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. 2003 Sep;110(1):80–85. doi: 10.1046/j.1365-2567.2003.01707.x

Inhibition of DC-SIGN-mediated trans infection of T cells by mannose-binding lectin

Gregory T Spear 1, M Reza Zariffard 1, Ji Xin 1, Mohammed Saifuddin 1
PMCID: PMC1783022  PMID: 12941144

Abstract

Some dendritic cells (DC) express a cell-surface lectin called ‘dendritic cell-specific intracellular adhesion molecule 3 (ICAM-3)-grabbing non-integrin’ (DC-SIGN). DC-SIGN has been shown to mediate a type of infection called ‘trans’ infection, where DC bind human immunodeficiency virus (HIV) and efficiently transfer the virus to T cells. We investigated the possibility that mannose-binding lectin (MBL), a soluble lectin that functions as a recognition molecule in innate immunity and that binds to HIV, could block trans infection mediated by DC-SIGN. Binding studies with glycoprotein (gp)120/gp41-positive and -negative virus preparations suggested that DC-SIGN and MBL bind primarily to glycans on gp120/gp41, as opposed to glycans on host-cell-derived proteins, indicating a close overlap in the binding site of the two lectins and supporting the notion that MBL could prevent binding of HIV to DC-SIGN. Preincubation of X4, R5 or dual-tropic HIV strains with MBL prevented DC-SIGN-mediated trans infection of T cells. The mechanism of MBL blocking trans infection of T cells was at least partly caused by blocking of virus binding to DC-SIGN positive cells. This study shows that MBL prevents DC-SIGN-mediated trans infection of T cells in vitro and suggests that in infected persons, MBL may inhibit DC-SIGN-mediated uptake and spread of HIV.

Introduction

Some dendritic cells (DC) express the cell-surface type II lectin DC-specific intracellular adhesion molecule 3 (ICAM-3)-grabbing non-integrin (DC-SIGN; CD209). This C-type lectin is proposed to have several functions, including promoting adhesion of DC to T cells during antigen presentation, trafficking of DC through the endothelium, and uptake of microbes and antigens by DC.1–3 Expression of DC-SIGN also mediates binding of human immunodeficiency virus type 1 (HIV-1) to DC via carbohydrates on the virus surface. HIV captured by DC via DC-SIGN efficiently infects T cells during adhesion between DC and T cells.4 This type of infection has been termed ‘trans’ infection of T cells. DC-SIGN expressed on cells has also been shown to capture HIV-2, simian immunodeficiency virus (SIV) and Ebola virus, and to lead to trans infection with these viruses.5,6 While DC were originally found to express DC-SIGN, other cell types were subsequently shown to express this molecule and could consequently bind HIV.7 Therefore, alveolar macrophages, macrophages in the placenta, as well as several subsets of immature DC, express DC-SIGN.

Antigen-presenting cells (APC), phagocytic cells and other cell types have been shown to express lectins other than DC-SIGN that could also be involved in the binding of HIV. For example, it was recently reported that a molecule which is related to DC-SIGN (called DC-SIGNR or L-SIGN) binds HIV and mediates efficient infection of T cells with HIV.8,9 DC-SIGNR is not expressed on DC but is expressed on liver sinusoidal cells and in lymph nodes. HIV has also been reported to bind to the mannose receptor expressed on DCs.10,11

Mannose-binding lectin (MBL), a soluble C-type lectin, is an effector molecule of the innate immune system.12,13 MBL binds to repetitive mannose and/or N-acetylglucosamine residues on microorganisms, leading to opsonization and activation of the lectin complement pathway.14 MBL also interacts with carbohydrates on the glycoprotein (gp)120 of HIV-1.15–17

As both MBL and DC-SIGN appear to bind to carbohydrates on HIV, it is possible that exposure of HIV to soluble MBL could prevent subsequent virus binding to cell-surface lectins. Therefore, binding of MBL to HIV could prevent binding of HIV to DC-SIGN, DC-SIGNR or the mannose receptor expressed on macrophages, dendritic cells or liver epithelial cells. In this study, we investigated whether MBL can prevent HIV trans infection of T cells mediated by cell-surface DC-SIGN.

