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Journal of Virology, April 1999, p. 3449-3454, Vol. 73, No. 4
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Human Immunodeficiency Virus Type 1 Derived from Cocultures of Immature Dendritic Cells with Autologous T Cells Carries T-Cell-Specific Molecules on Its Surface and Is Highly Infectious

Ines Frank,1 Laco Kacani,1 Heribert Stoiber,1 Hella Stössel,2 Martin Spruth,1 Franz Steindl,3 Nikolaus Romani,2 and Manfred P. Dierich1,*

Institute for Hygiene and Ludwig Boltzmann Institute for AIDS Research1 and Department of Dermatology,2 University of Innsbruck, Innsbruck, and Institute for Applied Microbiology, University of Agriculture, Vienna,3 Austria

Received 16 September 1998/Accepted 5 January 1999


    ABSTRACT
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During the budding process, human immunodeficiency virus type 1 (HIV-1) acquires cell surface molecules; thus, the viral surface of HIV-1 reflects the antigenic pattern of the host cell. To determine the source of HIV-1 released from cocultures of dendritic cells (DC) with T cells, immature DC (imDC), mature DC (mDC), T cells, and their cocultures were infected with different HIV-1 isolates. The macrophage-tropic HIV-1 isolate Ba-L allowed viral replication in both imDC and mDC, whereas the T-cell-line-tropic primary isolate PI21 replicated in mDC only. By a virus capture assay, HIV-1 was shown to carry a T-cell- or DC-specific cell surface pattern after production by T cells or DC, respectively. Upon cocultivation of HIV-1-pulsed DC with T cells, HIV-1 exclusively displayed a typical T-cell pattern. Additionally, functional analysis revealed that HIV-1 released from imDC-T-cell cocultures was more infectious than HIV-1 derived from mDC-T-cell cocultures and from cultures of DC, T cells, or peripheral blood mononuclear cells alone. Therefore, we conclude that the interaction of HIV-1-pulsed imDC with T cells in vivo might generate highly infectious virus which primarily originates from T cells.


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Dendritic cells (DC) are the most competent antigen (Ag)-presenting cells in vivo (1, 7, 24). During the immature developmental state, DC are well equipped to capture Ag. Maturation of DC is reflected by an enhanced expression of costimulatory and accessory molecules like CD80, CD86, CD40, and CD54 (1). During this differentiation and maturation state, DC migrate from the periphery via the afferent lymph to the T-cell areas in secondary lymphoid organs where T-cell activation can occur (1, 19, 23).

There is substantial evidence that immature DC (imDC), which are present in the skin and mucosal surfaces, e.g., Langerhans cells, are directly involved in the transmission of human immunodeficiency virus type 1 (HIV-1) to CD4+ T cells (4, 5, 28, 29, 31). In this respect, DC appear to be unique since monocytes (Mo), macrophages, B cells, and T cells pulsed in a similar manner fail to induce high levels of infection upon coculture with T cells (3, 6, 28, 31, 39). In vivo studies in rhesus monkeys have shown that DC might be an important carrier of simian immunodeficiency virus from skin or mucosal surfaces to lymph nodes (20, 37). The presence of productively infected DC-derived syncytia (multinucleated giant cells) at the mucosal surface of adenoids (14) and in T-cell-rich areas of lymph nodes (13) further underlines the importance of DC in HIV infection.

Considerable effort has been made to model the primary HIV infection in vitro by exposing DC derived from skin or blood (4) or from proliferating (3, 4, 9, 41) or nonproliferating (3, 16, 17, 34, 40) precursors to HIV-1. Depending on the type of DC used for infection, controversial results were obtained concerning viral replication in these cells (4). The ability to generate DC from CD14+ human blood monocytes in the presence of cytokines (monocyte-derived DC [MDDC]) provides an opportunity to induce the DC phenotype in different stages of maturation (2, 8, 26, 27, 32, 33, 42).

In contrast to infection of DC, consistent results demonstrated vigorous viral replication when DC pulsed with HIV-1 were subsequently cocultured with T cells (3, 5, 30, 40). Presently, it is not known whether DC, T cells, or a putative fusion product resulting from DC-T-cell conjugates (18, 29, 31) is the primary site of viral replication. Furthermore, the involvement of T cells in the generation of multinucleated giant cells in vivo is still unclear.

