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Journal of Virology, June 2001, p. 5405-5409, Vol. 75, No. 11
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.11.5405-5409.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Integrin alpha vbeta 1 Is an Adenovirus Coreceptor†

Erguang Li, Swati L. Brown, Dwayne G. Stupack, Xose S. Puente, David A. Cheresh, and Glen R. Nemerow*

Department of Immunology, The Scripps Research Institute, La Jolla, California 92037

Received 19 January 2001/Accepted 9 March 2001


    ABSTRACT
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The human embryonic kidney (HEK293) cell line, commonly used for recombinant adenovirus (Ad) propagation, does not express the Ad coreceptor alpha vbeta 3 or alpha vbeta 5 integrins, yet these cells are efficiently infected by Ad vectors. Here we demonstrate that Ad binds to HEK293 cells via the fiber receptor CAR and is subsequently internalized via interaction with integrin alpha vbeta 1. Function-blocking antibodies directed against alpha v or beta 1, but not beta 3, beta 5, or alpha 5, integrin subunits block Ad infection and viral endocytosis. Therefore, alpha vbeta 1 serves as a coreceptor for Ad infection, and the lack of beta 3 and/or beta 5 but the relatively high expression of alpha vbeta 1 integrins on certain tumor cell types may explain why these cells are readily transduced by Ad vectors.


    TEXT
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Adenovirus (Ad) host cell entry requires initial attachment to cells mediated by the fiber interaction with its cellular receptor CAR. The subsequent association of penton base with alpha vbeta 3 or alpha vbeta 5 integrins promotes Ad entry (1, 21, 23). Integrins are heterodimeric receptors for extracellular matrix proteins and cell surface counterreceptors. alpha v integrins (alpha vbeta 1, alpha vbeta 3, alpha vbeta 5, alpha vbeta 6, and alpha vbeta 8) mediate cell adhesion to various matrix proteins, including fibronectin, vitronectin, and fibrinogen, that contain an arginine-glycine-aspartic acid (RGD) sequence (8, 19, 24). The interaction of the Ad penton base and alpha v integrin triggers the activation of several signaling molecules (14) that promote actin cytoskeletal reorganization and enhance Ad internalization. Although HEK293 cells have been widely used for propagation of recombinant Ad vectors, the integrin repertoire of these cells has not been clearly established. For example, several reports indicate that HEK293 cells do not express alpha vbeta 3 and alpha vbeta 5 integrins (10, 18), while another report indicates that they do (6). Furthermore, beta 5 integrin-deficient mouse fibroblast cells support Ad infection, suggesting that other integrins play a role in Ad infection (11). HEK293 cells were also reported to express alpha 5beta 1 and alpha vbeta 1 integrins (2), which have been identified as RGD-dependent receptors for both fibronectin and vitronectin (2, 15, 22). Considering the fact that soluble fibronectin or RGD-containing peptide reduced Ad infection (23) and that an alpha 5beta 1-activating antibody has been reported to enhance Ad-mediated gene delivery to certain melanoma cells (4), it was of interest to determine whether Ad uses either alpha vbeta 1 and/or alpha 5beta 1 integrins as alternative receptors for virus internalization.

The role of CAR and alpha v integrins in Ad infection of HEK293 cells. To investigate whether CAR or integrins promote Ad attachment, we preincubated HEK293 cells with an excess of recombinant Ad type 2 (Ad2) fiber protein or with anti-CAR monoclonal antibody (MAb ) (RmcB), with a function-blocking Fab fragment of a penton base MAb (DAV-1) (20), or with function-blocking alpha vbeta 5 (P1F6), alpha 5 (P1D6), or nonfunction-blocking alpha v (LM142) control MAb prior to measuring the specific binding of 125I-labeled Ad5 particles (Fig. 1A) as previously described (13). Pretreatment of cells with recombinant Ad fiber protein completely blocked 125I-Ad5 binding to HEK293 cells, and the RmcB antibody also partially blocked binding. These findings indicated that Ad binding to HEK293 cells is likely mediated by fiber association with CAR.


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  		FIG. 1.   Adenovirus infection of HEK293 cells is mediated by fiber and penton base proteins. (A) Fiber protein mediates Ad binding to HEK293 cells. HEK293 cells (1.5 × 106 cells/sample, in duplicate) in suspension were preincubated with recombinant Ad2 fiber, penton base (10 µg/ml), the anti-CAR antibody (RmcB), anti-penton base antibody (DAV-1), or anti-integrin antibodies at 20 µg/ml at 4°C for 60 min. Specific Ad binding to cells was determined by using 125I-labeled Ad2 as previously described (13). (B) Penton base interaction with alpha v integrins promotes Ad-mediated gene delivery. HEK293 cells (106 cells/sample) were preincubated with fiber protein, anti-CAR, anti-penton base, or anti-integrin antibodies (20 µg/ml) as described above, followed by incubation with Ad.CMV.LacZ at an MOI of 1 particle/cell at 4°C for another 30 min. The cells were then warmed to 37°C for 15 min. Noninternalized virus was removed by trypsinization. Ad-mediated gene delivery was determined at 20 h postinfection by expression of beta -galactosidase. Representative data from two independent experiments were plotted as the mean ± standard deviation.