Materials and methods

Viruses

The gp120/gp41-positive and gp120/gp41-negative HIV particles were prepared by transfecting 293 cells with pNL4-3 and pNL4-3 (E−) plasmids, obtained from the AIDS Research and Reference Reagent Program (ARRRP) and contributed by Malcolm Martin [National Institutes of Health (NIH), Rockville, MD] and Nathaniel Landau (Aaron Diamond AIDS Research Center, New York, NY), respectively, using Lipofectamine Reagent (Gibco BRL, Grand Island, NY). The HIVBAL (R5) and HIV89·6 (R5, X4) strains of HIV were obtained through the ARRRP, and the HIVGP (X4) strain was isolated as described previously.18 The viruses were produced in peripheral blood mononuclear cells (PBMCs) stimulated with phytohaemagglutinin (PHA-P; Sigma Chemical Co., St Louis, MO) plus 30 units/ml interleukin-2 (IL-2) (obtained through the ARRRP from Dr Maurice Gately, Hoffman LaRoche, Inc.), as described previously.18

Preparation and purification of MBL

MBL was obtained by infecting the HLF liver-cell line with a recombinant vaccinia virus expressing the cDNA sequence for human MBL, as previously described.19 Supernatants were collected and MBL was purified by passage over a mannan–Sepharose 4B column. The concentration of purified MBL was determined using the bicinchoninic acid (BCA) protein assay (Pierce, Rockford, IL). The purified MBL was >95% pure, as determined by silver staining of gels. The majority of the purified material was estimated, by Western blot, to contain multimers with molecular weights (MW) of ≥ 200 000, with some material of lower MW (Fig. 1a). The MBL was detected on Western blots using anti-MBL monoclonal antibody (mAb) HYB31-01 (Statens Serum Institut, Copenhagen, Denmark).

Figure 1.

Figure 1

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Mannose-binding lectin (MBL) structure and dendritic cell-specific intracellular adhesion molecule 3 (ICAM-3)-grabbing non-integrin (DC-SIGN) expression by THP cells. (a) Purified recombinant MBL and serum MBL were analysed by Western blotting with anti-MBL monoclonal antibody (mAb) after electrophoresis on 8% polyacrylamide gels under non-reducing conditions. (b) Expression of DC-SIGN by DC-SIGN-positive (THPD) and -negative (THP) THP cells was determined by flow cytometric analysis of cells stained with either DC28 anti-DC-SIGN mAb (Ab) or an isotype-matched control mAb (C) followed by incubation with fluorescein isothiocyanate (FITC)-labelled goat anti-mouse IgG.

HIV binding and trans infection mediated by DC-SIGN

THP cells expressing DC-SIGN, and control THP cells, were kindly provided by Dr Dan Littman (New York University School of Medicine) and were confirmed to express or not express DC-SIGN, respectively (Fig. 1b), by staining with DC28 mAb obtained from the ARRRP (NIH). Cells were grown in RPMI-1640 containing 10% heat-inactivated fetal bovine serum (FBS; Whittaker Bioproducts, North Brunswick, NJ) and gentamycin (50 µg/ml). For MBL-inhibition studies, virus was preincubated with MBL (0·1–25 µg/ml), mannan (250 µg/ml), bovine serum albumin (BSA; 0·2–20 µg/ml), transferrin (0·2–20 µg/ml), PHA-P (0·1–10) or cyanovirin (0·2–20 µg/ml), for 1 hr at 37° before incubation with THP cells. Cyanovirin-N was kindly provided by Michael Boyd (National Cancer Institute, Frederick, Cancer Research and Development Center, Frederick, MD). To evaluate binding of virus to cells, 106 THP cells were incubated with virus (1–5 ng of p24) for 3 hr at 37°. Cells were then washed and lysed with 0·5% Triton-X-100. Bound virus was measured by p24 enzyme-linked immunosorbent assay (ELISA) (AIDS Vaccine Program, Frederick, MD). The ELISA has a lower limit for detection of p24 of 25 pg/ml.16 For trans infection studies, virus was preincubated with MBL and then incubated with THP cells, as described above. Cells were washed and then cultured with 2 × 105 PHA-stimulated PBMCs plus 30 units/ml IL-2. After 10 days, virus replication was assessed by p24 ELISA of culture supernatants.