To analyze the main source of viral replication in DC-T-cell cocultures and to prove productive infection of DC, phenotypic analysis of virions was performed by a virus capture assay (VCA). Since during the budding process HIV-1 incorporates host cell membrane-derived molecules (10, 12, 38) into its envelope---in addition to the viral glycoproteins gp41 and gp120 (15)---the surface pattern of HIV-1 reflects the Ag pattern of the host cell and is therefore a footprint of its origin (12, 38). Thus, phenotypic analysis of HIV-1 should identify the major source of HIV-1 virions in DC-T-cell cocultures.

(This work is part of the Ph.D. thesis of I. Frank.)

Generation and characterization of MDDC. DC used in this study were generated from CD14+ Mo (>98%) in the presence of interleukin-4 (IL-4) (1,000 U/ml) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (800 U/ml) as described recently (2, 35). To remove possible contaminations with T cells, DC were further purified on day 5 by cell sorting as large CD2- and CD3- cells. Purified cells were cultured for two more days in complete RPMI 1640 (RPMI 1640-10% fetal calf serum-5% L-glutamine [cRPMI]) in the presence of penicillin-streptomycin (100 IU of each), IL-4 (1,000 U/ml), and GM-CSF (800 U/ml). Full maturation was achieved by addition of Mo-conditioned medium (20%) (2, 32) and tumor necrosis factor alpha (TNF-alpha ; 1,000 U/ml) on day 5 for an additional 48 h. Fluorescence-activated cell sorting (FACS) analysis revealed a typical imDC or mature DC (mDC) phenotype as described previously (1, 22). Molecules such as B7.2, HLA class II, and intercellular adhesion molecule 1 (ICAM-1) were found to a higher extent on mDC, while CD4, CD11b, CD11c, and CD43 were less well expressed on mDC (data not shown). Expression of CXCR4 (with monoclonal antibody [MAb] 12G5) was too low for detection by FACS analysis. In contrast, chemokine receptor 5 (clone MAb 2D7) was found to be up-regulated during maturation. imDC and mDC were found to be negative for the T-lymphocyte markers CD5 and CD3 as well as for the monocytic marker CD14, the receptor for lipopolysaccharide (data not shown).

Productive infection of imDC and mDC by HIV-1Ba-L. Initially, the replication of macrophage-tropic (M-tropic) and T-cell-line-tropic (T-tropic) HIV-1 isolates in imDC and mDC generated from CD14+ Mo was examined and compared to virus production in T cells and cocultures of HIV-1-infected DC with T cells. The ability of both isolates (Ba-L and IIIB) to replicate in these cells was determined by p24 Ag enzyme-linked immunosorbent assay (ELISA) (Fig. 1). DC were exposed to HIV-1 (2 ng of p24 Ag/100 µl/106 cells). After incubation for 1.5 h at 37°C, cells were washed three times to remove unbound virus and were cultured for 14 days in cRPMI containing IL-4 (1,000 U/ml) and GM-CSF (800 U/ml). For cocultures, HIV-1-pulsed DC were subsequently added to unstimulated, uninfected syngeneic T cells (1:2) without additional cytokines. T cells were enriched by depletion of B cells on a nylon wool column (>97% purity) and checked by FACS analysis with anti-CD3, anti-CD19, and anti-CD14 MAbs. Purified T cells were grown and maintained in cRPMI supplemented with IL-2 (20 U/ml).


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  		FIG. 1.   Replication of HIV-1Ba-L in DC, T cells, and DC-T-cell cocultures. At different time points after exposure of cells to HIV-1, aliquots of culture supernatants were assayed for p24 Ag. (A and B) imDC (A) or mDC (B) were harvested on day 7 and pulsed with HIV-1Ba-L (2 ng of p24 Ag for 106 cells) for 90 min at 37°C. After incubation, cells were washed three times to remove unbound virus and were cultured in the presence of IL-4 and GM-CSF. (C) T cells were isolated from PBMC by nylon wool column separation and stimulated with IL-2 (20 U/ml) for 48 h prior to infection with HIV-1Ba-L; infection was performed as described for DC. T cells were cultivated in the presence of IL-2 (20 U/ml). (D and E) imDC (D) or mDC (E) (5 × 105) were exposed to HIV-1Ba-L as described for panels A and B and cocultured with T cells (5 × 105) without adding further cytokines. Results are given as means ± standard errors of the means of four (T cells and imDC) or six (mDC) independent experiments. (F) mDC were pulsed and cultivated with the T-tropic primary isolate PI21 as described for panels A and B. Means ± standard errors of the means of three independent experiments are shown.