Experiments were next performed to determine if CAR and/or integrins regulate Ad-mediated gene delivery (Fig. 1B). Cells were infected with Ad5.CMV.LacZ at a multiplicity of infection (MOI) of 1 and then assayed for beta -galactosidase expression at 20 h postinfection. As expected from the binding studies, soluble fiber protein and anti-CAR antibody significantly inhibited Ad infection. Furthermore, anti-penton base antibody (DAV-1) and the alpha v integrin function-blocking antibody (L230) inhibited Ad-mediated gene delivery by approximately 40%. In contrast, the function-blocking alpha vbeta 3 (LM609) and alpha vbeta 5 (P1F6) integrin antibodies failed to significantly inhibit infection. These results suggested that other members of the alpha v integrin family, such as alpha vbeta 1, may facilitate Ad infection of HEK293 cells.

HEK293 cells express alpha vbeta 1 integrins. Since conflicting results have been reported with regard to alpha v integrin expression on HEK293 cells (6, 10, 18), we next sought to determine the repertoire of different alpha v integrins expressed on HEK293 cells using flow cytometry. These studies demonstrated that HEK293 cells expressed significant levels of alpha v, alpha 5, and beta 1 integrins (Fig. 2). In contrast, alpha vbeta 3 and alpha vbeta 5 integrin expression was undetectable on HEK293 cells, whereas these alpha v integrins were expressed on A549 cells. To verify integrin expression, cell surface proteins of HEK293 cells were biotinylated and then solubilized with 1% Nonidet P-40. Cell lysates were then immunoprecipitated with anti-alpha v, anti-alpha 5, or anti-beta 1 or with anti-alpha vbeta 1 integrin antibodies and then analyzed on a 6% sodium dodecyl sulfate-polyacrylamide gel under reducing conditions, followed by immunoblotting with a horseradish peroxidase-conjugated antibiotin antibody (Sigma, St. Louis, Mo.). As shown in Fig. 3A, the anti-alpha v antibody (L230) immunoprecipitated two proteins of approximately 155 and 121 kDa. In contrast, the anti-alpha vbeta 5 (P1F6) and anti-alpha vbeta 3 (LM609) antibodies failed to immunoprecipitate these integrins, although both antibodies immunoprecipitated the corresponding alpha  and beta  chains from A549 cells (Fig. 3B). The 155- and 121-kDa as well as a 200-kDa protein were also recognized by a pan-specific beta 1 antibody (P4C10). The 200-kDa protein is likely the alpha 1 integrin subunit, which is known to form a heterodimer with the beta 1 integrin subunit. An alpha 5-specific antibody (P1D6) also immunoprecipitated a 155- and a 121-kDa protein. Integrin alpha 5 also associates with the beta 1 subunit and exhibits mobility similar to that of the alpha v integrin subunit. These findings indicated that beta 1 integrins form heterodimeric receptors with alpha v and alpha 5 but not with beta 3 and beta 5 subunits on HEK293 cells. Moreover, these findings indicated that alpha vbeta 1 is the major alpha v integrin on HEK293 cells. To verify this, we performed immunoprecipitation detection experiments with an alpha vbeta 1-specific antibody (9EG7). As expected, this antibody also immunoprecipitated 155- and 121-kDa proteins on HEK293 cells.


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  		FIG. 2.   Flow cytometric analysis of integrin expression on HEK293 cells. HEK293 or A549 cells were incubated with 20 µg of anti-integrin antibodies/ml at 4°C for 60 min. Cell surface-bound antibody was detected by incubation with an R-phycoerythrin-labeled goat anti-mouse secondary antibody. Dashed line, secondary antibody control; solid line, indicated integrin antibodies.


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  		FIG. 3.   Immunoprecipitation analyses of integrin expression on HEK293 cells. HEK293 (A) and A549 (B) cells (107 cells) were detached with 1 mM EDTA and then biotinylated with 1 mg of sulfo-N-hydroxysuccinimide-biotin. After being washed with phosphate-buffered saline four times, labeled cells were then lysed in 1 ml of lysis buffer containing 1% Nonidet P-40 and protease inhibitors. Lysates from biotinylated cells (equal to 106 cells) were immunoprecipitated with 2 µg of anti-integrin antibodies followed by capture with protein A/G beads. The immunoprecipitates were then separated on 6% sodium dodecyl sulfate gels under reducing conditions. After transfer to a polyvinylidene difluoride membrane, the filter was probed with a horseradish peroxidase-conjugated anti-biotin antibody.

alpha vbeta 1 integrins promote Ad infection of HEK293 cells. We next analyzed whether the alpha vbeta 1 integrins expressed on HEK293 cells were capable of interacting with Ad by performing cell adhesion assays in the presence or absence of function-blocking integrin antibodies. HEK293 cells adhered to fibronectin, and adhesion could be inhibited with a function-blocking anti-alpha 5 (P1D6), anti-alpha v (L230), or anti-beta 1 (P4C10) MAb (Fig. 4). HEK293 cells also adhered to penton base; however, adhesion to penton base could only be inhibited by anti-alpha v or the anti-beta 1 antibodies. This finding indicated that integrin alpha vbeta 1 but not alpha 5beta 1 serves as a receptor for Ad penton base.