Binding of HIV to MBL

Ninety-six-well tissue culture plates (Costar, Cambridge, MA) were coated overnight with 100 µl of MBL (10 µg/ml) diluted in a buffer containing 5 mm veronal (pH 7·5), 0·145 m NaCl and 10 mm CaCl2 (VBS-Ca).16 Wells were blocked with 3% BSA for 1 hr, washed with VBS-Ca and then incubated for 4 hr with 100 µl (500 pg of p24) of virus. The plates were washed, bound virus was lysed with 0·5% Triton-X-100 and p24 measured by ELISA.

Results

HIV virions incorporate not only gp120/gp41 into the viral membrane during budding from host lymphocytes, but also incorporate numerous host cell proteins, many of which possess N-linked glycans. Previous studies in our laboratory showed that virus particles which lack gp120/gp41 do not bind efficiently to MBL, indicating that carbohydrates on gp120/gp41 are critical for the interaction between HIV and MBL.16 However, because DC-SIGN has a much higher affinity for binding carbohydrates than MBL,20 we explored the possibility that HIV particles which lack gp120/gp41 could exhibit some binding to DC-SIGN through host-cell glycoproteins or glycolipids. Virus with gp120/gp41 bound to THP cells expressing DC-SIGN (Fig. 2), as reported previously.4 Moreover, similarly to what was previously observed,4 THP cells that do not express DC-SIGN bound, on average, only 4% of the virus bound by the same number of DC-SIGN-positive cells (data not shown, P ≤ 0·05, Mann–Whitney U-test, based on nine experiments). Chelation of Ca2+ with EDTA (results not shown) reduced HIV binding by 93%, consistent with DC-SIGN requiring calcium for lectin function and providing further evidence of the important role of DC-SIGN in the binding of HIV to DC-SIGN-positive cells. Approximately seven times more virus bound to THP cells expressing DC-SIGN when gp120/gp41 was present on virus than when it was absent (Fig 2; P < 0·05, Mann–Whitney U-test), suggesting that carbohydrates on gp120/gp41 are critical for binding of HIV to DC-SIGN. Similarly, significantly (P < 0·05, Mann–Whitney U-test) more (four times) of the gp120/gp41-positive virus than of the gp120/gp41-negative virus bound to microtitre wells coated with MBL (Fig. 2). In contrast, gp120/gp41-positive virus bound at much lower levels (<10%) to control-coated microtitre wells or to DC-SIGN-negative THP cells, and there was no difference between the level of binding of gp120/gp41-positive and gp120/gp41-negative particles to those surfaces (data not shown). The above data, showing that glycans on gp120/gp41 are critical for binding of HIV to both DC-SIGN and MBL, and other studies showing that both DC-SIGN and MBL bind to high mannose and/or hybrid glycans,20 together suggest the possibility that both lectins bind to the same glycans on gp120/gp41. If both lectins bind at the same sites, then MBL could block the interaction between DC-SIGN and HIV.

Figure 2.

Figure 2

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Binding of human immunodeficiency virus (HIV) to dendritic cell-specific intracellular adhesion molecule 3 (ICAM-3)-grabbing non-integrin (DC-SIGN) and mannose-binding lectin (MBL) is dependent on glycoprotein (gp)120/gp41 glycans. Equal amounts (5000 pg of p24) of either gp120/gp41-positive (Env+) or gp120/gp41-negative (Env–) virus were incubated with THP cells expressing DC-SIGN (DC-SIGN) or in MBL-coated microtitre wells (MBL). After incubation, unbound virus was removed by washing, and bound virus detected by p24 enzyme-linked immunosorbent assay (ELISA) after lysis in detergent. Data shown represent mean values ± standard deviation (SD) from one experiment representative of three different experiments.

To determine whether MBL can inhibit the interaction between HIV and DC-SIGN, DC-SIGN-positive or -negative monocytic THP cells were incubated with an HIV X4 primary isolate (HIVGP) either in the presence or absence of MBL. The THP cells were then washed and cultured with PHA-stimulated PBMCs for 10 days. In the absence of MBL, DC-SIGN-positive THP cells efficiently transferred virus to the PBMCs, as significant virus replication (determined by the level of p24) was observed on day 10 (Fig. 3a). In contrast, DC-SIGN-negative THP cells appeared to mediate little or no trans infection of PBMCs, as only background levels of virus replication were observed on day 10. Preincubation of virus with as little as 1 µg/ml MBL inhibited DC-SIGN-mediated trans infection of PBMCs by ≈ 50%, while higher amounts of MBL led to further decreases in virus replication (P < 0·05, Kruskal–Wallis statistic). Addition of mannan, which inhibits the interaction between DC-SIGN and HIV, also significantly decreased trans infection of the PBMCs (Fig. 3a). Similar inhibition of DC-SIGN-mediated trans infection of PBMCs by MBL was observed when the R5 isolate, HIVBAL (Fig. 3b), or the dual-tropic isolate, HIV89·6 (results not shown), was incubated with DC-SIGN-positive THP cells.