In five of six independent experiments, productive infection, as measured by p24 Ag production, was observed for imDC and mDC pulsed with the M-tropic HIV-1 isolate Ba-L (Fig. 1A and B). No virus was released from DC with use of the T-tropic HIV-1 strain IIIB for infection, although the same amount of virus was able to infect primary T cells and T-cell lines (data not shown). The amount of HIV-1Ba-L produced by imDC and mDC differed only slightly in comparison to that by T cells (Fig. 1A to C). However, in DC-T-cell cocultures (Fig. 1D and E) viral replication started at an earlier time and was usually up to three times higher than that with DC or T-cell cultures (Fig. 1A and D and B and E). In contrast to imDC, mDC pulsed with the primary isolate PI21, which induced syncytia on MT-2 cells but did not infect macrophages, resulted in a p24 Ag concentration comparable to that for infection of imDC by the HIV-1Ba-L isolate (Fig. 1A and F).

During the course of infection, mDC did not change their phenotype while imDC acquired an intermediate phenotype which still significantly differed from mDC. This effect was not HIV-1 specific, since the same phenotype was observed in the case of imDC pulsed with the supernatant of IL-2-stimulated peripheral blood mononuclear cells (PBMC), too (data not shown).

It was reported previously that in cocultures viral replication occurred independently of virus strain and viral tropism (3, 16, 30, 39, 40). In our study, virus replication in imDC and mDC occurred with M-tropic virus only. Observed results are in accordance with data obtained by A. Granelli-Piperno, who also reported productive infection of imDC (16) and mDC (15a) with M-tropic isolates. A preferential infection of DC with M-tropic isolates might be due to substantial expression of chemokine receptor 5 on imDC and on mDC. In contrast, the expression of CXCR4, the main coreceptor for T-tropic HIV-1 strains (11), was too low for detection by FACS analysis. However, lack of CXCR4 expression on MDDC has not been reported by others (34), and there is still disagreement whether MDDC might be productively infected by T-tropic virus (3, 16, 17, 34, 40). These discrepancies might be due to the type or DC used for infection, different purification methods, and/or stimuli used to obtain an mDC phenotype (16, 17, 30, 34).

In our study, mDC were shown to be productively infected with the primary syncytium-inducing HIV-1 isolate PI21, while no infection was achieved with HIV-1IIIB. Recently, productive infection of MDDC independent of CXCR4 by T-tropic isolates and primary syncytium-inducing isolates was reported (34, 36). HIV-1 entry was inhibited by the alpha -chemokine SDF-1, the natural ligand of CXCR4, but not by the anti-CXCR4 MAb 12G5. Therefore, an SDF-1 receptor on MDDC was postulated (34, 36), different from CXCR4, which functions as coreceptor for some T-tropic isolates or primary HIV-1 strains.

Phenotypic analysis of HIV-1. To characterize the surface pattern of HIV-1 virions, supernatants containing virus were used to examine the presence of host cell-derived molecules by a VCA. Virus propagated in imDC or mDC, T cells, or DC cocultures with T cells was screened for the presence of adhesion molecules and activation markers including cell-type-specific Ag.

For VCA, virus-containing culture supernatants were purified by centrifugation (750 × g) and filtration (0.22-µm pore size) to remove cell debris. The assay was performed as described earlier (12, 25) with slight modifications. Briefly, immunoglobulin (Ig) (rabbit anti-mouse IgG; 200 ng/100 µl in 100 mM NaHCO3, pH 9.5)-precoated microtiter plates were incubated with MAbs (250 ng/50 µl/well) directed against different cell Ags. After an incubation of 4 h at room temperature, plates were washed and unspecific binding was blocked (phosphate-buffered saline [PBS]-3% bovine serum albumin for 40 min at room temperature). Virus-containing supernatants (400 pg/50 µl/well) were added and incubated overnight at 4°C. Unbound virus was removed while antibody (Ab)-captured virus was lysed (PBS-1% Nonidet P-40, 50 µl/well) to release the viral core protein p24. After virolysis, the amount of p24 Ag was determined by ELISA. Nonspecific binding of HIV-1 to Ig was determined by unspecific isotype controls. The presence of gp120 (MAb 2G12) was detected in every experiment independent of the virus source (data not shown). To confirm that HIV-1 bound to Ig-immobilized Ab instead of cell vesicles, transmission electron microscopic studies were performed. Ultrastructural analysis of vertical sections of three independent experiments revealed neither a contamination with cell vesicles nor clumping of virions. Additionally, this method allowed us to exclude the presence of p24 Ag in cell vesicles which might cause false-positive signals in the VCA. No virus was captured by isotype controls.

