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Journal of Virology, February 2001, p. 1565-1570, Vol. 75, No. 3
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.3.1565-1570.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Human Papillomavirus Infection Requires Cell Surface Heparan Sulfate

Tzenan Giroglou, Luise Florin, Frank Schäfer, Rolf E. Streeck, and Martin Sapp*

Institute for Medical Microbiology and Hygiene, University of Mainz, 55101 Mainz, Germany

Received 20 September 2000/Accepted 2 November 2000


    ABSTRACT
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Abstract
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Using pseudoinfection of cell lines, we demonstrate that cell surface heparan sulfate is required for infection by human papillomavirus type 16 (HPV-16) and HPV-33 pseudovirions. Pseudoinfection was inhibited by heparin but not dermatan or chondroitin sulfate, reduced by reducing the level of surface sulfation, and abolished by heparinase treatment. Carboxy-terminally deleted HPV-33 virus-like particles still bound efficiently to heparin. The kinetics of postattachment neutralization by antiserum or heparin indicated that pseudovirions were shifted on the cell surface from a heparin-sensitive into a heparin-resistant mode of binding, possibly involving a secondary receptor. Alpha-6 integrin is not a receptor for HPV-33 pseudoinfection.


    TEXT
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Papillomaviruses are highly species- and tissue-specific viruses primarily found in higher vertebrates. They infect exclusively basal cells of epithelia and induce squamous epithelial and fibroepithelial tumors, e.g., warts (papillomas) and condylomata. To date, more than a hundred human papillomaviruses (HPVs) have been identified, and some of them are strongly associated with malignant epithelial lesions, particularly genital carcinoma (for a review, see reference 13). Infectious virions recovered from naturally occurring warts of rabbits, cattle, or humans are nonenveloped particles of icosahedral symmetry, about 55 nm in diameter (11). They include a single molecule of circular double-stranded DNA of about 8,000 bp associated with histones to form a minichromosome (10). Cryoelectron microscopic analysis has shown that virion particles consist of 72 capsomeres, and each capsomer is a pentamer of the major capsid protein, L1 (1). In addition, there are some copies of a minor capsid protein, L2, probably 12 per virion (19, 28, 33). The replication of papillomaviruses is linked to the differentiation program of keratinocytes. This has hampered the efficient propagation of papillomaviruses. By now, some HPVs have been successfully propagated, albeit in minute amounts, using either a xenograft (20) or raft culture system (22). However, attempts to propagate papillomaviruses in cell culture have been unsuccessful until now.

Due to the lack of good infectivity assays, little is known about the initial steps of papillomavirus uptake. Virus-like particles (VLPs) generated by synthesis of the capsid proteins L1 and L2 in various expression systems (18, 27, 35) have shed some light on the mode of interaction between the cell surface and the viral capsid (26, 24, 36). It was demonstrated that the binding moiety on cell surfaces is highly conserved within the animal kingdom and that, with few exceptions, all cell lines tested were able to bind VLPs (25, 36). In addition, VLPs generated from the capsid proteins of different papillomaviruses were shown to compete for the same binding receptor (26). Treatment of cells with various reagents has disclosed that a protein component is involved in binding (36, 24). Recently, alpha 6 integrin was suggested as the binding receptor for HPV-6 VLPs (9), but further analyses revealed that it is not obligatory for either bovine papillomavirus type 4 (BPV-4) infection (31) or HPV-11 VLP binding to cells. (15). More recently VLPs of HPV-11 were shown to bind to heparin and to cell surfaces via heparan sulfate (15). However, binding assays cannot distinguish between productive and nonproductive interaction with the cell surface.