Figure 3.

Figure 3

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Mannose-binding lectin (MBL) inhibits human immunodeficiency virus (HIV) trans infection and binding mediated by dendritic cell-specific intracellular adhesion molecule 3 (ICAM-3)-grabbing non-integrin (DC-SIGN). HIVGP (a) or HIVBAL (b) were incubated with THP cells expressing DC-SIGN (THPD) or DC-SIGN-negative THP cells (THP) either in the absence of inhibitors or in the presence of mannan (THPD + Man) or the presence of MBL. Unbound virus was removed by washing and THP cells were then co-cultured with phytohaemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs). The level of p24 in culture supernatants was measured on day 10. (c) and (d) THP cells were incubated with virus as in (a) and (b) and the amount of p24 antigen associated with THPD and THP cells was determined by enzyme-linked immunosorbent assay (ELISA) after lysis in detergent. Data shown represent mean values ± standard deviation (SD) from one experiment representative of three different experiments (for HIVGP) or two different experiments (for HIVBAL).

The above experiments suggested that MBL inhibits trans infection by preventing binding of virus to DC-SIGN. To assess this possibility, the effect of MBL on the amount of virus bound to DC-SIGN-positive THP cells was evaluated. The DC-SIGN-positive THP cells bound HIVGP and HIVBAL and binding was inhibited by mannan, while the DC-SIGN-negative THP cells bound relatively little virus (Fig. 3c, 3d). Addition of as little as 1 µg/ml MBL inhibited the binding of HIVGP or HIVBAL to DC-SIGN-positive THP cells by ≈ 32–36%.

To determine whether inhibition of HIV binding to DC-SIGN-positive cells was specific, HIV was incubated with different concentrations of MBL, BSA and transferrin. While inhibition of HIV binding to DC-SIGN-positive cells was significantly inhibited by as little as 0·3 µg/ml of MBL (P < 0·05, Kruskal–Wallis statistic), BSA and transferrin, at concentrations up to 20 µg/ml, did not inhibit virus binding (Fig. 4). The ability of MBL to inhibit virus binding to DC-SIGN-positive THP cells was compared with Cyanovirin-N, an 11 000 MW protein derived from cyanobacterium that was previously shown to bind to N-linked high-mannose oligosaccharides on HIV gp120.21 Both MBL and Cyanovirin-N significantly inhibited binding of HIV to THP cells, although Cyanovirin-N inhibited to a higher level (82% inhibition for Cyanovirin-N versus 40% inhibition for MBL) (Fig. 4). In contrast, PHA-P, a tetrameric plant lectin that binds to oligosaccharides on human T lymphocytes,22 was not detected to affect binding of HIV to DC-SIGN. Thus, the ability of MBL to inhibit binding of HIV to DC-SIGN appears to be shared by some, but not all, lectins.

Figure 4.

Figure 4

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Comparison of mannose-binding lectin (MBL) with other compounds for inhibition of human immunodeficiency virus (HIV) binding to dendritic cell-specific intracellular adhesion molecule 3 (ICAM-3)-grabbing non-integrin (DC-SIGN)-positive cells. THP cells expressing DC-SIGN were incubated with virus in the presence of MBL, bovine serum albumin, transferrin, phytohaemagglutinin (PHA) or Cyanovirin-N, and the amount of p24 antigen associated with cells was determined. Data shown represent mean values from one experiment representative of three different experiments.

Interestingly, MBL increased the amount of virus that bound to DC-SIGN-negative THP cells to levels similar to the amount bound to DC-SIGN-positive THP cells in the presence of MBL (Fig. 3c, 3d). MBL was found to increase binding of HIV to THP cells at concentrations as low as 6 µg/ml (results not shown) and also for the HIV89·6 virus (results not shown). These data suggest that MBL opsonizes a portion of HIV for binding by THP cells utilizing receptors other than DC-SIGN.

