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Originally published online as doi:10.1189/jlb.0306158 on August 21, 2006

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(Journal of Leukocyte Biology. 2006;80:1001-1012.)
© 2006 by Society for Leukocyte Biology

HIV interactions with dendritic cells: has our focus been too narrow?

Heather Donaghy, John Wilkinson and Anthony L. Cunningham1

Centre for Virus Research, Westmead Millennium Institute and University of Sydney, Sydney, New South Wales, Australia

1 Correspondence: Centre for Virus Research, Westmead Millennium Institute, Westmead Hosptial, Darcy Rd., Sydney, NSW 2145, Australia. E-mail: tony_cunningham{at}wmi.usyd.edu.au


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ABSTRACT
 
Although few in number, dendritic cells (DCs) are heterogeneous, ubiquitous, and are crucial for protection against pathogens. In this review, the different DC subpopulations have been described and aspects of DC biology are discussed. DCs are important, not only in the pathogenesis of HIV, but also in the generation of anti-HIV immune responses. This review describes the roles that DC are thought to play in HIV pathogenesis, including uptake and transport of virus. We have also discussed the effects that the virus exerts on DCs such as infection and dysfunction. Then we proceed to focus on DC subsets in different organs and show how widespread the effects of HIV are on DC populations. It is clear that the small number of studies on tissue-derived DCs limits current research into the pathogenesis of HIV.

Key Words: pathogenesis • immune responses


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DENDRITIC CELL SUBSETS
 
Dendritic cells (DCs), the most potent of antigen-presenting cells are a heterogeneous population of cells located throughout the blood, tissues, and lymphoid organs and are derived from different lineages [1 ]. They are involved in the generation of both innate and acquired immune responses, including release of cytokines (such as IL12, IL10, and IFN{alpha}), stimulation of naïve T lymphocyte clonal expansion [2 , 3 ], natural killer cell stimulation [4 ], as well as having a crucial role in peripheral tolerance to self peptides [5 ]. They are derived from CD34+ stem cells via at least 2 generation pathways: myeloid and lymphoid [6 , 7 ]. Myeloid DCs (mDCs), characterized by CD1a and CD11c expression, are found in most tissues except the brain and testes [3 ]. They are further subdivided into Langerhans cells (LCs) in squamous epithelium; dermal, or submucosal DCs; interdigitating DCs in the T cell areas of the lymph nodes and blood mDCs (CD11c+ CD123-). In addition, DCs can be generated from blood monocytes (known as monocyte derived DCs or MDDCs) or bone marrow precursors [8 , 9 ]. In contrast, DCs of lymphoid lineage, commonly called plasmacytoid DCs (pDCs), have a more restricted distribution being found predominantly in the blood (BDCA4+ CD123+) and lymphoid tissues [10 , 11 ].

Dendritic cells express different pattern recognition receptors (PRR), depending on the cell subset and probably to some extent on location. These PRR are able to recognize motifs unique to different classes of pathogen [12 ]. The 2 main types of PRR are C type lectin receptors (CLR), which recognize glycosylated carbohydrate domains [13 ] and Toll like receptors (TLR), which have a high degree of specificity for individual pathogen associated molecular patterns [14 ]. A summary of expression of different PRR on DC subpopulations can be found in Table 1 .


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  		Table 1. Summary of Receptors on Immature DC Subpopulations

Myeloid DC
Blood DC
Myeloid DCs in the blood are HLA-DR+CD11c+BDCA1+ (Table 1) . They circulate in small numbers (~0.5% of mononuclear cells). It is thought that they migrate from the blood to the tissues. However, there is limited information regarding the maturation of a blood DC into a tissue DC [15 , 16 ], and more recent evidence suggests that, at least some of these blood mDCs are programmed to migrate directly to the lymph nodes or thymus [16 ].

Langerhans cells
Langerhans cells are distributed in the skin, as well as within the stratified squamous epithelia covering the male and female genital tracts (6). They constitute ~2-4% of total epidermal cell population. These cells were first described in the skin by Langerhans in 1868, and Steinman first identified cells in the lymphoid tissue of mice that were potent stimulators of primary immune responses [17 ]. It was not until much later, however, that LCs were described as a stage of DC development [18 ]. Initially identified by the presence of Birbeck granules, LCs are now described as HLA-DR+CD1a+CD4+CCR5+Langerin+E-Cadherin+ DC-SIGN- CD83- (Table 1) . In mice, they express TLR 2, 4, and 9 but not 7 [19 ]. As the most superficially located DCs, LCs are thought to be crucial in the generation of an immune response to cutaneous antigens. However, this may be more complex than previously thought. During herpes simplex virus (HSV) infection, murine skin LCs may carry viral antigen to lymph nodes but then transfer it to CD8{alpha}+ DCs for presentation to T lymphocytes [20 ]. Furthermore, mice lacking epidermal LCs have an enhanced contact hypersensitivity response [21 ], suggesting a role of LCs in peripheral tolerance.

Interstitial DCs
The interstitial or dermal DCs are found in most tissues, including the heart, liver, and kidneys, where they are associated with vascular structures [3 ]. They lack langerin and Birbeck granules but express CD2, CD9, CD68, the coagulation factor XIIIa, the scavenger receptor CD36, and the CLR DC-SIGN (see Table 1 ). In vitro derived dermal DCs were found to have up to 10 times the antigen uptake capacity of LCs [22 ].

Model MDDCs
Epidermal and dermal DCs derived freshly from human skin explants are difficult to isolate in high numbers; therefore, a suitable model for in vitro generation of DC is required. Monocytes from blood can be induced to differentiate into monocyte-derived DCs (MDDC) in 5–7 days in the presence of IL4 and GMCSF [8 ], and these serve as a convenient in vitro model for DCs. MDDCs express CD11b, CD11c, MHC class II, CD1a, DC-SIGN, and low levels of the costimulatory molecules CD80 and CD86 (Table 1) and resemble the immature dermal DC subset in vivo. However, they should really be considered a unique in vitro DC phenotype because differences in the levels of expression of CD14, CD1a, and DC-SIGN on in vitro derived MDDC and in vivo dermal DCs exist [23 ]. Moreover, MDDC have rarely been identified in vivo in areas of inflammation.

Dendritic cells can also be generated from CD34+ stem cells, which can be readily isolated from umbilical cord blood. Culture of these cells for 5 days in GM-CSF, TNF{alpha}, SCF, and Flt-3 ligand results in the generation of two cell populations: a CD1a+ CD14- and a CD1a- CD14+ population [24 ]. Isolated CD1a+ CD14- cells cultured for a further 5-7 days in GM-CSF, TNF, and TGFß give rise to CD11b, DC-SIGN negative, CD1a Langerin-positive Langerhans-like cells [25 ]. Cultured CD1a- CD14+ cells differentiate into dermal-like DCs in the presence of GM-CSF and IL-4 and are negative for Langerin but express CD11b, DC-SIGN, and CD1a [25 ]. Our group has generated Langerhans-like cells from peripheral blood monocytes cultured in the presence of IL4, GMCSF, TNF{alpha}, and TGFß (Dable et al., unpublished results).

Plasmacytoid DCs
The pDCs are both functionally and phenotypically distinct from mDCs, exhibit a more restricted distribution, and have not been subclassified. They lack myeloid markers such as CD13, CD14, and CD33 but do express HLA-DR, CD4, and IL3R (CD123). In addition, they are CD11c negative and CD45RA+ (Table 1) . They express BDCA4 (neuropilin 1) and BDCA2 [26 ], a CLR that can internalize antigens that are subsequently presented to T lymphocytes [27 ]. Plasmacytoid DCs express TLR7 and TLR9, intracellular PRR that detect RNA and DNA viruses, respectively, within endosomal/lysosomal compartments following acidification [28 29 30 ]. Isolated blood dendritic cells were found to produce more IFN{alpha} than monocytes in response to several viruses, including HIV and HSV [31 ]. Further purification of blood DCs has enabled identification of pDCs as the professional interferon producing cell. Using these purified pDCs, Siegel et al. [11 ] showed that these cells produce IFN{alpha} in response to viruses, including herpes simplex virus (HSV), and it was also shown that these cells produce IFN{alpha} in response to HIV [32 ] and influenza [33 ]. Indeed, viruses do not need to be replication competent in order to induce IFN{alpha} production. In the case of HSV, it seems that an intact envelope is required for endocytosis as UV-inactivated HSV is able to stimulate production, but heat-killed virus is not [28 , 32 , 34 ]. However, intact HIV gp120 alone seems sufficient to induce IFN{alpha} production [31 ]. Virally stimulated pDCs have been implicated in the induction of cytotoxic T lymphocytes (CTL) [35 ], although these CTL may be regulatory in function [36 ].

Plasmacytoid DCs are thought to migrate directly from the blood to the lymphoid tissues and are not found in normal noninflamed tissues. There is evidence to suggest they may move into tissues during inflammatory or allergic conditions [37 , 38 ], although they were not detected in intestinal tissue of Crohns disease patients [39 ].

Dendritic cell maturation and migration
Dendritic cells exist in three distinct stages of maturation; precursors, immature and mature, and their location in the body is dependent on the state of maturation. Precursor mDCs in the blood are believed to migrate to the tissues where they remain in an immature state. This view might oversimplify matters because dermal DCs have been generated from blood mDC precursors [16 ]; however, Langerhans cells have only rarely been generated from mDCs. Instead, LCs have been shown to be generated from a dividing precursor population in the skin and these, not blood-derived precursors, may be responsible for maintaining skin LCs [40 , 41 ]. Additionally, blood mDC did not differentiate into LC in vitro [16 ], while isolated blood monocytes can be differentiated into Langerhans-like cells in vitro (Dable et al., unpublished data). Langerhans cells and dermal DCs as described above are immature DC. Immature mDCs are highly endocytic but less potent immune stimulators. Maturation diminishes endocytosis but increases immunostimulatory function, especially to T lymphocytes. Mature DCs are largely found in the lymphoid tissue, having migrated from site of antigen encounter to the site of T cell stimulation.