As shown in Fig. 2A, the phenotypic comparison of virions released from imDC or mDC exhibited some important differences: CD1a, expressed on imDC and less frequently on mDC, was found on virions derived from imDC but not on virions from mDC. In contrast, CD83, a DC-specific maturation marker, was detected on virions released from mDC only. Cell surface markers such as CD40, CD43, CD54, CD55, HLA-DR, and HLA-DQ Ag were present on the virions from imDC and mDC in similar amounts. The signal for CD4 in the capture assay was negative. No virus was captured by using Ab directed against molecules which were not expressed on the host cell, like the T-cell markers CD3, CD5, and CD25; the monocytic marker CD14; or the B-cell marker CD19 (data not shown). The absence of CD3 and CD14 on DC-derived virions indicated that replication of HIV-1 occurs in DC and excluded the possibility that contaminating T cells or Mo are the site of HIV-1 production.


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  		FIG. 2.   Phenotypic characterization of HIV-1Ba-L derived from DC, T cells, and DC-T-cell cocultures. HIV-1Ba-L released from various cell culture supernatants was analyzed for the presence of cell surface Ag listed on the x axis. For VCA, IgG-precoated microtiter plates were incubated with MAbs directed against different cell surface Ags including isotype controls (5 µg/ml) prior to overnight incubation at 4°C with HIV-1Ba-L-containing supernatants (8 ng/ml). Unbound virus was removed, and Ab-captured virus was lysed (PBS-1% Nonidet P-40, 50 µl/well). After virolysis, the amount of p24 Ag was determined by ELISA. The virus binding capacity of the VCA was about 15% of input virus; data represented in bar graphs were calculated as follows: sample - (isotype control + 3 × standard error of the mean). Bars represent means ± standard errors of the means of duplicates of three independent experiments. (A) imDC or mDC were pulsed with HIV-1Ba-L as described for Fig. 1A and B and were cultivated for 14 days in the presence of IL-4 and GM-CSF. (B) imDC or mDC (106/ml) were pulsed with HIV-1Ba-L and cocultivated with T cells (106/ml) for 8 days as described for Fig. 1D and E. (C) T cells were isolated, infected with HIV-1Ba-L or HIV-1IIIB, and cultivated as described for Fig. 1C.

Next, we investigated the Ag pattern of HIV-1 released from cocultures of HIV-1Ba-L-infected DC with syngeneic T cells. As described above, virus-containing supernatants were used for VCA. imDC or mDC were pulsed with Ba-L and added to autologous T cells. Independently of whether imDC or mDC were used for cocultivation, (i) progeny virus bound to the same MAb, and (ii) no significant difference was detected with respect to the amount of captured virus (Fig. 2B). Compared to Ag patterns on virions derived from imDC or mDC, HIV-1 released from cocultures showed a completely different surface Ag composition: anti-CD1a, anti-CD83, anti-CD11b, or anti-CD40 Ab failed to capture virus from coculture experiments. Instead of these DC markers, T-cell-specific surface markers like CD3, CD4, CD5, and CD25 were detected on the virus surface.

Since the Ag pattern of HIV-1Ba-L derived from DC-T-cell conjugates corresponded to a T-cell origin rather than a DC origin, the phenotype of HIV-1 derived from primary T cells was analyzed. In addition, the T-tropic isolate IIIB was used for infection. As shown in Fig. 2C, cell surface markers specific for T lymphocytes like CD3, CD5, CD11a, and CD25 could be easily detected, and again, no virus was captured with anti-CD1a, anti-CD83, anti-CD11b, anti-CD40, or anti-CD14 and CD3 MAbs. Compared to the results obtained from coculture, the Ag pattern of T-cell-derived virions did not significantly differ. Independently of the virus strain, the same Ag pattern was observed for HIV-1Ba-L and HIV-1IIIB released from T cells.

Results obtained by VCA revealed that HIV-1 which budded from DC or T cells was coated with a host-cell-specific spectrum of surface molecules. In contrast, HIV-1 derived from DC-T-cell cocultures entirely reflected a T-cell-specific phenotype. No detectable amount of HIV-1 derived from DC was present in cocultures with T cells. Presently, it is still unclear whether T cells become infected by transmission of HIV-1 by direct cell-to-cell contact or by HIV-1 which is derived from productively infected DC. The first possibility is supported by findings showing that blood DC transmit HIV-1 to uninfected T cells without being infected (5). A similar mechanism was recently described for the transmission of HIV-1 from DC to Mo or macrophages (21, 22). In both cases, HIV-1-loaded DC were cocultured with Mo in the absence of exogenous cytokines. Other reports indicate that productive infection of DC and their ability to capture virus are mediated through separate pathways (3). In this study, productive infection was reported to be dependent on the presence of IL-4, GM-CSF, and coreceptors, while virus transmission occurred independently of these factors. However, it is difficult to exclude the chance that productive infection of DC in DC-T-cell conjugates occurs, since small amounts of virus are still sufficient for infection of clustered T cells (4, 31, 40). The observation that HIV-1 does not replicate in coculture after pretreatment of DC with zidovudine is a further indication for a possible productive infection of DC in cocultures (31, 39). Independent of whether DC are productively infected, they might provide additional signals for T-cell activation which in turn could enhance virus production by DC. Indeed, HIV-1 production in virus-pulsed DC was reported to be potentiated through stimulation of CD40 (28, 39, 40).