Discussion

This study shows that MBL can efficiently block DC-SIGN-mediated trans infection of T cells. The mechanism of this blocking appears to be at least partly owing to MBL preventing a portion of the virus from binding to DC-SIGN. However, the data suggest that there may be other mechanisms that contribute to blocking. Mannose-binding lectin (MBL) appears to mediate some binding of HIV to DC-SIGN-negative THP cells (Fig. 3c, 3d), but the bound virus does not result in trans infection of T cells (Fig. 3a, 3b). MBL has been shown, in previous studies, to opsonize particles for phagocytosis.23 This suggests that MBL may mediate some binding and subsequent phagocytosis of HIV by THP cells. The receptor for binding of MBL-opsonized particles to phagocytic cells was previously identified as complement receptor 1 (CR1; CD35),24 and THP cells express CR1.25

Another mechanism that may contribute to the blocking of DC-SIGN-mediated trans infection of T cells by MBL could be some intrinsic neutralizing activity of MBL for HIV. While direct neutralization of HIV by MBL may contribute to the blocking of trans infection, we believe that the contribution is minor as, in an extensive series of experiments, the MBL preparation used in this study and several other MBL preparations (including serum-derived MBL) had relatively low (<5%) neutralizing activity for HIVGP, HIVBAL, and HIV89·6, the three isolates used in this study (M.Saifuddin, personal communication).

The in vitro experiments in this study show that MBL blocks the interaction between HIV and DC-SIGN. Therefore, MBL in plasma could block the interaction between HIV and DC-SIGN or other HIV-binding lectins in vivo. For example, MBL may block binding of HIV to DC or to DC precursors in blood that express DC-SIGN.1,26 The interaction between HIV and DC-SIGNR on liver sinusoidal endothelial cells8 could also be blocked by MBL.

The results of this study also suggest that other soluble lectins, such as collectins surfactant protein A (SPA) or surfactant protein D (SPD) in the lung, or ficolins in blood, could prevent the interaction between HIV and cells that express DC-SIGN, DC-SIGN homologues or other HIV-binding lectins. This hypothesis is supported by the finding in this study that Cyanovirin-N, a carbohydrate-binding protein isolated from cyanobacterium, also blocks the binding of HIV to DC-SIGN. Both SPA and SPD play a role in enhancing the opsonization and killing of pathogens in the lung by phagocytic cells.27 SPA shares some carbohydrate-binding specificity with MBL, as both bind fucose, glucose and mannose,28 and therefore SPA could inhibit DC-SIGN binding to HIV. However, SPD binds to a different spectrum of sugars and hence will probably not inhibit the binding of DC-SIGN to HIV to any significant extent.29 Ficolins appear to have a specificity for N-acetylglucosamine and therefore may not block binding of DC-SIGN to HIV.30 Ficolins have not been tested for binding to HIV.

Blocking of HIV binding to DC-SIGN by MBL could have beneficial effects in vivo, as the interaction between HIV and DC has been proposed to have deleterious effects, such as efficient infection of T cells through the trans infection mechanism and spread of virus from peripheral sites in the body to lymphoid tissues.4,11 Additionally, a previous report suggests that MBL may also be beneficial by directly neutralizing HIV in vivo.17 A wide variation in MBL levels is found in humans owing to both point mutations within the coding region of the protein as well as polymorphisms in the MBL promoter region.12,13,31 While a number of studies have sought to determine whether MBL levels are associated with the course of disease caused by HIV, some studies reported that higher MBL levels were associated with a more favourable disease course while other studies did not support this finding.32–36 Recently, it has been postulated that MBL could have deleterious effects during infections, such as HIV, which may help to explain the conflicting findings in studies that relate MBL to clinical outcome of HIV infection.37 Similarly, while there are possible beneficial effects of MBL blocking of HIV binding to DC-SIGN (see above), there could also be as-yet-undefined deleterious effects. Further studies in appropriate animal models will help to determine the overall effects of MBL during virus infections.

Acknowledgments

This work was supported by National Institutes of Health Grant no. AI46963. We thank Bradley Hooker for excellent technical assistance.

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