Maturation of epithelial DCs is often associated with their emigration to lymphatic tissues and lymph nodes. Immature DCs act as sentinels, sampling the surrounding area for evidence of pathogens. They are highly efficient at antigen uptake, express moderate amounts of MHC class II, and low levels of costimulatory molecules. They express the chemokine receptors CCR1 and CCR5. DCs will mature in response to both endogenous (such as antigen uptake or viral replication in DCs) or exogenous stimuli [including lipopolysaccharide (LPS) or cytokines such as TNF{alpha}, prostaglandins]. Maturation results in 1) up-regulation of DC adhesion and costimulatory molecules: CD40, CD80, CD83, CD86, and also MHC class II are all up-regulated. The adhesion molecules ICAM-1 and VLA-4 are also up-regulated, which enables more prolonged DC-T lymphocyte interaction [42 , 43 ]; 2) modulation of chemokine receptors: CCR7 expression on DC is increased, which induces migration to the secondary lymphoid tissue [44 ] in response to CCL21 and CCL4 produced in the lymph node [45 , 46 ]. Maturation of DCs results in decreased CCR5 and increased CXCR4 expression in slightly different patterns in LCs and MDDCs in vitro [47 ]; 3) secretion of cytokines (IL-12, IL-15, IL-18) and chemokines (MDC, TARC, ELC), which stimulate DC-T cell interactions, which drive helper and cytotoxic T lymphocytes activation [48 ]; and 4) modulation of CLR: DC-SIGN, mannose receptor (MR) and to a lesser degree, Langerin are all down-regulated by maturation. This coordinated alteration in DC phenotype and function during maturation ensures that upon entry into the lymph node, the DC is highly specialized at presenting antigen to T lymphocytes.

In addition to the conventional mechanism of DC maturation, it has now been shown that other antigen-presenting mechanisms can be used by DCs. The first of these occurs in the steady state, in the absence of maturation stimuli. DCs spontaneously migrate to the lymph nodes and present self peptides to T lymphocytes. The lack of costimulatory molecule expression on these DCs induces T lymphocytes anergy and contributes to maintenance of peripheral self-tolerance [5 , 49 ].

Resident DCs in the lymph nodes have also been shown to take up soluble antigens that have been applied peripherally. These antigens are expressed in lymph nodes on the surface of DCs in association with MHC class II molecules within a few hours of subcutaneous injection [50 , 51 ]. Migration of DCs to the lymph nodes is believed to take longer than this, probably 12 or more hours. More recently, a mechanism for the delivery of soluble antigens from the periphery to lymph node DCs has been described in which the antigens are transported within the reticular network of lymph nodes [52 ].

Antigen presentation to T lymphocytes
In contrast to the highly endocytic immature DC, a mature DC is a more efficient antigen-presenting cell. Dendritic cells express high levels of MHC molecules on their surface, enabling one DC to interact with multiple T lymphocytes at any one time. Once DCs engage T lymphocytes the MHC class II molecules move to the DC surface from a late endosomal compartment along microtubules [53 , 54 ]. The MHC class II molecules are then expressed on the surface within contact regions with T lymphocytes termed the immunological synapse [55 ]. Visualization of these DC-T lymphocytes interactions in the lymph nodes have revealed that, in the presence of antigen, DCs form stable, long-lasting contacts with both CD4+ [56 ] and CD8+ [57 ] T lymphocytes.

The fate of mature DCs once they have interacted with T lymphocytes in the lymph node is not clear. They are not found in the efferent lymph and are therefore thought to undergo apoptosis in the lymph nodes [58 ]. This results in a feedback mechanism, whereby continued migration to the lymph nodes reflects continued antigen stimulation. Once the stimulus has been removed, the migration of mature DCs to the lymph nodes stops and T lymphocyte activation ceases.


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HIV AND DCs
 
Dendritic cells have a number of roles in HIV pathogenesis, including infection in the genital tract, uptake and transport of virus to lymphoid tissue, and transmission to T lymphocytes stimulating explosive HIV replication. In addition, as antigen-presenting cells, DCs are crucial in priming of HIV-specific CD4 and CD8 cell-mediated immunity.

HIV Receptors on DCs
Different DC populations express CD4 and the chemokine receptors CXCR4 and CCR5 to varying degrees [59 60 61 ]. They have also been shown to express a diversity of CLRs [24 , 62 ].

CD4, CXCR4, and CCR5
Several groups have shown that different DC populations express CD4 and the chemokine receptors CXCR4 and CCR5 to varying degrees [59 , 60 , 63 64 65 66 ]. CCR5 genotype is a major determinant of HIV susceptibility, with individuals homozygous for CCR5 containing a 32 base pair deletion being protected from infection. In addition, ex vivo LCs from CCR5{Delta}32 homozygotes were less susceptible to HIV infection than LC from wild-type individuals [60 ]. The importance of CCR5 in HIV transmission is further delineated by evidence that LCs emigrating from epidermal sheets pretreated with PSC-RANTES, a molecule that binds to CCR5, were resistant to HIV infection in a dose-dependent manner [67 ], and topical application of PSC-RANTES prevented vaginal transmission of SHIV in rhesus macaques [68 ].

C-type lectin receptors
The function of CLRs is to facilitate endocytosis, and many different CLRs have now been identified on the surface of different DC subpopulations. DC-SIGN (CD209), a CLR found on the model MDDC, has been most intensively studied because it was shown to bind HIV via the highly glycosylated gp120 [69 ]. However, in uninflamed tissues, in vivo expression of DC-SIGN is limited to dermal and lamina propria DCs and is not found on LCs in superficial epithelium or on fresh mDCs or pDCs in blood. Epidermal LCs express the CLR Langerin [62 , 70 ] which is thought to bind HIV by its mannose-bearing ligands [23 ].

Myeloid DCs in noninflamed tonsil and probably lymph nodes express very low to undetectable levels of CLRs (DC-SIGN and MR). However, in inflammatory conditions, cytokine production may result in CLR up-regulation that is, GM-CSF for MR and IL-4 for DC-SIGN [71 ]. A potential role of CLRs and DCs in mucosal lymphatic tissue, lymph nodes, thymus, and placenta in enhancing HIV replication in such inflammatory conditions needs to be examined. DC-SIGN and possibly other CLRs are expressed on DCs in normal uninflamed placenta, thymus, and lung [71 ]. To date, the only CLR found to be expressed by pDCs is BDCA-2 [27 ]

Other CLRs include Dectin1, Dec205, BDCA-2 (expressed by pDC), and DC-SIGNR (a DC-SIGN related molecule). The roles of each CLR in HIV is not fully understood but as they are studied further, it is likely that they will be found to have a role in HIV uptake, especially given recent findings that polymorphisms within DC-SIGNR may influence susceptibility to HIV-1 [72 ].

HIV infection of DC
In 1987, LCs from HIV-1-infected patients were shown to be infected with HIV-1 [73 ], and in the same year, Patterson and Knight [75 ] showed that crude populations of DC isolated from normal individuals were susceptible to HIV-1 infection in vitro. Several subsequent studies have shown HIV-1 infection of blood DCs in vitro [61 , 75 , 76 ] and in vivo [75 , 77 , 78 ], while LCs have been found to be infected in vivo [79 , 80 ]; splenic DCs showed low levels of infection [81 ] and p24+ pDCs have been detected in the tonsil of an HIV-infected patient [76 ]. However, uninfected interdigitating DCs were observed in close proximity to SIV-infected cells in lymph nodes of SIV-infected monkeys, suggesting that in this instance, the DCs were not productively infected with SIV [64 ].

One feature that these studies share is the low levels of productive infection of DCs when compared with CD4 lymphocytes. In one study, levels of infection of blood DC isolated from patients were estimated at between 0.02 and 0.1% in both mDCs and pDCs, with higher frequencies in T lymphocytes [78 ]. However, even DC infection levels of less than 1% are more than sufficient to provide an explosive viral infection in CD4 lymphocytes [82 ]; indeed, infection of DCs may not be a requirement for the DC to be able to transmit virus to T lymphocytes (see below).

Transfer of HIV from DC to T cells
Sessile immature DCs, such as LCs in the epidermis and interstitial DCs in the dermis, lamina propria or submucosa are likely to be the first DCs to contact HIV (or SIV) following mucosal exposure. HIV may infect epidermal LCs through intact or abraded mucosa and dermal/lamina propria DCs through mucosa ulcerated by other pathogens (such as HSV2) or trauma. HIV probably binds initially to Langerin or DC-SIGN on DC in the genital tract before internalization into endosomal compartments where it briefly retains infectivity [83 ].

Work in our laboratory suggests that trans enhancement, which persists for ~6 to 12 h with a tail to 24 h after HIV binding, is likely to be an important factor in the local transfer of virus to intraepithelial lymphocytes and possibly, at lower levels to lamina propria T lymphocytes (Fig. 1 ). However, because DC migration to lymph nodes requires ~12 to 24 h, trans enhancement may not result in large virus dissemination, as the majority of virus is likely to be degraded during this time via the endosomal acidic proteolytic environment in the DC [70 , 84 ] (Fig. 1) .


Figure 1
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  		Figure 1. Mechanisms of HIV transfer from DCs to CD4 lymphocytes In this model, HIV is internalized by DCs expressing DC-SIGN. The virus enters endosomes where the majority of the virus is degraded for antigen presentation. A small amount of virus, however, is not degraded but enters the nucleus where low level de novo HIV production takes place. At the same time as the HIV antigens are presented to T lymphocytes to induce an immune response, the de novo produced virions are transferred to T lymphocytes at the immunological synapse. This leads to explosive viral production in the T lymphocytes.

An alternative mechanism for the dissemination of the virus is through cis infection or neutral fusion of virus to DCs. 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 [23 , 85 ] and may act to concentrate virus on cells where CD4 and CCR5 expression is low [86 ]. This results in slowly developing de novo virus production in immature but not mature DC more than 24 h after HIV binding [70 ]. This is the period when DCs would certainly have reached underlying lamina propria T lymphocytes and also the lymph nodes. Therefore, transfer of de novo-produced virus is more likely to be important for viral dissemination in the lymph nodes than trans infection (Fig. 1) . Furthermore, in vitro cis transfer is relatively more efficient than trans transfer and occurs at low viral input multiplicity [87 ].

In DC-T cell conjugates viewed by live-cell microscopy, the HIV receptors CD4, CCR5, and CXCR4 on the T lymphocyte were recruited to the interface, while the MDDCs concentrated HIV to the same region [88 ] to form an infectious synapse and enhance transmission of HIV. Recently, Lore et al. [89 ] have shown evidence that DC-T lymphocytes conjugates are the primary sites for HIV production and that DCs transfer virus to antigen-specific CD4+ T lymphocytes [89 ]. This correlates with previous work showing that HIV preferentially infects HIV-specific CD4+ T lymphocytes [90 ].