We have recently established an infectivity system using COS-7 cells and HPV pseudovirions encapsidating a marker plasmid. This system allows fast and easy analysis of infection events (34). Although the validity of pseudoinfection of cell lines as a model for infection with papillomaviruses may seem somewhat uncertain, this system exhibits a number of characteristics which closely parallel those of a natural infection and therefore merits further analysis. These include the high specificity of neutralization (12), the importance of the minor capsid protein L2 (34), which is not required for VLP binding to cells (26, 24, 36), and the lack of competition by other papovaviruses, such as simian virus 40 (34). The similarity of postattachment neutralization of pseudoinfection described in this paper (see below) to the neutralization of HPV-11 observed using the xenograft system (6) is a further hint to the physiological relevance of this surrogate system. We have therefore used the pseudoinfection system to study the role of proteoglycans and alpha 6 integrin in infection by pseudovirions.

Heparin inhibits pseudoinfection. To analyze if VLPs of other HPVs exhibit the same binding to heparin reported for HPV-11 (15), we initially performed enzyme-linked immunosorbent assays (ELISAs) using heparin-bovine serum albumin (BSA) complex (Sigma Aldrich) immobilized on microtiter plates and VLPs of HPV types 16, 33, and 39. All VLPs tested bound efficiently, whereas no specific binding to BSA-coated control plates was observed (data not shown). Next we studied the effect of various glycosaminoglycans on HPV pseudoinfection using pseudovirions which carried a marker plasmid coding for a dimeric green fluorescent protein (GFP) (12). Pseudovirions treated with DNase I (100 µg/ml) for 1 h at 37°C were preincubated in 30 µl of phosphate-buffered saline (PBS, pH 6.8)-10 mM MgCl2 with increasing amounts of glycosaminoglycans and subsequently added to 7 × 104 COS-7 cells suspended in 300 µl of PBS (pH 6.8), supplemented with BSA (100 µg/ml) and kept for 1 h at 4°C with gentle agitation. The cells were then seeded into 24-well plates, grown for 72 h at 37°C with 1 ml of culture medium, and subsequently monitored for infection by counting fluorescent cells. Heparin present at 0.05 mg/ml (2 µM) during pseudoinfection completely suppressed the infectivity of HPV-16 and -33 pseudovirions. Other glycosaminoglycans, like dermatan sulfate and chondroitin sulfate, had no significant effect on HPV-33 pseudoinfection (Fig. 1).


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  		FIG. 1.   Heparin is an inhibitor of pseudoinfection. Pseudovirions were preincubated with glycosaminoglycans for 1 h at 4°C at the indicated concentrations, and 30 µl of this mixture was added to 270 µl of COS-7 cell suspension and incubated for 1 h at 4°C. Cells were washed with PBS, subsequently plated, and grown for 72 h in culture medium. A value of 100% infectivity corresponded to 36 fluorescent cells. The average of at least three independent experiments is shown.

Cell surface heparan sulfate is essential for pseudoinfection. If interaction between HPV capsids and heparan sulfate is specific and required for infection, then removal of heparan sulfate from the cell surface should abolish infection. We therefore digested cell surface-bound heparan sulfate by treating COS-7 cells with heparinase I (Sigma Aldrich) prior to infection. COS-7 cells were grown to 80% confluency in Dulbecco's modified Eagle's medium (DMEM; Gibco-BRL) and washed once with 20 mM Tris-HCl-50 mM NaCl-4 mM CaCl2-0.01% BSA (pH 7.5). The cells were incubated for 1 h at 37°C with heparinase I, transferred to ice, and washed thoroughly with PBS (pH 6.8). Successful removal of heparan sulfate was monitored by fluorescence-assisted cell sorting (FACS) analysis. Pseudovirions were added and kept on ice for 1 h. Treatment with 1 U of heparinase I strongly reduced and treatment with 2 U completely abolished infection by HPV-33 pseudovirions (Fig. 2A).


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  		FIG. 2.   Cell surface heparan sulfate is essential for pseudoinfection. (A) COS-7 cells were treated with the indicated amounts of heparinase I and subsequently subjected to infectivity assays. (B) COS-7 cells were grown for 40 h in the presence of the indicated concentrations of sodium chlorate dissolved in culture medium and subsequently subjected to infectivity assays. A value of 100% infectivity corresponded to 45 (A) or 53 (B) fluorescent cells.