Infectivity of HIV-1Ba-L derived from DC, DC-T-cell conjugates, T cells, and PBMC. To examine the infectivity of HIV-1Ba-L derived from imDC, mDC, T cells, cocultures of imDC or mDC with T cells, or PBMC, virus-containing supernatants were used for infection of IL-2-prestimulated PBMC (20 U/ml). After 10 days of culture, the 50% tissue culture infectious dose (TCID50) was calculated for each virus supernatant (ID50 software provided by J. L. Spouge, National Center for Biotechnology Information, National Institutes of Health) and given as TCID50 per nanogram of p24 Ag per milliliter. Virus-containing culture supernatants of respective host cells (2 ng of p24 Ag/100 µl/well; purified by centrifugation and filtration) were serially diluted in cRPMI before PBMC were seeded (105 cells/50 µl/well). After overnight incubation at 37°C to allow viral entry, cells were washed three times and fresh medium (cRPMI supplemented with 20 U of IL-2 per ml) was added to a final volume of 200 µl/well. Cells were cultured for 10 days at 37°C before virus replication was determined by monitoring p24 Ag production. Three replicates per dilution step were made.

Although productive infection was achieved in all six cases, virus supernatants differed in their infectivities (Fig. 3). The most infectious virus was obtained from cocultures of imDC with T cells. Cultures of mDC with T cells released significantly less infectious virus than did cocultures of imDC with T cells (P < 0.05). Virus released from imDC or mDC did not show any difference in infectivity but was significantly less infectious than HIV-1 derived from imDC-T-cell cocultures or PBMC or T-cell-derived virus. No significant differences in infectivity were observed for HIV-1 derived from PBMC and that from T cells. Therefore, we suggest that, depending on the maturation stage of DC, different cytokines might be produced during the interaction with T cells, which in turn can influence the infectivity of HIV-1. Further studies are necessary to identify the role of soluble factors in HIV-1 infection.


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  		FIG. 3.   Infectivity of HIV-1Ba-L isolated from DC, T cells, DC-T-cell cocultures, and PBMC. HIV-1Ba-L derived from respective host cells was used for infection of IL-2-stimulated PBMC. Each virus supernatant (2 ng of p24 Ag/100 µl) was serially diluted and incubated with target cells (105 cells/well) for up to 12 h. After overnight incubation at 37°C, cells were washed and resuspended in cRPMI supplemented with IL-2. At 10 days postinfection, p24 Ag production was detected by p24 Ag ELISA. The TCID50 was calculated by Spearman-Kaerber fit. Results represent the means ± standard errors of the means of two independent experiments.

In summary, we demonstrated that MDDC were preferentially infected with M-tropic HIV-1 isolates and release infectious virus. On the other hand, functional analysis revealed that highly infectious virions derived from cocultures of imDC with T cells were produced by T lymphocytes. Whether DC produce infectious virus in vivo or transmit captured virions to T cells remains to be elucidated. Also, this study demonstrates that the VCA offers an interesting approach to analyze the origin of HIV-1 in vitro and in vivo and to monitor the course of infection since the host cell's Ag pattern is reflected on the viral envelope.


    ACKNOWLEDGMENTS

We thank Martin Purtscher for providing the human neutralizing MAb 2G12 and Brigitte Müllauer for technical assistance.

This work was supported by the federal state of Tyrol, the Ludwig Boltzmann Gesellschaft, and the BMAGS.


    FOOTNOTES

* Corresponding author. Mailing address: Institut für Hygiene, Leopold-Franzens-Universität, Fritz-Pregl-Str. 3/III, A-6020 Innsbruck, Austria. Phone: 43-512-507-3401. Fax: 43-512-507-2870. E-mail: hygiene{at}uibk.ac.at.


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Journal of Virology, April 1999, p. 3449-3454, Vol. 73, No. 4
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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