, 82
]. Thus, at a low viral multiplicity of infection, HIV capture and transfer to (and concentration at) the CD4 lymphocyte contact point ensure efficient infection of CD4 lymphocytes. Presumably, contacting CD4 lymphocytes are also responding to HIV antigen presented by DCs during this process, resulting in lymphocyte activation and increased permissiveness to viral infection.
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Influence of duration of HIV retention within DCs on transfer to T cells
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In epithelium there are DC-T-lymphocyte clusters suggesting that DCs may transfer HIV locally to CD4 lymphocytes, as well as in lymph nodes. In vivo, there may be only a short time lag for local transfer, but there will be a much longer lag time until DCs reach lymph nodes and contact occurs. The length of this lag time will have profound effects on the mechanism of viral transfer, given that virus is progressively degraded in DCs over 24 h (unpublished observations). In particular, the efficiency of direct viral transfer from DC to T cells without infection ("in trans") will decay and may or may not be functional by the time DCs make contact with T cells in the lymph node. In studies on mice and macaques, the peak appearance of DCs in the lymph node contact FITC contact sensitization is 24 h [95
, 96
]. However in immature MDDC, the efficiency of viral transfer "in trans" after 24 h is barely detectable (unpublished observations). At this stage, transfer from infected DCs may be more important. In studies by Reece et al. [97
] and Kawamura et al. [90
], skin explants that had been exposed to virus contained emigrant LC populations, which even after several days could transfer virus very efficiently to CD4 lymphocytes. The selective transfer of only HIV R5 strains suggested that de novo infection was necessary. Thus, it seems that viral transfer in vivo may occur both with and without DC infection, that is, "in cis" or "in trans"(summarized visually in Fig. 3A
and 3B
, respectively). We have shown these two processes occur sequentially over 24-48 h. When immature MDDC are pulsed with virus for 2 h, washed and subsequently mixed with CD4 lymphocytes, a declining proportion of endocytosed virus remains intact over time and can be successfully transferred from DCs to CD4 lymphocytes for up to 24 h [82
]. After this, de novo infection of DCs is essential for transfer. In the explant model, a significantly different methodologic approach is used. Skin explants are cultured, infected with HIV and DC, and isolated after migration from tissue sections over several days. As this takes more than 24 h, endocytosed virus would be degraded, and the only means of transfer would be through infected DCs. Thus infection of the tissue resident DC is essential for long-term viral persistence prior to transfer to CD4 lymphocytes. Thus, it is likely that the explant models are more representative of DC-T cell transfer in these tissues.
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CONCLUSIONS
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These advances in the understanding of the mechanisms of binding, internalization of HIV by DCs, and transfer to T lymphocytes permit the construction of hypotheses regarding the events immediately following sexual transmission of HIV. It is likely that in uninflamed vaginal or rectal mucosa, HIV will encounter LCs whose processes extend to the very superficial layers of the mucosa. Binding and internalization of HIV by LCs may be followed either by transfer to resting CD4 lymphocytes in the mucosa [98
] directly or by infection of immature LCs and after subsequent transport to draining lymph nodes infection of activated or resting CD4 lymphocytes. In traumatized or inflamed mucosa, either Langerhans cells or dermal DCs or lamina propria DCs may be infected and transfer to already activated CD4 lymphocytes in the mucosa. However, direct transfer of HIV from the endosomal pathway within DCs to CD4 lymphocytes is unlikely to be selective, whereas de novo infection of DCs is likely to select for R5 virions, which is characteristic of sexual transmission of HIV. The differences in the repertoire of CLRs expressed by LC and dermal DCs and their down-regulation during migration and maturation suggest that these cells are capable of binding a different range of glycoproteins on invading pathogens. However the extent and diversity of glycosylation of the envelope protein allows HIV to bind to at least three different CLRs on each of three different subtypes of DCs within stratified squamous epithelium.
The range of CLRs on different subtypes of DCs within the genital skin and mucosa has implications for the development of both antiviral agents aimed at blocking initial infection and for vaccine development. For post exposure prophylaxis, cellular HIV receptor blockers have been advocated. However, development of blocking agents for CCR5, CXCR4, CD4, intermediates of gp120-CD4-CCR binding, and DC-SIGN will not be sufficient. Blocking agents for Langerin, MR, and perhaps other CLRs may be required. The role of DCs in amplifying HIV infection at other sites, especially within lymphoid tissue should also be considered as these agents are developed.
Furthermore when considering the role of neutralizing antibodies to HIV in vaccine development, particularly in mucosal immunity, the role of antibodies in inhibiting interactions between oligomeric gp120 and CLRs on the surface of DCs should be considered.
Received May 8, 2003;
revised July 11, 2003;
accepted July 11, 2003.
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- MacDonald
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ABSTRACT
The dendritic cell family