We further investigated the role of sulfate groups for infection by treating COS-7 cells with 20 to 80 mM sodium chlorate as described (14). This treatment had previously been shown to reduce the extent of sulfation of heparan sulfate up to 60% (14). Concentrations above 80 mM had a severe cytopathic effect and therefore could not be used. When sulfate-deprived cells were subjected to pseudoinfection, the infectivity was also reduced up to 70% (Fig. 2B). This correlates closely with the relative reduction in sulfation, implying that sulfate groups play an important role in the interaction with HPV virions.

Our results clearly demonstrate that heparan sulfate present on the cell surface is required for infection by HPV-16 and HPV-33 pseudovirions. According to previous estimates (25, 36), only 20,000 VLPs can bind to a given cell at saturation, whereas proteoglycans are common on all cells, with up to 106 molecules per cell (37). It is therefore tempting to speculate that a specific proteoglycan may mediate virion attachment. Steric occlusion or charge repulsion is an unlikely explanation, since we estimate that only 1 to 2% of the cell surface is occupied by VLPs under saturating conditions. Alternatively, the density or spacing of sulfate groups may determine a subset of proteoglycans binding VLPs.

The L1 carboxy terminus is not required for HPV-33 interaction with heparan sulfate. Joyce and coworkers had suggested that the carboxy-terminal 15 amino acids of HPV-11 L1 are responsible for interaction with heparan sulfate (15). This prompted us to use the corresponding carboxy-terminal peptide of HPV-33 L1 in a pseudoinfection competition assay. The peptide did not significantly reduce the infectivity of HPV-33 pseudovirions even at concentrations as high as 5 mg/ml. Likewise, a high-titered rabbit polyclonal antiserum generated against the same peptide had no inhibitory effect either (data not shown). VLPs lacking the carboxy-terminal seven (1/492) or 22 (1/477) amino acids of HPV-33 L1 could still bind to heparin-BSA, as shown by ELISA (Fig. 3). These data suggest that the carboxy terminus of L1 is not required for binding and infection by HPV-33 pseudovirions. This is in line with the recently published structure of BPV-1 VLPs, which revealed that the carboxy terminus of L1 is hidden inside the viral capsid (4). Even though this structure was obtained with small VLPs of T = 1 symmetry composed of only 12 capsomeres, it seems plausible that the carboxy terminus is also hidden in large VLPs with T = 7 symmetry.


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  		FIG. 3.   VLPs of carboxy-terminally deleted L1 bind to heparin-BSA. Wild-type (wt) VLPs and VLPs lacking the carboxy-terminal seven (1/492) or 22 (1/477) amino acids of HPV-33 L1 were reacted with heparin-BSA or BSA, respectively, which had been immobilized to microtiter plates. Bound VLPs were visualized with VLP-specific antiserum and horseradish peroxidase-coupled secondary antibodies using tetramethylbenzidine as the substrate.

Pseudovirion interaction with the cell surface changes from heparin sensitive to heparin resistant. Various viruses use heparan sulfate as a primary receptor but specific secondary and tertiary receptors for viral uptake. If this is also true for HPV infection, then heparin should only inhibit the initial attachment to heparan sulfate, whereas neutralizing VLP antiserum should interfere with binding to additional receptors as well. Using the mouse xenograft system, Christensen and coworkers demonstrated some years ago that infection of human keratinocytes by HPV-11 virions could still be completely neutralized by VLP antiserum several hours postattachment (6). This promoted us to compare the kinetics of neutralization by polyclonal VLP antiserum with the inhibition of pseudoinfection by heparin. To do so, pseudovirions were bound to COS-7 cells at 4°C, which were subsequently shifted to 37°C, and HPV-33 VLP-specific antiserum K53 (diluted 1:500) or heparin (100 µM) was added at intervals. As shown in Fig. 4, complete neutralization by antiserum K53 was achieved up to 4 h after attachment of pseudovirions to cells. When heparin was used instead of antiserum, postattachment neutralization was also observed. However, the time course was shifted by approximately 4 h, i.e., the pseudovirions became refractory to heparin when they were still fully accessible to antibody. This indicates that pseudovirion binding to the cells changes from heparin sensitive to heparin resistant. To account for this finding, we hypothesize that virions may initially bind to a single proteoglycan from which they can be displaced by free heparin. Additional proteoglycan molecules may later on be recruited to the complex, stabilizing virion binding and rendering the pseudovirions resistant to competing soluble heparin. Alternatively, since virions accessible to neutralizing antibodies are still on the cell surface, this shift may indicate the transfer from heparan sulfate to a secondary receptor. Various viruses have been shown to use this strategy for infection, i.e., initial binding to heparan sulfate and transfer to a secondary receptor allowing invasion of cells, e.g., herpesviruses (29, 30), human cytomegalovirus (8), human immunodeficiency virus (23), adenovirus type 2 and 5 (32), dengue virus (5), Sindbis virus (3), and vaccinia virus (7).