Although trans enhancement may not be critical in viral dissemination in the lymph node, the contribution in the establishment of infection should not be overlooked. Transfer of virus from DCs to T lymphocytes in submucosa (i.e., within first few hours) may help contribute to the development of small founder populations. Indeed, LCs and T lymphocytes are often observed in direct contact in the human cervical and vaginal epithelium [91 ], which could facilitate trans infection of the T lymphocytes with HIV. Ex vivo studies using human cervical tissue indicate that HIV may also be disseminated to draining lymph nodes by migrating CD4+ T lymphocytes [92 ], possibly from submucosal sites [93 ]. Recent evidence that found transmission of HIV from mDC to T lymphocytes in the presence of neutralizing antibody [94 ] suggests that DCs transmit virus to T lymphocytes during an immunological synapse, when the two cell types are closely linked, thereby shielding the virus from neutralization.

Effect of DC maturation on level of HIV infection
There is evidence that the maturation status of the DC affects the susceptibility to infection. Immature DCs are thought to be more susceptible to infection [95 , 96 ]. Some reports found that mature DCs were resistant to infection [97 ] or that HIV was unable to replicate in mature DCs [47 , 98 ], because of a block at the level of reverse transcription [65 ]. However, despite higher infection of immature DCs, mature DCs have been shown to be HIV infected, as measured by p24 in the supernatants 7 days after infection [66 ]. Interestingly, while some groups have found productive viral infection of unstimulated pDC [61 , 99 , 100 ], others show that pDC require postinfection activation for HIV replication [76 ].

HIV binds and enters a different compartment in mature to immature DCs [101 ]. HIV is found within a single, large Clathrin-coated compartment in mature DCs that has recently been shown to label for CD9, CD63, and CD81 [102 ]. Virus can be transferred to CD4 T lymphocytes from this compartment in trans. Mature DCs are less endocytic and phagocytic than iDCs, although they retain intact infectious particles within the endosome for longer periods and are more efficient at antigenic stimulation of T lymphocytes and HIV transfer to these cells. Maturation enhances the formation of both immunologic and viral synapses with T lymphocytes. Of note, mature DCs stimulate both CD4- and CD8 HIV/SIV-specific lymphocytes, whereas immature DCs trigger only CD4 lymphocyte responses [103 ]. LFA-ICAM interactions and the tetraspannins are involved in this synapse formation, but the CLRs appear not to be concentrated at the synapse [102 ]. CLRs are essential for uptake of HIV into the endocytic compartment in iDCs. Maturation down-regulates CCR5 and up-regulates CXCR4. After maturation and/or migration, endocytosed virus is transferred with greater efficiency to T lymphocytes than by immature DCs. The ability of HIV to fuse with DC declines with maturation [104 ].

Impact of HIV on DC function
While there may be differences in the level of infection of DCs depending on their maturation status, it is important to consider that HIV exposure affects the ability of DCs to function correctly and may inhibit or alter the generation of immune responses to HIV.

The published literature on the function of myeloid DCs in vitro is somewhat contradictory and requires further clarification (see Chougnet and Gessani in this issue). The reasons for the confusion are probably due to differences in HIV inoculum, purification techniques, and duration of infection.

In short-term in vitro cultures, blood DCs exposed to HIV do not undergo full maturation as determined by costimulatory molecule expression [100 ]; however, blood DCs derived from HIV-infected individuals have increased CD86 expression [105 , 106 ]. Patient DCs appear functionally impaired, as the ability of patient blood DCs to stimulate T cell proliferation was impaired [78 ], and chemokine receptor expression of blood DCs is altered in patients with HIV [107 ]. Peripheral blood mononuclear cells from patients have reduced the ability to produce IFN{alpha} in response to viral stimulation, likely reflecting a dysfunction in pDCs [108 ]. In vitro infection of isolated pDCs resulted in maturation and production of large amounts of IFN{alpha} in contrast to mDCs, which did not mature; however, the HIV-exposed pDCs were able to induce maturation of mDCs [32 ]. In another study, however, where a higher inoculum was used, a partial maturation of both mDCs and pDCs was observed, without compromising the ability of DCs to produce TNF{alpha} in response to further stimulation [100 ].

We have found up-regulation of maturation markers by monocyte-derived DCs and ex vivo LCs following in vitro infection with HIV (A. Harman et al, unpublished data). This was clearly dependent on the size of the inoculum. HIV exposure resulted in partial up-regulation of costimulatory molecules, as well as increased CCR7 expression on MDDCs, and migration along a chemokine gradient [109 ]. However, Kawamura et al. [110 ] found that 12 days after HIV infection, p24+ DCs had decreased surface expression of CD4, CD1a, and MHC class 1. When isolated, these p24+ DCs were found to have a reduced allostimulatory capacity and lower IL-2 production compared with uninfected cells. Similarly, Granelli-Piperno et al. [111 ] found that HIV-infected BDCA1+ DCs isolated from blood had reduced capacity to stimulate T lymphocyte proliferation. In addition, IL12 production by DC is impaired in DCs infected with HIV in vitro [112 ]. This may be mediated by vpr, which has been shown to inhibit IL-12 production and enhance IL10 production by DCs in response to CD40L or LPS stimulation [113 ].


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INTERACTIONS OF HIV WITH BLOOD AND LYMPH NODE pDC
 
The number of circulating DCs, particularly the pDCs, may play a role in control of viremia as patients infected for more than 10 years with CD4 counts above 400 cells/µl maintained their DC numbers, whereas patients with AIDS-defining illnesses tended to have significantly lower pDC numbers [114 ]. An important indicator of pDC function is to assess IFN{alpha} production [11 ]. Recombinant gp120 has been shown to induce IFN{alpha} production by pDCs [115 ]. However, HIV-infected patients have reduced capacity to produce IFN{alpha} in response to stimulation with HSV, or influenza and this has been correlated with pDC frequency [116 ]. Stimulation of pDC by HIV does not induce as much IFN{alpha} production as stimulation with HSV [99 ].

In response to virus, pDCs secrete chemokines and interferons to prevent infection, but these molecules attract other cells, and this may enhance transmission to other cell types. For example, pDCs produce higher CCL2 (MCP1), CCL3 (MIP1a), and CCL4 (MIP 1b) in response to inactivated HIV than mDCs [115 ]. Secretion of these chemokines may enhance T lymphocyte migration.

Plasmacytoid DC interactions with HIV in the thymus and brain are described below.


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INTERACTIONS OF HIV WITH SPECIALIZED MYELOID DC IN DIFFERENT ORGANS
 
There is a wealth of information regarding HIV/DC interactions using in vitro derived DCs. It is important to validate this research by investigation of the interactions of HIV with DC from different organs (Fig. 2 ). These studies may elucidate viral reservoirs, as well as possible avenues for vaccine development.


Figure 2
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  		Figure 2. Summary of known HIV/DC interactions in different organs (Adapted from Scientific American).

Blood
Initial studies [75 , 117 ] indicated that blood DC numbers are decreased in HIV-1 infection. The recent advances in the identification of DCs by flow cytometry and the recognition of different DC subpopulations within the blood have facilitated cross-sectional studies of the effect of HIV-1 on blood DC populations. Several studies have shown decreased numbers of blood DCs in HIV-1 infection [63 , 106 , 114 , 118 , 119 ]. The loss in DC subpopulations was apparent even in primary infection, suggesting that it is not due to chronic activation of the immune system [119 ]. The number of circulating DCs, particularly the pDCs, may play a role in control of viraemia, as patients infected for more than 10 years with CD4 counts above 400 cells/µl maintained their DC numbers, whereas patients with AIDS-defining illnesses tended to have significantly lower pDC numbers [114 ]. The mechanisms of loss of DCs from the blood remain unclear, although may reflect enhanced migration from the blood to the lymph node (see lymph node section) or diminished production by the bone marrow. Because of the low frequency of infected DCs in HIV-infected individuals [78 ], the loss of DCs from the circulation is unlikely to be due to direct killing by the virus.

Early studies provided conflicting reports regarding the ability of DCs from HIV-1-infected patients to stimulate T lymphocyte proliferation [75 , 120 ]. More recently, both mDCs and pDCs of HIV-infected individuals were shown to have reduced capacity to stimulate allogeneic T lymphocyte proliferation [78 , 121 ].

Skin
Reduced numbers of LCs in the skin of HIV-infected individuals has been reported [65 , 123 ]. However, others found no difference in LC numbers in patients and controls [124 ].

Genital tract
Female genital tract
The human female genital tract is mostly composed of stratified squamous epithelial (SSE) cells, interspersed with both LCs and interstitial DCs. The superficial LCs are likely to be the first DCs to contact HIV. They are found in higher frequencies in the ectocervical epithelium than in the vaginal epithelium with dendrites that reach toward the luminal surfaces. Whether these dendrites are exposed in the lumen of the vagina as in the murine colon [124 ] is debatable. Ulceration or abrasion, caused by the trauma of intercourse (microabrasion or full breach) other genital tract pathogens, especially HSV 1 and 2, results in breaches in epithelial integrity allowing direct access of the virus to underlying DCs in the lamina propria, whereby they can transport virus to mucosal lymphoid tissue or lymph nodes.

Although several mechanisms have been proposed to transfer virus across the mucous membranes, such as direct infection of epithelial cells and transmigration of infected macrophages and T lymphocytes from the lumen, there is evidence in macaque and mouse models that uptake of HIV/SIV by DCs may be important in intact and breached mucosa [92 , 93 ].

Male genital tract
The majority of work on sexual transmission of HIV focuses on male to female transmission; however, the glans penis and inner foreskin of men are rich in LCs, which may facilitate entry of virus [125 ] in female to male transmission. A recent report of reduced HIV transmission in circumcised men may reflect the role of LCs in male sexual transmission [126 ].

