Identification of PDGFR as a receptor for AAV-5 transduction

Understanding the process of vector transduction has important implications for the application and optimal use of a vector system for human gene therapy. Recent studies with vectors based on adeno-associated virus type 5 (AAV-5) have shown utility of this vector system in the lung, central nervous system, muscle and eye. To understand the natural tropism of this virus and to identify proteins necessary for AAV-5 transduction, we characterized 43 cell lines as permissive or nonpermissive for AAV-5 transduction and compared the gene expression profiles derived from cDNA microarray analyses of those cell lines. A statistically significant correlation was observed between expression of the platelet-derived growth factor receptor (PDGFR-α-polypeptide) and AAV-5 transduction. Subsequent experiments confirmed the role of PDGFR-α and PDGFR-β as receptors for AAV-5. The tropism of AAV-5 in vivo also correlated with the expression pattern of PDGFR-α.

[1]  D. Botstein,et al.  A gene expression database for the molecular pharmacology of cancer , 2000, Nature Genetics.

[2]  G. Nemerow,et al.  Integrins α v β 3 and α v β 5 promote adenovirus internalization but not virus attachment , 1993, Cell.

[3]  R. Kotin,et al.  Cloning of adeno-associated virus type 4 (AAV4) and generation of recombinant AAV4 particles , 1997, Journal of virology.

[4]  David Botstein,et al.  SOURCE: a unified genomic resource of functional annotations, ontologies, and gene expression data , 2003, Nucleic Acids Res..

[5]  R. Ross,et al.  Platelet‐derived growth factor: Morphologic and biochemical studies of binding, internalization, and degradation , 1984, Journal of cellular physiology.

[6]  L. Williams.  Signal transduction by the platelet-derived growth factor receptor involves association of the receptor with cytoplasmic molecules. , 1989, Clinical research.

[7]  D A Scudiero,et al.  Display and analysis of patterns of differential activity of drugs against human tumor cell lines: development of mean graph and COMPARE algorithm. , 1989, Journal of the National Cancer Institute.

[8]  M. Grever,et al.  Rhodamine efflux patterns predict P-glycoprotein substrates in the National Cancer Institute drug screen. , 1994, Molecular pharmacology.

[9]  J. Escobedo,et al.  Biosynthetic and glycosylation studies of cell surface platelet-derived growth factor receptors. , 1987, The Journal of biological chemistry.

[10]  Lili Wang,et al.  Hybrid Vectors Based on Adeno-Associated Virus Serotypes 2 and 5 for Muscle-Directed Gene Transfer , 2001, Journal of Virology.

[11]  R. Samulski,et al.  Cross-Packaging of a Single Adeno-Associated Virus (AAV) Type 2 Vector Genome into Multiple AAV Serotypes Enables Transduction with Broad Specificity , 2002, Journal of Virology.

[12]  Christian A. Rees,et al.  Systematic variation in gene expression patterns in human cancer cell lines , 2000, Nature Genetics.

[13]  R. Kotin,et al.  Adeno-Associated Virus Type 5 (AAV5) but Not AAV2 Binds to the Apical Surfaces of Airway Epithelia and Facilitates Gene Transfer , 2000, Journal of Virology.

[14]  Lili Wang,et al.  Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[15]  H. Delius,et al.  Human Adeno-Associated Virus Type 5 Is Only Distantly Related to Other Known Primate Helper-Dependent Parvoviruses , 1999, Journal of Virology.

[16]  D. Russell,et al.  Infectious Clones and Vectors Derived from Adeno-Associated Virus (AAV) Serotypes Other Than AAV Type 2 , 1998, Journal of Virology.

[17]  B. Hub,et al.  Endocytosis of Adeno-Associated Virus Type 5 Leads to Accumulation of Virus Particles in the Golgi Compartment , 2002, Journal of Virology.

[18]  A. Baron-Van Evercooren,et al.  Developmental Expression of Platelet-Derived Growth Factor α-Receptor in Neurons and Glial Cells of the Mouse CNS , 1997, The Journal of Neuroscience.

[19]  R. Samulski,et al.  Membrane-Associated Heparan Sulfate Proteoglycan Is a Receptor for Adeno-Associated Virus Type 2 Virions , 1998, Journal of Virology.