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  		FIG. 4.   Postattachment neutralization of HPV-33 pseudovirions. Pseudovirions were bound to COS-7 cells for 1 h at 4°C. Cells were washed with PBS, supplied with culture medium, and grown at 37°C. VLP antiserum (1:500) or heparin (100 µM) was added at the indicated times. Fluorescent cells were counted 72 h after the temperature shift. The average of at least three independent experiments is shown.

We can conceive of several explanations for why the shift to a putative secondary receptor is such a slow process: (i) the affinity for the secondary receptor is low, (ii) the number of receptor molecules is small, and (iii) the number of receptor binding sites on the viral surface is small, e.g., if L2 mediates interaction with the secondary receptor. Evidence is accumulating that L2 protein is indeed important for infection (16, 17, 34) even though the stages for which L2 protein is required have not yet been identified. It is impossible to distinguish among these possibilities unless the postulated secondary receptor and the viral structures mediating uptake by cells have been identified.

alpha 6 integrin is not essential for HPV-33 pseudoinfection. Evander and coworkers presented evidence that alpha 6 integrin serves as a receptor for HPV-6 VLP binding (9, 21). To investigate if this protein is a secondary receptor for HPV-33 pseudovirions, we performed pseudoinfection assays in the presence of alpha 6 integrin-specific monoclonal antibody GoH3 (Serotec), which had been shown to reduce binding of HPV-6 VLPs to cells by about 60% (9). A monoclonal antibody directed against beta 4 integrin (Gibco-BRL), which is not expressed in COS cells, served as a negative control (21). COS-7 cells grown to 80% confluency in 24-well plates were incubated with antibody (20 µg/ml) for 1 h on ice, and pseudovirions were subsequently added. After 1 h at 4°C, nonbound pseudovirions were removed, and culture medium supplemented with integrin antibody was added. GoH3 did not inhibit pseudoinfection of COS-7 cells, indicating that alpha 6 integrin is not a receptor for HPV-33 (data not shown). In order to confirm these observations, we wanted to exclude that heparinase treatment of COS cells, which completely blocks pseudoinfection (Fig. 2), had removed alpha 6 integrin from the cell surface. FACS was used to analyze the presence of alpha 6 integrin before and after heparinase treatment. As shown in Fig. 5A, treatment with heparinase did not reduce binding of GoH3 to COS-7 cells.


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  		FIG. 5.   alpha 6 integrin-negative cell line DG75 is susceptible to HPV-33 pseudovirions. (A) Flow cytometry analysis of alpha 6 integrin expression before (left panel) and after (right panel) treatment with heparinase. Fine lines represent autofluorescence, and bold lines show expression of alpha 6 integrin stained with antibody GoH3. (B) Cells were subjected to HPV-33 pseudoinfection. RNA was isolated 72 h postinfection and subsequently reverse transcribed. RNA coding for dimeric GFP was amplified by nested PCR, and PCR products were analyzed by agarose gel electrophoresis. Tubulin mRNA amplification served as a control.