Lymph node and spleen
During acute HIV-1 infection, the numbers of DCs in the lymph nodes were found to be raised compared with HIV-1 negative individuals [127 ], suggesting that the reasons for the loss of DCs from the blood and skin may be due to migration to the draining lymph nodes (at least during primary infection). However, such migration cannot account for all of the loss in circulating DCs as patients with AIDS had a reduced number of DCs in the lymph node [127 ]. Indeed, the migration of LCs was found to be normal in monkeys infected with SIV but was impaired in monkeys with AIDS [64 , 128 ], accounting for the reduced numbers in the lymph nodes of patients with AIDS [127 ]. DCs in lymph nodes failed to mature, characterized by incomplete up-regulation of CD80 and CD86 [127 ], which, in turn, limited the generation of HIV-1-specific CD4 T helper lymphocyte responses. In monkeys with AIDS, the proportion of lymph node DCs was similar to uninfected monkeys, but the cells had lower expression of CD83 [128 ]. In normal macaques, DCs in sinusoidal, marginal zone, and indigitating DCs were stained for DC-SIGN, and these cells appear to be absent or down-regulate their DC-SIGN in SIV-infected macaques [129 ]. Follicular DCs, nonhematopoeitic cells found in the germinal centers of secondary lymphoid organs are not productively infected with HIV [130 ] but are known to trap HIV particles that remain infectious in vivo for more than 9 months [131 ]. In a sequencing study, this cell-free HIV appears to be produced locally [132 ], corresponding to data showing a shorter half-life of the virus when patients start antiretroviral therapy [133 ].

Thymus
CCR5 tropic viruses are predominant in early infection, and the appearance of X4 viruses tends to indicate disease progression. In vitro, both R5 and X4 viruses replicate in thymic pDCs [134 ], while in thymocytes CXCR4 tropic viruses replicate more efficiently than R5 tropic viruses [135 ], and mDCs preferentially replicate R5 viruses [134 ]. A situation like this where X4 and R5 virions are produced and transmitted to thymocytes may enhance X4 virion numbers and contribute to the switch in coreceptor usage. Furthermore, pDCs in the thymus secrete IFN-{alpha} in response to HIV, which, in turn, drives up-regulation of MHC class I on thymocytes, leading to generation of CD3+CD8lo thymocytes, which were less responsive to stimulation [136 , 137 ], leading to the proposal that pDC-derived IFN-{alpha} in the thymus may be detrimental to the generation of effective CD8 T lymphocytes in HIV.

Brain
Although, under normal circumstances there are no DCs in the brain, some inflammatory stimuli can recruit pDCs to the brain parenchyma [138 ]. Both mDCs and pDCs have been found in the cerebrospinal fluid and choroid plexi under normal conditions and during inflammatory disease [139 , 140 ] and may enter brain during inflammatory conditions such as multiple sclerosis [141 ]. In the choroid plexes from HIV-infected asymptomatic patients, as well as those with AIDS, there is direct infection of both stromal macrophages and DCs. As viral sequences obtained from the choroid plexi are similar to those found in both brain and blood [142 ], it has been suggested that choroid plexi may form one avenue for access of HIV to the brain.

Gut
Interstitial DCs expressing DC-SIGN are abundant in the lamina propria and submucosa of the gut and rectum [143 ]. In SIV macaque models, there is productive infection of macaque intestinal DCs, especially those expressing DC-SIGN [143 ]. During SIV infection, the DC networks remain intact, and there was apparently an increased expression of DC-SIGN. In the rectum, there are no HLA-DR cells in the epithelium [126 ]. However, DCs expressing DC-SIGN, CD4, and CCR5 were localized just beneath the luminal epithelium, indicating their susceptibility to HIV infection [144 ].

Placenta
In the placenta, DC-SIGN is expressed on maternal decidual macrophages, as well as fetal Hofbauer cells [145 ]. Separating these 2 macrophage-like cells is the trophoblast, and any inflammation or abrasion would allow maternal decidual macrophages and fetal Hofbauer cells to come into contact with each other. The expression of DC-SIGN on these cells and CD4 and CCR5 on Hofbauer cells [145 ] may enable transmission of HIV from mother to child across the placenta.

Lungs
Both mDCs and pDCs have recently been isolated from bronchoalveolar lavage fluid [146 ], although the role of lung DC in HIV infection has yet to be investigated.


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CONCLUSIONS
 
There is a great deal of current research using model DCs; however, a survey of the literature reporting HIV or SIV infection of DCs in the key organs bearing the major burden of infection by HIV shows the data to be patchy, with most of the recent reports emphasizing the DC-SIGN expression by these cells during HIV or SIV infection. More research needs to be done on the patterns of HIV infection and local spread, the fate of infected DCs, and functional impairments, which may have an effect on spread of the virus or susceptibility to opportunistic infections in those organs, particularly in relation to mucosal immunity. At an individual cell level, similarities and differences between the patterns of HIV binding, uptake, degradation, infection, and transfer to T-cells of HIV needs to be known for each subtype of DC and whether this is altered during the course of AIDS or opportunistic infection. This will help us to understand much more about the role of DC in infection and local immunosuppression and susceptibility to specific opportunistic pathogens.


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ACKNOWLEDGEMENTS
 
The authors are supported by NHMRC program (358399) and NIH R01 grants. We would like to thank our collaborators, Melissa Robbiani, Stuart Turville, and Paul Cameron.

Received March 4, 2006; revised April 12, 2006; accepted May 17, 2006.


