Abstract
The role of two receptors, previously proposed to mediate the entry of adenoviruses into human cells, the coxsackie and adenovirus receptor (CAR) and the major histocompatibility complex (MHC) class I heavy chain has been investigated. The expression of MHC class I in many tumours is reduced or absent, therefore if this were a means by which adenoviruses gained entry into cells, it would have important implications for their application in cancer treatment. In order to determine if MHC class I heavy chain is involved in adenovirus type 5 (Ad5) uptake, the binding of recombinant Ad5 fibre knob domain (which mediates viral attachment) to human cell lines that had greatly different levels of surface MHC class I was studied. We also created derivatives of a non-permissive Chinese hamster ovary (CHO) cell line that expressed human class I (HLA-A2) and found that these cells did not bind fibre or take up virus. In addition, the extracellular domain of CAR was expressed in E. coli and used to generate a polyclonal anti-CAR antibody. This antibody blocked both 125I labelled fibre knob binding and virus uptake. Thus CAR, and not MHC class I, is a receptor for human adenoviruses in cultured tumour cells. Tissue CAR levels may therefore be an important factor in the efficiency of adenovirus-mediated gene therapy.
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References
Smith AE . Viral vectors for gene therapy Ann Rev Microbiol 1995 49: 807–838
Freytag SO et al. A novel three-pronged approach to kill cancer cells selectively: concomitant viral, double suicide gene and radiotherapy Hum Gene Ther 1998 9: 1323–13333
Philipson L, Lonberg-Holm K, Pettersson U . Virus–receptor interaction in the adenovirus system J Virol 1968 2: 1064–1075
Stevenson SC et al. Human adenovirus serotypes 3 and 5 bind to two different cellular receptors via the fiber head domain J Virol 1995 69: 2850–2857
Wickham TJ et al. Integrins αvβ3 and αvβ5 promote adenovirus internalisation but not virus attachment Cell 1993 73: 309–319
Bergelson JM et al. Isolation of a common receptor for coxsackie B viruses and adenoviruses 2 and 5 Science 1997 275: 1320–1323
Tomko RP, Xu R, Philipson L . HCAR and MCAR: the human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses Proc Natl Acad Sci USA 1997 94: 3352–3356
Hidaka C et al. CAR-dependent and CAR-independent pathways of adenovirus vector-mediated gene transfer and expression in human fibroblasts J Clin Invest 1999 103: 579–587
Kaner RJ et al. Modification of the genetic program of human alveolar macrophages by adenovirus vectors in vitro is feasible but inefficient, limited in part by the low level of expression of coxsackie/adenovirus receptor Am J Respir Cell Mol Biol 1999 20: 361–370
Leon RP et al. Adenoviral-mediated gene transfer in lymphocytes Proc Natl Acad Sci USA 1998 95: 13159–13164
Hong SS et al. Adenovirus type 5 fiber knob binds to MHC class I α2 domain at the surface of human epithelial and B lymphoblastoid cells EMBO J 1997 16: 2294–2306
Gillott DJ et al. Accurate and rapid assessment of MHC antigen upregulation following cytokine stimulation J Immunol Meth 1993 165: 231–239
Wildner O, Blaese RM, Morris JC . Therapy of colon cancer with oncolytic adenvirus is enhanced by addition of herpes simplex virus-thymidine kinase Cancer Res 1999 59: 410–413
Heise C et al. ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and anti-tumoral efficacy that can be augmented by standard chemotherapeutic agents Nature Med 1997 3: 639–645
Garrido F et al. HLA class I antigen in human tumors Adv Cancer Res 1995 67: 155–195
Hemmi S et al. The presence of human coxsackie and adenovirus receptor is associated with efficient adenovirus-mediated transgene expression in human melanoma cell cultures Hum Gene Ther 1998 9: 2363–2373
Long EO et al. Efficient cDNA expression vectors for stable and transient expression of HLA-DR in transfected fibroblast and lymphoid cells Hum Immunol 1991 31: 229–235
Michael SL et al. Addition of a short peptide ligand to the adenovirus fiber protein Gene Therapy 1995 2: 660–668
Mittal SK et al. Monitoring foreign gene expression by a human adenovirus-based vector using the firefly luciferase gene as a reporter Virus Res 1993 28: 67–90
Tollefson AE et al. Preparation and titration of CsCl-banded adenovirus stock. In: Wold WSM (ed) . Methods in Molecular Medicine, Vol 21: Adenovirus Protocols and Methods Humana Press: Totawa, NJ 1998 1–9
Acknowledgements
We thank Drs A Nouri, R Finberg and A Tolkovsky for the provision of cells, antibody and recombinant adenovirus respectively, Mrs A Trejdosiewicz and Mrs J Jarvis for technical assistance and the Wellcome Trust, Action Research and Yorkshire Cancer Research for research support.
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McDonald, D., Stockwin, L., Matzow, T. et al. Coxsackie and adenovirus receptor (CAR)-dependent and major histocompatibility complex (MHC) class I-independent uptake of recombinant adenoviruses into human tumour cells. Gene Ther 6, 1512–1519 (1999). https://doi.org/10.1038/sj.gt.3301006
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DOI: https://doi.org/10.1038/sj.gt.3301006
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