[20]  R. Samulski,et al.  αVβ5 integrin: a co-receptor for adeno-associated virus type 2 infection , 1999, Nature Medicine.

[21]  A. Orth,et al.  Large-scale analysis of the human and mouse transcriptomes , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  A. Ullrich,et al.  Growth factor receptor tyrosine kinases. , 1988, Annual review of biochemistry.

[23]  M. Hosang.  Characterization of a platelet-derived growth factor receptor on Swiss 3T3 cells by affinity crosslinking. , 1988, Journal of receptor research.

[24]  D. Zaharevitz,et al.  COMPARE: a web accessible tool for investigating mechanisms of cell growth inhibition. , 2002, Journal of molecular graphics & modelling.

[25]  James M. Wilson,et al.  Gene Therapy Vectors Based on Adeno-Associated Virus Type 1 , 1999, Journal of Virology.

[26]  C. Heldin,et al.  Surface binding and internalization of platelet-derived growth factor in human fibroblasts. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[27]  J. Bonner,et al.  Regulation of interleukin-1beta -induced platelet-derived growth factor receptor-alpha expression in rat pulmonary myofibroblasts by p38 mitogen-activated protein kinase. , 2000, The Journal of biological chemistry.

[28]  I. Martins,et al.  Recombinant adeno-associated virus type 2, 4, and 5 vectors: transduction of variant cell types and regions in the mammalian central nervous system. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[29]  L. Cantley,et al.  Internalization of activated platelet-derived growth factor receptor-phosphatidylinositol-3' kinase complexes: potential interactions with the microtubule cytoskeleton , 1993, Molecular and cellular biology.

[30]  S. Aaronson,et al.  Isolation of a novel receptor cDNA establishes the existence of two PDGF receptor genes. , 1989, Science.

[31]  J. Chiorini,et al.  Adeno-Associated Virus Serotype 4 (AAV4) and AAV5 Both Require Sialic Acid Binding for Hemagglutination and Efficient Transduction but Differ in Sialic Acid Linkage Specificity , 2001, Journal of Virology.

[32]  K. Malcolm,et al.  A Genomic and Proteomic Analysis of Activation of the Human Neutrophil by Lipopolysaccharide and its Mediation by p 38 Mitogen-Activated Protein Kinase , 2002 .

[33]  N. Young,et al.  Nucleotide sequencing and generation of an infectious clone of adeno-associated virus 3. , 1996, Virology.

[34]  Linda Yang,et al.  Cloning and Characterization of Adeno-Associated Virus Type 5 , 1999, Journal of Virology.

[35]  H. zur Hausen,et al.  Analysis of proteins, helper dependence, and seroepidemiology of a new human parvovirus. , 1984, Virology.

[36]  J. Bonner,et al.  Regulation of Interleukin-1β-induced Platelet-derived Growth Factor Receptor-α Expression in Rat Pulmonary Myofibroblasts by p38 Mitogen-activated Protein Kinase* , 2000, The Journal of Biological Chemistry.

[37]  Keyun Qing,et al.  Human fibroblast growth factor receptor 1 is a co-receptor for infection by adeno-associated virus 2 , 1999, Nature Medicine.

[38]  N. Young,et al.  Adeno-associated virus type 2 binds to a 150-kilodalton cell membrane glycoprotein. , 1996, Virology.

[39]  W G Alvord,et al.  Enhanced sensitivity to 1-beta-D-arabinofuranosylcytosine and topoisomerase II inhibitors in tumor cell lines harboring activated ras oncogenes. , 1996, Cancer research.

[40]  B. Davidson,et al.  Transduction of murine cerebellar neurons with recombinant FIV and AAV5 vectors , 2000, Neuroreport.

[41]  K. Malcolm,et al.  A Genomic and Proteomic Analysis of Activation of the Human Neutrophil by Lipopolysaccharide and Its Mediation by p38 Mitogen-activated Protein Kinase* , 2002, The Journal of Biological Chemistry.

[42]  M. Welsh,et al.  Binding of Adeno-associated Virus Type 5 to 2,3-Linked Sialic Acid Is Required for Gene Transfer* , 2001, The Journal of Biological Chemistry.