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REFERENCES
 
    1
  1. Shortman, K., Liu, Y. J. (2002) Mouse and human dendritic cell subtypes Nat. Rev. Immunol. 2,151-161[CrossRef][Medline]
    2. 2
  2. Banchereau, J., Steinman, R. M. (1998) Dendritic cells and the control of immunity Nature 392,245-252[CrossRef][Medline]
    3. 3
  3. Hart, D. N. (1997) Dendritic cells: unique leukocyte p opulations which control the primary immune response Blood 90,3245-3287[Free Full Text]
    4. 4
  4. Fernandez, N. C., Lozier, A., Flament, C., Ricciardi-Castagnoli, P., Bellet, D., Suter, M., Perricaudet, M., Tursz, T., Maraskovsky, E., Zitvogel, L. (1999) Dendritic cells directly trigger NK cell functions: Cross-talk relevant in innate anti-tumor immune responses in vivo Nat. Med. 5,405-411[CrossRef][Medline]
    5. 5
  5. Steinman, R. M., Nussenzweig, M. C. (2002) Avoiding horror autotoxicus: The importance of dendritic cells in peripheral T cell tolerance Proc. Natl. Acad. Sci. USA 99,351-358[Abstract/Free Full Text]
    6. 6
  6. Rissoan, M. C., Soumelis, V., Kadowaki, N., Grouard, G., Briere, F., de-Waal-Malefyt, R., Liu, Y. J. (1999) Reciprocal control of T helper cell and dendritic cell differentiation Science 283,1183-1186(see comments)[Abstract/Free Full Text]
    7. 7
  7. Robinson, S. P., Patterson, S., English, N. E., Davies, D., Knight, S. C., Reid, C. D. L. (1999) Human peripheral blood contains two distinct lineages of dendritic cells Eur. J. Immunol. 29,2769-2778[CrossRef][Medline]
    8. 8
  8. Romani, N., Gruner, S., Brang, D., Kampgen, E., Lenz, A., Trockenbacher, B., Konwalinka, G., Fritsch, P., Steinman, R., Schuler, G. (1994) Proliferating dendritic cell progenitors in human blood J. Exp. Med. 180,83-93[Abstract/Free Full Text]
    9. 9
  9. Caux, C., Dezutter-Dambuyant, C., Schmitt, D., Banchereau, J. (1992) GM-CSF and TNF{alpha} cooperate in the generation of dendritic Langerhans cells Nature 360,258-261[CrossRef][Medline]
    10. 10
  10. Grouard, G., Rissoan, M.C., Filgueira, L., et al (1997) The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin (IL)-3 and CD40-ligand J. Exp. Med. 185,1101-1111[Abstract/Free Full Text]
    11. 11
  11. Siegal, F. P., Kadowaki, N., Shodell, M., Fitzgerald, B. P., Shah, K., Ho, S., Antonenko, S., Liu, Y. J. (1999) The nature of the principal type 1 interferon-producing cells in human blood Science 284,1835-1837[Abstract/Free Full Text]
    12. 12
  12. Medzhitov, R., Janeway, J., Charles, (2000) The Toll receptor family and microbial recognition Trends Microbiol. 8,452-456[CrossRef][Medline]
    13. 13
  13. Figdor, C. G., van Kooyk, Y., Adema, G. J. (2002) C-type lectin receptors on dendritic cells and langerhans cells Nat. Rev. Immunol. Nat. Rev. Immunol. 2,77-84
    14. 14
  14. Takeda, K., Kaisho, T., Akira, S. (2003) Toll-like receptors Annu. Rev. Immunol. 21,335-376[CrossRef][Medline]
    15. 15
  15. Ito, T., Inaba, M., Inaba, K., Toki, J., Sogo, S., Iguchi, T., Adachi, Y., Yamaguchi, K., Amakawa, R., Valladeau, J., et al (1999) A CD1a+/CD11c+ subset of human blood dendritic cells is a direct precursor of Langerhans cells J. Immunol. 163,1409-1419[Abstract/Free Full Text]
    16. 16
  16. Patterson, S., Donaghy, H., Amjadi, P., Gazzard, B., Gotch, F., Kelleher, P. (2005) Human BDCA-1-positive blood dendritic cells differentiate into phenotypically distinct immature and mature populations in the absence of exogenous maturational stimuli: Differentiation failure in HIV infection J. Immunol. 174,8200-8209[Abstract/Free Full Text]
    17. 17
  17. Steinman, R. M., Witmer, M. D. (1978) Lymphoid dendritic cells are potent stimulators of the primary mixed leukocyte reaction in mice Proc. Natl. Acad. Sci. USA 75,5132-5136[Abstract/Free Full Text]
    18. 18
  18. Romani, N., Schuler, G. (1992) The immunological properties of epidermal Langerhans cells as part of the dendritic cell system Springer Semin. Immunopathol. 13,265-279[Medline]
    19. 19
  19. Mitsui, H., Watanabe, T., Saeki, H., Mori, K., Fujita, H., Tada, Y., Asahina, A., Nakamura, K., Tamaki, K. (2004) Differential expression and function of Toll-like receptors in Langerhans cells. Comparison with splenic dendritic cells J. Invest. Dermatol. 122,95-102[CrossRef][Medline]
    20. 20
  20. Allan, R. S., Smith, C. M., Belz, G. T., van Lint, A. L., Wakim, L. M., Heath, W. R., Carbone, F. R. (2003) Epidermal viral immunity induced by CD8{alpha}+ dendritic cells but not by Langerhans cells Science 301,1925-1928[Abstract/Free Full Text]
    21. 21
  21. Kaplan, D. H., Jenison, M. C., Saeland, S., Shlomchik, W. D., Shlomchik, M. J. (2005) Epidermal Langerhans cell-deficient mice develop enhanced contact hypersensitivity Immunity 23,611-620[CrossRef][Medline]
    22. 22
  22. Caux, C., Massacrier, C., Vanbervliet, B., Dubois, B., Durand, I., Cella, M., Lanzavecchia, A., Banchereau, J. (1997) CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to granulocyte-macrophage colony-stimulating factor plus tumor necrosis factor {alpha}.2. Functional analysis Blood 90,1458-1470[Abstract/Free Full Text]
    23. 23
  23. Turville, S. G., Cameron, P. U., Handley, A., Lin, G., Pohlmann, S., Doms, R. W., Cunningham, A. L. (2002) Diversity of receptors binding HIV on dendritic cell subsets Nat. Immunol. 3,975-983[CrossRef][Medline]
    24. 24
  24. Caux, C., Vanbervliet, B., Massacrier, C., DezutterDambuyant, C., deSaintVis, B., Jacquet, C., Yoneda, K., Imamura, S., Schmitt, D., Banchereau, J. (1996) CD34(+) hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF+TNF alpha J. Exp. Med. 184,695-706[Abstract/Free Full Text]
    25. 25
  25. Rozis, G., de Silva, S., Benlahrech, A., Papagatsias, T., Harris, J., Gotch, F., Dickson, G., Patterson, S. (2005) Langerhans cells are more efficiently transduced than dermal dendritic cells by adenovirus vectors expressing either group C or group B fibre protein: Implications for mucosal vaccines Eur. J. Immunol. 35,2617-2626[CrossRef][Medline]
    26. 26
  26. Dzionek, A., Fuchs, A., Schmidt, P., Cremer, S., Zysk, M., Miltenyi, S., Buck, D. W., Schmitz, J. (2000) BDCA-2, BDCA-3, and BDCA-4: Three markers for distinct subsets of dendritic cells in human peripheral blood J. Immunol. 165,6037-6046[Abstract/Free Full Text]
    27. 27
  27. Dzionek, A., Sohma, Y., Nagafune, J., Cella, M., Colonna, M., Facchetti, F., Gunther, G., Johnston, I., Lanzavecchia, A., Nagasaka, T., et al (2001) BDCA-2, a novel plasmacytoid dendritic cell-specific type IIC- type lectin, mediates antigen capture and is a potent inhibitor of interferon alpha/beta induction J. Exp. Med. 194,1823-1834[Abstract/Free Full Text]
    28. 28
  28. Lund, J., Sato, A., Akira, S., Medzhitov, R., Iwasaki, A. (2003) Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells J. Exp. Med. 198,513-520[Abstract/Free Full Text]
    29. 29
  29. Lund, J. M., Alexopoulou, L., Sato, A., Karow, M., Adams, N. C., Gale, N. W., Iwasaki, A., Flavell, R. A. (2004) Recognition of single-stranded RNA viruses by Toll-like receptor 7 Proc. Natl. Acad. Sci. USA 101,5598-5603[Abstract/Free Full Text]
    30. 30
  30. Latz, E., Schoenemeyer, A., Visintin, A., Fitzgerald, K. A., Monks, B. G., Knetter, C. F., Lien, E., Nilsen, N. J., Espevik, T., Golenbock, D. T. (2004) TLR9 signals after translocating from the ER to CpG DNA in the lysosome Nat. Immunol. 5,190-198[CrossRef][Medline]
    31. 31
  31. Ferbas, J. J., Toso, J. F., Logar, A. J., Navratil, J. S., Rinaldo, C. (1994) CD4+ blood dendritic cells are potent inducers of IFN-{alpha} in response to HIV-1 infection J. Immunol. 152,4649-4662[Abstract]
    32. 32
  32. Fonteneau, J.-F., Larsson, M., Beignon, A.-S., McKenna, K., Dasilva, I., Amara, A., Liu, Y.-J., Lifson, J. D., Littman, D. R., Bhardwaj, N. (2004) Human immunodeficiency virus type 1 activates plasmacytoid dendritic cells and concomitantly induces the bystander maturation of myeloid dendritic cells J. Virol. 78,5223-5232[Abstract/Free Full Text]
    33. 33
  33. Cella, M., Facchetti, F., Lanzavecchia, A., Colonna, M. (2000) Plasmacytoid dendritic cells activated by influenza virus on CD40L drive a potent TH1 polarisation Nat. Immunol. 1,305-310[CrossRef][Medline]
    34. 34
  34. Hochrein, H., Schlatter, B., O’Keeffe, M., Wagner, C., Schmitz, F., Schiemann, M., Bauer, S., Suter, M., Wagner, H. (2004) Herpes simplex virus type-1 induces IFN-{alpha} production via Toll-like receptor 9-dependent and -independent pathways Proc. Natl. Acad. Sci. USA 101,11416-11421[Abstract/Free Full Text]
    35. 35
  35. Yoneyama, H., Matsuno, K., Toda, E., Nishiwaki, T., Matsuo, N., Nakano, A., Narumi, S., Lu, B., Gerard, C., Ishikawa, S., et al (2005) Plasmacytoid DCs help lymph node DCs to induce anti-HSV CTLs J. Exp. Med. 202,425-435[Abstract/Free Full Text]
    36. 36
  36. Kawamura, K., Kadowaki, N., Kitawaki, T., Uchiyama, T. (2006) Virus-stimulated plasmacytoid dendritic cells induce CD4+ cytotoxic regulatory T cells Blood 107,1031-1038[Abstract/Free Full Text]
    37. 37
  37. Jahnsen, F. L., Lund-Johansen, F., Dunne, J. F., Farkas, L., Haye, R., Brandtzaeg, P. (2000) Experimentally induced recruitment of plasmacytoid (CD123high) dendritic cells in human nasal allergy J. Immunol. 165,4062-4068[Abstract/Free Full Text]
    38. 38
  38. Wollenberg, A., Wagner, M., Gunther, S., Towarowski, A., Tuma, E., Moderer, M., Rothenfusser, S., Wetzel, S., Endres, S., Hartmann, G. (2002) Plasmacytoid dendritic cells: a new cutaneous dendritic cell subset with distinct role in inflammatory skin diseases J. Invest. Dermatol. 119,1096-1102[CrossRef][Medline]
    39. 39
  39. Bell, S. J., Rigby, R., English, N., Mann, S. D., Knight, S. C., Kamm, M. A., Stagg, A. J. (2001) Migration and maturation of human colonic dendritic cells J. Immunol. 166,4958-4967[Abstract/Free Full Text]
    40. 40