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  		FIG. 4.   Integrin-dependent cell adhesion to fibronectin (A) or penton base (B). Non-tissue culture-treated cluster plates were precoated with 10 µg of recombinant penton base or fibronectin/ml. HEK293 cells were preincubated with 20 µg of anti-integrin antibodies/ml before the cells were allowed to attach to coated plates for 15 min at 37°C. Attached cells were quantitated after fixation and stained with crystal violet. Data are presented as the mean ± standard deviation of duplicate samples. Antibodies: LM609, anti-alpha vbeta 3; P1F6, anti-alpha vbeta 5; L230, anti-alpha v; P4C10, anti-beta 1; P1D6, anti-alpha 5; 1973z, anti-alpha 1.

To determine whether Ad uses alpha vbeta 1 integrin for infection, we treated HEK293 cells with anti-alpha v integrin antibody (L230), anti-alpha 5 antibody (P1D6), or anti-beta 1 integrin antibody (P4C10) and then measured Ad-mediated gene delivery to these cells (Fig. 5A). Pretreatment of HEK293 cells with anti-alpha v, anti-beta 1, or a combination of anti-alpha v and anti-beta 1 antibodies significantly blocked Ad infection. In contrast, the anti-alpha 5 antibody alone inhibited Ad infection by less than 10%. Pretreatment with a combination of anti-beta 1 and anti-alpha 5 antibodies did not further decrease gene delivery relative to that achieved with anti-beta 1 alone (data not shown). These data indicated that alpha vbeta 1 integrin also facilitates Ad infection of HEK293 cells.


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  		FIG. 5.   Integrin alpha vbeta 1 promotes Ad-mediated gene delivery and virus internalization. (A) HEK293 cells in suspension were preincubated with anti-integrin antibodies for 60 min at 4°C, followed by incubation with Ad.CMV.LacZ at an MOI of 1 viral particle/cell. After being warmed to 37°C for 15 min, noninternalized virus was removed by trypsinization. Cells were plated in 6-well plates, and beta -galactosidase expression was determined at 20 h postinfection (mean ± standard deviation). (B) HEK293 cells were pretreated with 20 µg of anti-integrin antibodies/ml at 4°C for 60 min, followed by the addition of 125I-labeled Ad2 (2 × 105 cpm/cell). Bound virus particles were then allowed to internalize by warming the cells at 37°C for 15 min. Internalized virions were determined by measuring their resistance to trypsinization. The data represent the percentage of trysin-resistant cpm/total cpm of specifically bound Ad ± standard deviation of duplicate samples.

Further studies investigated whether penton base interaction with integrin alpha vbeta 1 promotes Ad internalization. Cells were preincubated with function-blocking anti-integrin antibodies prior to the addition of 125I-labeled Ad2 (Fig. 5B). Virus uptake was then assayed by measuring the resistance of Ad particles to trypsin treatment. Pretreatment with anti-beta 1 or anti-alpha v antibody significantly inhibited Ad internalization by 63 and 42%, respectively, compared to that of untreated control cells. The combination of anti-alpha v and anti-beta 1 antibodies inhibited Ad internalization by 76%. In contrast, the anti-alpha 5 or LM609 antibody (alpha vbeta 3) had little if any effect on virus entry. These studies demonstrated that alpha vbeta 1 integrin promotes Ad infection by enhancing virus internalization.

Here we demonstrated that HEK293 cells use alpha vbeta 1 integrin, instead of alpha vbeta 3 or alpha vbeta 5 integrin, for virus internalization and infection. The ability of alpha vbeta 1 to promote Ad infection may also explain why mice genetically deficient in beta 5 integrin are susceptible to Ad infection (11). It will be of interest to determine whether other cell types that express alpha vbeta 1 or perhaps other beta 1 integrins (3, 12) are also susceptible to Ad infection. In this regard, human melanoma, breast cancer, and neuroblastoma cells have been shown to express integrin alpha vbeta 1 (5, 7,9, 16). Integrin alpha vbeta 1 may also regulate the migration of human oligodendritic cells in the central nervous system (17).


    ACKNOWLEDGMENTS

We are extremely grateful to David Schlaepfer and Richard Klemke (The Scripps Research Institute) for valuable discussions and advice. We thank Joan Gausepohl and Kelly White for preparation of the manuscript.

This work was supported by the NIH (grants HL54352 and EY11431).


    FOOTNOTES

* Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-8072. Fax: (858) 784-8472. E-mail: gnemerow{at}scripps.edu.

dagger This is manuscript no. 13843-IMM from the Department of Immunology.


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Journal of Virology, June 2001, p. 5405-5409, Vol. 75, No. 11
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.11.5405-5409.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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