To obtain further evidence, we used the alpha 6 integrin-negative cell line DG75, which had been reported not to bind HPV-6 VLPs, for pseudoinfection (9). Absence of alpha 6 integrin from the cell surface was confirmed by FACS analysis using the GoH3 antibody (not shown). Since the GFP marker plasmid is not amplified in DG75 cells and the fluorescence intensity is therefore too low for visual inspection, we used reverse transcription (RT)-PCR to monitor expression of the marker gene. This assay was initially established using pseudoinfection of COS-7 and HeLa cells (Fig. 5B). Nested RT-PCR was performed with RT-PCR beads (Amersham Pharmacia) using 2 µg of total RNA as the template in a final volume of 50 µl. cDNA synthesis was performed for 30 min at 42°C using oligo(dT) as the primer. Subsequently, 25 pmol of first-round primers was added to the reaction, and 35 temperature cycles were run. For amplification of GFP, forward primer 5'-ATGGTGAAGCAAGGGCGAGGAGCTGTTCACC-3' and reverse primer 5'-CTTGTACAGCTCGTCCATGCCGAGAGTGAT-3' were used; 5 µl of the first-round PCR mixture was used as the template for 20 cycles of nested PCR using PCR beads supplemented with forward primer 5'-GGCGACGTAAACGGCCACAAGTTCAGCGTG-3' and reverse primer 5'-GACCATGTGATCGCGCTTCTCGTTGGGGTC-3'. For the amplification of alpha -tubulin, used as an internal control, the degenerate forward and reverse primers were 5'-AGGGAATTCAAYCARATGGTNAARTGYGA-3' and 5'-ATCAAGCTTYTCNCCNACRTACCARTG-3', respectively, yielding a 354-bp product. The PCR was dependent on RT excluding the amplification of plasmid DNA. Pseudoinfection of HeLa cells was inhibited by VLP antiserum K53 and heparin, suggesting that pseudoinfection of HeLa cells is similar to pseudoinfection of COS cells. DG75 cells also expressed the marker gene upon pseudoinfection (Fig. 5B) demonstrating that alpha 6 integrin is not essential for HPV-33 infection.

It had been shown recently that alpha 6 integrin is not the obligatory receptor for BPV-4 either (31), suggesting the possibility that it may be specific for HPV-6. It is well established that certain integrins interact with cell surface proteoglycans (2), and the reduction in HPV-6 VLP binding to cells induced by integrin-specific antibodies and laminin could be explained by inhibition of integrin-proteoglycan interactions. Whether reduced binding translates into reduced infectivity has not been investigated so far. Experiments using infectious HPV-6 virions or pseudovirions are needed to confirm the observations made for HPV-6 and to resolve the discrepancy.

To conclude, we have shown that pseudovirions of HPV-16 and -33, like many other viruses, use heparan sulfate for attachment to the cell surface. This interaction is a prerequisite for successful infection in this surrogate system. We have presented evidence for a qualitative change in binding throughout the uptake of pseudovirions, but further experiments using the appropiate target cells, human keratinocytes, are needed to definitively prove that a secondary receptor is involved and to identify the cellular factor(s) required for virion uptake.


    ACKNOWLEDGMENTS

We are grateful to Claus-Peter Baur and Hans-Christoph Selinka for helpful discussions and careful reading of the manuscript.

This work was supported by grants to M.S. and R.E.S. from the Deutsche Forschungsgemeinschaft (SFB490-B5) and the Stiftung Rheinland-Pfalz für Innovation (8031-38 62 61/405). L.F. and F.S. were supported by Graduiertenkolleg 194.


    FOOTNOTES

* Corresponding author. Mailing address: Institut für Medizinische Mikrobiologie und Hygiene, Universität Mainz, Hochhaus am Augustusplatz, 55101 Mainz, Germany. Phone: 49-6131-393-0211. Fax: 49-6131-393-2359. E-mail: sapp{at}mail.uni-mainz.de.


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Journal of Virology, February 2001, p. 1565-1570, Vol. 75, No. 3
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.3.1565-1570.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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