  40. Merad, M., Manz, M.G., Karsunky, H., Wagers, A., Peters, W., Charo, I., Weissman, I.L., Cyster, J.G., Engleman, E.G. (2002) Langerhans cells renew in the skin throughout life under steady-state conditions 3,1135-1141
    41. 41
  41. Ginhoux, F., Tacke, F., Angeli, V., Bogunovic, M., Loubeau, M., Dai, X.-M., Stanley, E.R., Randolph, G.J., Merad, M. (2006) Langerhans cells arise from monocytes in vivo 7,265-273
    42. 42
  42. Puig-Kroger, A., Sanz-Rodriguez, F., Longo, N., Sanchez-Mateos, P., Botella, L., Teixido, J., Bernabeu, C., Corbi, A. L. (2000) Maturation-dependent expression and function of the CD49d integrin on monocyte-derived human dendritic cells J. Immunol. 165,4338-4345[Abstract/Free Full Text]
    43. 43
  43. Xu, H., Guan, H. B., Zu, G. R., Bullard, D., Hanson, J., Slater, M., Elmets, C. A. (2001) The role of ICAM-1 molecule in the migration of Langerhans cells in the skin and regional lymph node Eur. J. Immunol. 31,3085-3093[CrossRef][Medline]
    44. 44
  44. Kellermann, S. A., Hudak, S., Oldham, E. R., Liu, Y. J., McEvoy, L. M. (1999) The CC chemokine receptor-7 ligands 6Ckine and macrophage inflammatory protein-3 beta are potent chemoattractants for in vitro- and in vivo-derived dendritic cells J. Immunol. 162,3859-3864[Abstract/Free Full Text]
    45. 45
  45. Chan, V. W. F., Kothakota, S., Rohan, M. C., Panganiban, L. L., Gardner, J. P., Wachowicz, M. S., Winter, J. A., Williams, L. T. (1999) Secondary lymphoid-tissue chemokine (SLC) is chemotactic for mature dendritic cells Blood 93,3610-3616[Abstract/Free Full Text]
    46. 46
  46. Dieu, M. C., Vanbervliet, B., Vicari, A., Bridon, J. M., Oldham, E., Ait-Yahia, S., Briere, F., Zlotnik, A., Lebecque, S., Caux, C. (1998) Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites J. Exp. Med. 188,373-386[Abstract/Free Full Text]
    47. 47
  47. Canque, B., Bakri, Y., Camus, S., Yagello, M., Benjouad, A., Gluckman, J. C. (1999) The susceptibility to X4 and R5 human immunodeficiency virus-1 strains of dendritic cells derived in vitro from CD34(+) hematopoietic progenitor cells is primarily determined by their maturation stage Blood 93,3866-3875[Abstract/Free Full Text]
    48. 48
  48. Banchereau, J., Briere, F., Caux, C., Davoust, J., Lebecque, S., Liu, Y. J., Pulendran, B., Palucka, K. (2000) Immunobiology of dendritic cells Annu. Rev. Immunol. 18,767-811[CrossRef][Medline]
    49. 49
  49. Hawiger, D., Inaba, K., Dorsett, Y., Guo, M., Mahnke, K., Rivera, M., Ravetch, J. V., Steinman, R. M., Nussenzweig, M. C. (2001) Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo J. Exp. Med. 194,769-779[Abstract/Free Full Text]
    50. 50
  50. Itano, A. A., McSorley, S. J., Reinhardt, R. L., Ehst, B. D., Ingulli, E., Rudensky, A. Y., Jenkins, M. K. (2003) Distinct dendritic cell populations sequentially present antigen to CD4 T cells and stimulate different aspects of cell-mediated immunity Immunity 19,47-57[CrossRef][Medline]
    51. 51
  51. Manickasingham, S., Reis e Sousa, C. (2000) Microbial and T cell-derived stimuli regulate antigen presentation by dendritic cells in vivo J. Immunol. 165,5027-5034[Abstract/Free Full Text]
    52. 52
  52. Sixt, M., Kanazawa, N., Selg, M., Samson, T., Roos, G., Reinhardt, D. P., Pabst, R., Lutz, M. B., Sorokin, L. (2005) The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node Immunity 22,19-29[CrossRef][Medline]
    53. 53
  53. Boes, M., Cerny, J., Massol, R., Op den Brouw, M., Kirchhausen, T., Chen, J., Ploegh, H.L. (2002) T-cell engagement of dendritic cells rapidly rearranges MHC class II transport 418,983-988
    54. 54
  54. Chow, A., Toomre, D., Garrett, W., Mellman, I. (2002) Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane 418,988-994
    55. 55
  55. Dustin, M. L., Olszowy, M. W., Holdorf, A. D., Li, J., Bromley, S., Desai, N., Widder, P., Rosenberger, F., van der Merwe, P. A., Allen, P. M., et al (1998) A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts Cell 94,667-677[CrossRef][Medline]
    56. 56
  56. Stoll, S., Delon, J., Brotz, T. M., Germain, R. N. (2002) Dynamic imaging of T cell-dendritic cell interactions in lymph nodes Science 296,1873-1876[Abstract/Free Full Text]
    57. 57
  57. Bousso, P., Robey, E. (2003) Dynamics of CD8(+) T cell priming by dendritic cells in intact lymph nodes Nat. Immunol. 4,579-585[CrossRef][Medline]
    58. 58
  58. Matsue, H., Edelbaum, D., Hartmann, A. C., Morita, A., Bergstresser, P. R., Yagita, H., Okumura, K., Takashima, A. (1999) Dendritic cells undergo rapid apoptosis in vitro during antigen-specific interaction with CD4(+) T cells J. Immunol. 162,5287-5298[Abstract/Free Full Text]
    59. 59
  59. Zaitseva, M., Blauvelt, A., Lee, S., Lapham, C. K., Klaus-Kovtun, V., Mostowski, H., Manischewitz, J., Golding, H. (1997) Expression and function of CCR5 and CXCR4 on human Langerhans cells and macrophages: Implications for HIV primary infection Nat. Med. 3,1369-1375[CrossRef][Medline]
    60. 60
  60. Kawamura, T., Gulden, F. O., Sugaya, M., McNamara, D. T., Borris, D. L., Lederman, M. M., Orenstein, J. M., Zimmerman, P. A., Blauvelt, A. (2003) R5 HIV productively infects Langerhans cells, and infection levels are regulated by compound CCR5 polymorphisms Proc. Natl. Acad. Sci. USA 100,8401-8406[Abstract/Free Full Text]
    61. 61
  61. Patterson, S., Rae, A., Hockey, N., Gilmour, J., Gotch, F. (2001) Plasmacytoid dendritic cells are highly susceptible to human immunodeficiency virus type 1 infection and release infectious virus J. Virol. 75,6710-6713[Abstract/Free Full Text]
    62. 62
  62. Turville, S., Wilkinson, J., Cameron, P., Dable, J., Cunningham, A. L. (2003) The role of dendritic cell C-type lectin receptors in HIV pathogenesis J. Leukoc. Biol. 74,710-718[Abstract/Free Full Text]
    63. 63
  63. Donaghy, H., Pozniak, A., Gazzard, B., Qazi, N., Gilmour, J., Gotch, F., Patterson, S. (2001) Loss of blood CD11c(+) myeloid and CD11c(-) plasmacytoid dendritic cells in patients with HIV-1 infection correlates with HIV-1 RNA virus load Blood 98,2574-2576[Abstract/Free Full Text]
    64. 64
  64. Zimmer, M. I., Larregina, A. T., Castillo, C. M., Capuano, S., Falo, L. D., Murphey-Corb, M., Reinhart, T. A., Barratt-Boyes, S. M. (2002) Disrupted homeostasis of Langerhans cells and interdigitating dendritic cells in monkeys with AIDS Blood 99,2859-2868[Abstract/Free Full Text]
    65. 65
  65. Bakri, Y., Schiffer, C., Zennou, V., Charneau, P., Kahn, E., Benjouad, A., Gluckman, J. C., Canque, B. (2001) The maturation of dendritic cells results in postintegration inhibition of HIV-1 replication J. Immunol. 166,3780-3788[Abstract/Free Full Text]
    66. 66
  66. MacDougall, T. H. J., Shattock, R. J., Madsen, C., Chain, B. M., Katz, D. R. (2002) Regulation of primary HIV-1 isolate replication in dendritic cells Clin. Exp. Immunol. 127,66-71[CrossRef][Medline]
    67. 67
  67. Kawamura, T., Bruce, S. E., Abraha, A., Sugaya, M., Hartley, O., Offord, R. E., Arts, E. J., Zimmerman, P. A., Blauvelt, A. (2004) PSC-RANTES blocks R5 human immunodeficiency virus infection of Langerhans cells isolated from individuals with a variety of CCR5 diplotypes J. Virol. 78,7602-7609[Abstract/Free Full Text]
    68. 68
  68. Lederman, M. M., Veazey, R. S., Offord, R., Mosier, D. E., Dufour, J., Mefford, M., Piatak, M., Jr, Lifson, J. D., Salkowitz, J. R., Rodriguez, B., et al (2004) Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5 Science 306,485-487[Abstract/Free Full Text]
    69. 69
  69. Geijtenbeek, T. B., Kwon, D. S., Torensma, R., van-Vliet, S. J., van-Duijnhoven, G. C., Middel, J., Cornelissen, I. L., Nottet, H. S., Kewalramani, V. N., Littman, D. R., et al (2000) DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells Cell 100,587-597(see comments)[CrossRef][Medline]
    70. 70
  70. Turville, S. G., Santos, J. J., Frank, I., Cameron, P. U., Wilkinson, J., Miranda-Saksena, M., Dable, J., Stossel, H., Romani, N., Piatak, M., Jr, et al (2004) Immunodeficiency virus uptake, turnover, and 2-phase transfer in human dendritic cells Blood 103,2170-2179[Abstract/Free Full Text]
    71. 71
  71. Soilleux, E. J., Morris, L. S., Leslie, G., Chehimi, J., Luo, Q., Levroney, E., Trowsdale, J., Montaner, L. J., Doms, R. W., Weissman, D., et al (2002) Constitutive and induced expression of DC-SIGN on dendritic cell and macrophage subpopulations in situ and in vitro J. Leukoc. Biol. 71,445-457[Abstract/Free Full Text]
    72. 72
  72. Liu, H., Carrington, M., Wang, C., Holte, S., Lee, J., Greene, B., Hladik, F., Koelle, D. M., Wald, A., Kurosawa, K., et al (2006) Repeat-region polymorphisms in the gene for the dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin-related molecule: Effects on HIV-1 susceptibility J. Infect. Dis. 193,698-702[CrossRef][Medline]
    73. 73
  73. Tschachler, E., Groh, V., Popovic, M., Mann, D. L., Konrad, K., Safai, B., Eron, L., Veronese, F. D., Wolff, K., Stingl, G. (1987) Epidermal Langerhans cells: A target for HTLV-III/LAV infection J. Invest. Dermatol. 88,233-237[CrossRef][Medline]
    74. 74
  74. Patterson, S., Knight, S. C. (1987) Susceptibility of human peripheral blood dendritic cells to infection by human immunodeficiency virus J. Gen. Virol. 68,1177-1181[Abstract/Free Full Text]
    75. 75
  75. Macatonia, S. E., Lau, R., Patterson, S., Pinching, A. J., Knight, S. C. (1990) Dendritic cell infection, depletion and dysfunction in HIV-infected individuals Immunology 71,38-45[Medline]
    76. 76
  76. Fong, L., Mengozzi, M., Abbey, N. W., Herndier, B. G., Engleman, E. G. (2002) Productive infection of plasmacytoid dendritic cells with human immunodeficiency virus type 1 is triggered by CD40 ligation J. Virol. 76,11033-11041[Abstract/Free Full Text]
    77. 77
  77. Weissman, D., Li, Y., Ananworanich, J., Zhou, L. J., Adelsberger, J., Tedder, T. F., Baseler, M., Fauci, A. S. (1995) Three populations of cells with dendritic cell morphology exist in peripheral blood, only one of which is infectable with human immunodeficiency virus type I Proc. Natl. Acad. Sci. USA 92,826-830[Abstract/Free Full Text]
    78. 78
  78. Donaghy, H., Gazzard, B., Gotch, F., Patterson, S. (2003) Dysfunction and infection of freshly isolated blood myeloid and plasmacytoid dendritic cells in patients infected with HIV-1 Blood 101,4505-4511[Abstract/Free Full Text]
    79. 79
  79. Cimarelli, A., Zambruno, G., Marconi, A., Girolomoni, G., Bertazzoni, U., Giannetti, A. (1994) Quantitation by competitive PCR of HIV-1 proviral DNA in epidermal Langerhans cells of HIV-infected patients J. Acquir. Immune Defic. Synd. 7,230-235
    80. 80
  80. Zambruno, G., Mori, L., Marconi, A., Mongiardo, N., Derienzo, B., Bertazzoni, U., Giannetti, A. (1991) Detection of HIV-1 in epidermal Langerhans cells of HIV-infected patients using the polymerase chain reaction J. Invest. Dermatol. 96,979-982[CrossRef][Medline]
    81. 81
  81. McIlroy, D., Autran, B., Cheynier, R., Wain-Hobson, S., Clauvel, J. P., Oksenhendler, E., Debre, P., Hosmalin, A. (1995) Infection frequency of dendritic cells and CD4+ T lymphocytes in spleens of human immunodeficiency virus-positive patients J. Virol. 69,4737-4745[Abstract]
    82. 82
  82. Kawamura, T., Cohen, S. S., Borris, D. L., Aquilino, E. A., Glushakova, S., Margolis, L. B., Orenstein, J. M., Offord, R. E., Neurath, A. R., Blauvelt, A. (2000) Candidate microbicides block HIV-1 infection of human immature Langerhans cells within epithelial tissue explants J. Exp. Med. 192,1491-1500[Abstract/Free Full Text]
    83. 83
  83. Kwon, D. S., Gregorio, G., Bitton, N., Hendrickson, W. A., Littman, D. R. (2002) DC-SIGN-mediated internalization of HIV is required for trans-enhancement of T cell infection Immunity 16,135-144[CrossRef][Medline]
    84. 84
  84. Nobile, C., Petit, C., Moris, A., Skrabal, K., Abastado, J.-P., Mammano, F., Schwartz, O. (2005) Covert human immunodeficiency virus replication in dendritic cells and in DC-SIGN-expressing cells promotes long-term transmission to lymphocytes J. Virol. 79,5386-5399[Abstract/Free Full Text]
    85. 85
  85. Lee, B., Leslie, G., Soilleux, E., O’Doherty, U., Baik, S., Levroney, E., Flummerfelt, K., Swiggard, W., Coleman, N., Malim, M., et al (2001) cis Expression of DC-SIGN allows for more efficient entry of human and simian immunodeficiency viruses via CD4 and a coreceptor J. Virol. 75,12028-12038[Abstract/Free Full Text]
    86. 86
  86. Lee, B., Sharron, M., Montaner, L. J., Weissman, D., Doms, R. W. (1999) Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages Proc. Natl. Acad. Sci. USA 96,5215-5220[Abstract/Free Full Text]
    87. 87
  87. Turville, S. G., Vermeire, K., Balzarini, J., Schols, D. (2005) Sugar-binding proteins potently inhibit dendritic cell human immunodeficiency virus type 1 (HIV-1) infection and dendritic-cell-directed HIV-1 transfer J. Virol. 79,13519-13527[Abstract/Free Full Text]
    88. 88
  88. McDonald, D., Wu, L., Bohks, S.M., KewalRamani, V.N., Unutmaz, D., Hope, T.J. (2003) Recruitment of HIV and its receptors to dendritic cell-T cell junctions Science 300,1295-1297[Abstract/Free Full Text]
    89. 89
  89. Lore, K., Smed-Sorensen, A., Vasudevan, J., Mascola, J. R., Koup, R. A. (2005) Myeloid and plasmacytoid dendritic cells transfer HIV-1 preferentially to antigen-specific CD4+ T cells J. Exp. Med. 201,2023-2033[Abstract/Free Full Text]
    90. 90
  90. Douek, D. C., Brenchley, J. M., Betts, M. R., Ambrozak, D. R., Hill, B. J., Okamoto, Y., Casazza, J. P., Kuruppu, J., Kuntsman, K., Wolinsky, S., et al (2002) HIV preferentially infects HIV-specific CD4(+) T cells Nature 417,95-98[CrossRef][Medline]
    91. 91
  91. Parr, M., Parr, E. (1991) Langerhans cells and T lymphocyte subsets in the murine vagina and cervix Biol. Reprod. 44,491-498[Abstract]
    92. 92
  92. Shattock, R. J., Moore, J. P. (2003) Inhibiting sexual transmission of HIV-1 infection Nat. Rev. Microbiol. 1,25-34[CrossRef][Medline]
    93. 93
  93. Miller, C. J., Li, Q., Abel, K., Kim, E.-Y., Ma, Z.-M., Wietgrefe, S., La Franco-Scheuch, L., Compton, L., Duan, L., Shore, M. D., et al (2005) Propagation and dissemination of infection after vaginal transmission of simian immunodeficiency virus J. Virol. 79,9217-9227[Abstract/Free Full Text]
    94. 94
  94. Ganesh, L., Leung, K., Lore, K., Levin, R., Panet, A., Schwartz, O., Koup, R. A., Nabel, G. J. (2004) Infection of specific dendritic cells by CCR5-tropic human immunodeficiency virus type 1 promotes cell-mediated transmission of virus resistant to broadly neutralizing antibodies J. Virol. 78,11980-11987[Abstract/Free Full Text]
    95. 95
  95. Chougnet, C., Cohen, S. S., Kawamura, T., Landay, A. L., Kessler, H. A., Thomas, E., Blauvelt, A., Shearer, G. M. (1999) Normal immune function of monocyte-derived dendritic cells from HIV-infected individuals: Implications for immunotherapy J. Immunol. 163,1666-1673[Abstract/Free Full Text]
    96. 96
  96. Tsunetsugu-Yokota, Y., Akagawa, K., Kimoto, H., Suzuki, K., Iwasaki, M., Yasuda, S., Hausser, G., Hultgren, C., Meyerhans, A., Takemori, T. (1995) Monocyte-derived cultured dendritic cells are susceptible to human immunodeficiency virus infection and transmit virus to resting T cells in the process of nominal antigen presentation J. Virol. 69,4544-4547[Abstract]
    97. 97
  97. Sapp, M., Engelmayer, J., Larsson, M., Granelli-Piperno, A., Steinman, R., Bhardwaj, N. (1999) Dendritic cells generated from blood monocytes of HIV-1 patients are not infected and act as competent antigen-presenting cells eliciting potent T-cell responses Immunol. Lett. 66,121-128[CrossRef][Medline]
    98. 98
  98. Granelli-Piperno, A., Delgado, E., Finkel, V., Paxton, W., Steinman, R. M. (1998) Immature dendritic cells selectively replicate macrophagetropic (M-tropic) human immunodeficiency virus type 1, while mature cells efficiently transmit both M- and T-tropic virus to T cells J. Virol. 72,2733-2737[Abstract/Free Full Text]
    99. 99
  99. Yonezawa, A., Morita, R., Takaori-Kondo, A., Kadowaki, N., Kitawaki, T., Hori, T., Uchiyama, T. (2003) Natural alpha interferon-producing cells respond to human immunodeficiency virus type 1 with alpha interferon production and maturation into dendritic cells J. Virol. 77,3777-3784[Abstract/Free Full Text]
    100. 100
  100. Smed-Sorensen, A., Lore, K., Vasudevan, J., Louder, M. K., Andersson, J., Mascola, J. R., Spetz, A.-L., Koup, R. A. (2005) Differential susceptibility to human immunodeficiency virus type 1 infection of myeloid and plasmacytoid dendritic cells J. Virol. 79,8861-8869[Abstract/Free Full Text]
    101. 101
  101. Frank, I., Piatak, M., Jr, Stoessel, H., Romani, N., Bonnyay, D., Lifson, J. D., Pope, M. (2002) Infectious and whole inactivated simian immunodeficiency viruses interact similarly with primate dendritic cells (DCs): differential intracellular fate of virions in mature and immature DCs J. Virol. 76,2936-2951[Abstract/Free Full Text]
    102. 102
  102. Garcia, E., Pion, M., Pelchen-Matthews, A., Collinson, L., Arrighi, J.-F., Blot, G., Leuba, F., Escola, J.-M., Demaurex, N., Marsh, M., et al (2005) HIV-1 trafficking to the dendritic cll-T-cell infectious synapse uses a pathway of tetraspanin sorting to the immunological synapse Traffic 6,488-501[CrossRef][Medline]
    103. 103
  103. Frank, I., Santos, J. J., Mehlhop, E., Villamide-Herrera, L., Santisteban, C., Gettie, A., Ignatius, R., Lifson, J. D., Pope, M., Villamide, L. A., et al (2003) Presentation of exogenous whole inactivated simian immunodeficiency virus by mature dendritic cells induces CD4+ and CD8+ T-cell responses J. Acquir. Immune Defic. Syndr. 34,7-19[CrossRef][Medline]
    104. 104
  104. Cavrois, M., Neidleman, J., Kreisberg, J. F., Fenard, D., Callebaut, C., Greene, W. C. (2006) Human immunodeficiency virus fusion to dendritic cells declines as cells mature J. Virol. 80,1992-1999[Abstract/Free Full Text]
    105. 105
  105. Barron, M.A., Blyveis, N., Palmer, B.E., MaWhinney, S., Wilson, C.C. (2003) Influence of plasma viremia on defects in number and immunophenotype of blood dendritic cell subsets in human immunodeficiency virus 1-infected individuals J. Infect. Dis. 187,26-37[CrossRef][Medline]
    106. 106
  106. Jones, G. J., Watera, C., Patterson, S., Rutebemberwa, A., Kaleebu, P., Whitworth, J. A., Gotch, F. M., Gilmour, J. W. (2001) Comparative loss and maturation of peripheral blood dendritic cell subpopulations in African and non-African HIV-1-infected patients AIDS 15,1657-1663[CrossRef][Medline]
    107. 107
  107. Almeida, M., Cordero, M., Almeida, J., Orfao, A. (2005) Different subsets of peripheral blood dendritic cells show distinct phenotypic and functional abnormalities in HIV-1 infection AIDS 19,261-271[Medline]
    108. 108
  108. Chehimi, J., Campbell, D. E., Azzoni, L., Bacheller, D., Papasavvas, E., Jerandi, G., Mounzer, K., Kostman, J., Trinchieri, G., Montaner, L. J. (2002) Persistent decreases in blood plasmacytoid dendritic cell number and function despite effective highly active antiretroviral therapy and increased blood myeloid dendritic cells in HIV-infected individuals J. Immunol. 168,4796-4801[Abstract/Free Full Text]
    109. 109
  109. Wilflingseder, D., Mullauer, B., Schramek, H., Banki, Z., Pruenster, M., Dierich, M. P., Stoiber, H. (2004) HIV-1-induced migration of monocyte-derived dendritic cells is associated with differential activation of MAPK pathways J. Immunol. 173,7497-7505[Abstract/Free Full Text]
    110. 110
  110. Kawamura, T., Gatanaga, H., Borris, D. L., Connors, M., Mitsuya, H., Blauvelt, A. (2003) Decreased stimulation of CD4+ T cell proliferation and IL-2 production by highly enriched populations of HIV-infected dendritic cells J. Immunol. 170,4260-4266[Abstract/Free Full Text]
    111. 111
  111. Granelli-Piperno, A., Shimeliovich, I., Pack, M., Trumpfheller, C., Steinman, R. M. (2006) HIV-1 selectively infects a subset of nonmaturing BDCA1-positive dendritic cells in human blood J. Immunol. 176,991-998[Abstract/Free Full Text]
    112. 112
  112. Smed-Sorensen, A., Lore, K., Walther-Jallow, L., Andersson, J., Spetz, A.-L. (2004) HIV-1 infected dendritic cells upregulate cell surface markers but fail to produce IL-12 p70 in response to CD40 ligand stimulation Blood 104,2810-2817[Abstract/Free Full Text]
    113. 113
  113. Majumder, B., Janket, M. L., Schafer, E. A., Schaubert, K., Huang, X.-L., Kan-Mitchell, J., Rinaldo, C. R., Jr, Ayyavoo, V. (2005) Human immunodeficiency virus type 1 Vpr impairs dendritic cell maturation and T-cell activation: implications for viral immune escape J. Virol. 79,7990-8003[Abstract/Free Full Text]
    114. 114
  114. Soumelis, V., Scott, I., Gheyas, F., Bouhour, D., Cozon, G., Cotte, L., Huang, L., Levy, J. A., Liu, Y. J. (2001) Depletion of circulating natural type 1 interferon-producing cells in HIV-infected AIDS patients Blood 98,906-912[Abstract/Free Full Text]
    115. 115
  115. Del Corno, M., Gauzzi, M. C., Penna, G., Belardelli, F., Adorini, L., Gessani, S. (2005) Human immunodeficiency virus type 1 gp120 and other activation stimuli are highly effective in triggering alpha interferon and CC chemokine production in circulating plasmacytoid but not myeloid dendritic cells J. Virol. 79,12597-12601[Abstract/Free Full Text]
    116. 116
  116. Feldman, S., Stein, D., Amrute, S., Denny, T., Garcia, Z., Kloser, P., Sun, Y., Megjugorac, N., Fitzgerald-Bocarsly, P. (2001) Decreased interferon-alpha production in HIV-infected patients correlates with numerical and functional deficiencies in circulating type 2 dendritic cell precursors Clin. Immunol. 101,201-210[CrossRef][Medline]
    117. 117
  117. Knight, S. C., Elsley, W., Wang, H. (1997) Mechanisms of loss of functional dendritic cells in HIV-1 infection J. Leukoc. Biol. 62,78-81[Abstract]
    118. 118
  118. Grassi, F., Hosmalin, A., McIlroy, D., Calvez, V., Debre, P., Autran, B. (1999) Depletion in blood CD11c-positive dendritic cells from HIV-infected patients AIDS 13,759-766[CrossRef][Medline]
    119. 119
  119. Pacanowski, J., Kahi, S., Baillet, M., Lebon, P., Deveau, C., Goujard, C., Meyer, L., Oksenhendler, E., Sinet, M., Hosmalin, A. (2001) Reduced blood CD123(+) (lymphoid) and CD11c(+) (myeloid) dendritic cell numbers in primary HIV-1 infection Blood 98,3016-3021[Abstract/Free Full Text]
    120. 120
  120. Cameron, P. U., Freudenthal, P. S., Barker, J. M., Gezelter, S., Inaba, K., Steinman, R. M. (1992) Dendritic cells exposed to human immunodeficiency virus type-1 transmit a vigorous cytopathic infection to CD4+ T cells Science 257,383-387[Abstract/Free Full Text]
    121. 121
  121. Hsieh, S. M., Pan, S. C., Hung, C. C., Chen, M. Y., Chang, S. C. (2003) Differential impact of late-stage HIV-1 infection on in vitro and in vivo maturation of myeloid dendritic cells J. Acquir. Immune Defic. Syndr. 33,413-419[Medline]
    122. 122
  122. Belsito, D. V., Sanchez, R., Baer, M. D., Valantine, F., Thorbecke, G. J. (1984) Reduced Langerhans’ cell Ia antigen and ATPase activity in patients with acquired immune deficiency syndrome N. Engl. J. Med. 310,1279-1282[Abstract]
    123. 123
  123. Blauvelt, A., Asada, H., Saville, M. W., KlausKovtun, V., Altman, D. J., Yarchoan, R., Katz, S. I. (1997) Productive infection of dendritic cells by HIV and their ability to capture virus are mediated through separate pathways J. Clin. Invest. 100,2043-2053[Medline]
    124. 124
  124. Rescigno, M., Urbano, M., Valzasina, B., Francolini, M., Rotta, G., Bonasio, R., Granucci, F., Kraehenbuhl, J.-P., Ricciardi-Castagnoli, P. (2001) Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria Nat. Immunol. 2,361-367[CrossRef][Medline]
    125. 125
  125. Hussain, L. A., Lehner, T. (1995) Comparative investigation of Langerhans’ cells and potential receptors for HIV in oral, genitourinary and rectal epithelia Immunology 85,475-484[Medline]
    126. 126
  126. Auvert, B., Taljaard, D., Lagarde, E., Sobngwi-Tambekou, J. E. L., Sitta, R. E. M., Puren, A. (2005) Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: The ANRS 1265 trial PLoS Med. 2
    127. 127
  127. Lore, K., Sonnerborg, A., Brostrom, C., Goh, L. E., Perrin, L., McDade, H., Stellbrink, H. J., Gazzard, B., Weber, R., Napolitano, L. A., et al (2002) Accumulation of DC-SIGN+CD40+ dendritic cells with reduced CD80 and CD86 expression in lymphoid tissue during acute HIV-1 infection AIDS 16,683-692[CrossRef][Medline]
    128. 128
  128. Barratt-Boyes, S. M., Zimmer, M. I., Harshyne, L. (2002) Changes in dendritic cell migration and activation during SIV infection suggest a role in initial viral spread and eventual immunosuppression J. Med. Primatol. 31,186-193[CrossRef][Medline]
    129. 129
  129. Schwartz, A. J., Alvarez, X., Lackner, A. A. (2002) Distribution and Immunophenotype of DC-SIGN-Expressing Cells in SIV-infected and uninfected macaques AIDS Res. Hum. Retroviruses 18,1021-1029[CrossRef][Medline]
    130. 130
  130. Reinhart, T. A., Rogan, M. J., Huddleston, D., Rausch, D. M., Eiden, L. E., Haase, A. T. (1997) Simian immunodeficiency virus burden in tissues and cellular compartments during clinical latency and AIDS J. Infect. Dis. 176,1198-1208[Medline]
    131. 131
  131. Smith, B. A., Gartner, S., Liu, Y., Perelson, A. S., Stilianakis, N. I., Keele, B. F., Kerkering, T. M., Ferreira-Gonzalez, A., Szakal, A. K., Tew, J. G., et al (2001) Persistence of infectious HIV on follicular dendritic cells J. Immunol. 166,690-696[Abstract/Free Full Text]
    132. 132
  132. Dumaurier, M.-J., Gratton, S., Wain-Hobson, S., Cheynier, R. (2005) The majority of human immunodeficiency virus type 1 particles present within splenic germinal centres are produced locally J. Gen. Virol. 86,3369-3373[Abstract/Free Full Text]
    133. 133
  133. Cavert, W., Notermans, D. W., Staskus, K., Wietgrefe, S. W., Zupancic, M., Gebhard, K., Henry, K., Zhang, Z.-Q., Mills, R., McDade, H., et al (1997) Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection Science 276,960-964[Abstract/Free Full Text]
    134. 134
  134. Schmitt, N., Nugeyre, M. T., Scott-Algara, D., Cumont, M. C., Barre-Sinoussi, F., Pancino, G., Israel, N. (2006) Differential susceptibility of human thymic dendritic cell subsets to X4 and R5 HIV-1 infection AIDS 20,533-542[Medline]
    135. 135
  135. Schmitt, N., Chene, L., Boutolleau, D., Nugeyre, M.-T., Guillemard, E., Versmisse, P., Jacquemot, C., Barre-Sinoussi, F., Israel, N. (2003) Positive regulation of CXCR4 expression and signaling by interleukin-7 in CD4+ mature thymocytes correlates with their capacity to favor human immunodeficiency X4 virus replication J. Virol. 77,5784-5793[Abstract/Free Full Text]
    136. 136
  136. Keir, M. E., Rosenberg, M. G., Sandberg, J. K., Jordan, K. A., Wiznia, A., Nixon, D. F., Stoddart, C. A., McCune, J. M. (2002) Generation of CD3+CD8 low thymocytes in the HIV type 1-infected thymus J. Immunol. 169,2788-2796[Abstract/Free Full Text]
    137. 137
  137. Keir, M. E., Stoddart, C. A., Linquist-Stepps, V., Moreno, M. E., McCune, J. M. (2002) IFN-{alpha} secretion by type 2 predendritic cells up-regulates MHC class I in the HIV-1-infected thymus J. Immunol. 168,325-331[Abstract/Free Full Text]
    138. 138
  138. Curtin, J. F., King, G. D., Barcia, C., Liu, C., Hubert, F. X., Guillonneau, C., Josien, R., Anegon, I., Lowenstein, P. R., Castro, M. G. (2006) Fms-like tyrosine kinase 3 ligand recruits plasmacytoid dendritic cells to the brain J. Immunol. 176,3566-3577[Abstract/Free Full Text]
    139. 139
  139. Hanly, A., Petito, C. K. (1998) HLA-DR-positive dendritic cells of the normal human choroid plexus: a potential reservoir of HIV in the central nervous system Hum. Pathol. 29,88-93[CrossRef][Medline]
    140. 140
  140. Pashenkov, M., Huang, Y.-M., Kostulas, V., Haglund, M., Soderstrom, M., Link, H. (2001) Two subsets of dendritic cells are present in human cerebrospinal fluid Brain 124,480-492[Abstract/Free Full Text]
    141. 141
  141. Plumb, J., Armstrong, M. A., Duddy, M., Mirakhur, M., McQuaid, S. (2003) CD83-positive dendritic cells are present in occasional perivascular cuffs in multiple sclerosis lesions Mult. Scler. 9,142-147[Abstract/Free Full Text]
    142. 142
  142. Chen, H., Wood, C., Petito, C. K. (2000) Comparisons of HIV-1 viral sequences in brain, choroid plexus and spleen: potential role of choroid plexus in the pathogenesis of HIV encephalitis J. Neurovirol. 6,498-506[Medline]
    143. 143
  143. Gurney, K. B., Elliott, J., Nassanian, H., Song, C., Soilleux, E., McGowan, I., Anton, P. A., Lee, B. (2005) Binding and transfer of human immunodeficiency virus by DC-SIGN+ cells in human rectal mucosa J. Virol. 79,5762-5773[Abstract/Free Full Text]
    144. 144
  144. Jameson, B., Baribaud, F., Pohlmann, S., Ghavimi, D., Mortari, F., Doms, R. W., Iwasaki, A. (2002) Expression of DC-SIGN by dendritic cells of intestinal and genital mucosae in humans and rhesus macaques J. Virol. 76,1866-1875[Abstract/Free Full Text]
    145. 145
  145. Soilleux, E. J., Morris, L. S., Lee, B., Pöhlmann, S., Trowsdale, J., Doms, R. W., Coleman, N. (2001) Placental expression of DC-SIGN may mediate intrauterine vertical transmission of HIV J. Pathol. 195,586-592[CrossRef][Medline]
    146. 146
  146. Tsoumakidou, M., Tzanakis, N., Papadaki, H. A., Koutala, H., Siafakas, N. M. (2006) Isolation of myeloid and plasmacytoid dendritic cells from human bronchoalveolar lavage fluid Immunol. Cell Biol. 84,267-273[CrossRef][Medline]



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