Adeno-associated virus biology.

Adeno-associated virus (AAV) was first discovered as a contaminant of adenovirus stocks in the 1960s. The development of recombinant AAV vectors (rAAV) was facilitated by early studies that generated infectious molecular clones, determined the sequence of the genome, and defined the genetic elements of the virus. The refinement of methods and protocols for the production and application of rAAV vectors has come from years of studies that explored the basic biology of this virus and its interaction with host cells. Interest in improving vector performance has in turn driven studies that have provided tremendous insights into the basic biology of the AAV lifecycle. In this chapter, we review the background on AAV biology and its exploitation for vectors and gene delivery.

[1]  J. Qiu,et al.  Processing of adeno-associated virus RNA. , 2008, Frontiers in bioscience : a journal and virtual library.

[2]  M. Weitzman.  The parvovirus life cycle: an introduction to molecular interactions important for infection , 2005 .

[3]  M. Weitzman,et al.  Characterization of a nuclear localization signal in the C-terminus of the adeno-associated virus Rep68/78 proteins. , 2004, Virology.

[4]  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.

[5]  D. Pintel,et al.  Adeno-Associated Virus RNAs Appear in a Temporal Order and Their Splicing Is Stimulated during Coinfection with Adenovirus , 2000, Journal of Virology.

[6]  L. Gissmann,et al.  Detection of infectious adeno-associated virus particles in human cervical biopsies. , 1998, Virology.

[7]  L. Zentilin,et al.  Involvement of Cellular Double-Stranded DNA Break Binding Proteins in Processing of the Recombinant Adeno-Associated Virus Genome , 2001, Journal of Virology.

[8]  Juan Li,et al.  Overcoming adeno-associated virus vector size limitation through viral DNA heterodimerization , 2000, Nature Medicine.

[9]  B. Carter,et al.  Mutagenesis of an AUG codon in the adeno-associated virus rep gene: effects on viral DNA replication. , 1989, Virology.

[10]  W. Rice,et al.  DNA Structure Modulates the Oligomerization Properties of the AAV Initiator Protein Rep68 , 2009, PLoS pathogens.

[11]  R. Kotin,et al.  Adeno-associated virus DNA replication in vitro: activation by a maltose binding protein/Rep 68 fusion protein , 1994, Journal of virology.

[12]  G. Jayandharan,et al.  Strategies for improving the transduction efficiency of single-stranded adeno-associated virus vectors in vitro and in vivo , 2008, Gene Therapy.

[13]  Eithne Costello,et al.  High mobility group chromosomal protein 1 binds to the adeno‐associated virus replication protein (Rep) and promotes Rep‐mediated site‐specific cleavage of DNA, ATPase activity and transcriptional repression , 1997, The EMBO journal.

[14]  R. Heilbronn,et al.  A subset of herpes simplex virus replication genes provides helper functions for productive adeno-associated virus replication , 1991, Journal of virology.

[15]  D. Ward,et al.  Mapping and direct visualization of a region-specific viral DNA integration site on chromosome 19q13-qter. , 1991, Genomics.

[16]  D. Duan,et al.  Expanding AAV packaging capacity with trans-splicing or overlapping vectors: a quantitative comparison. , 2001, Molecular therapy : the journal of the American Society of Gene Therapy.

[17]  D. Duan,et al.  Expanding Adeno-associated Viral Vector Capacity: A Tale of Two Vectors , 2007, Biotechnology & genetic engineering reviews.

[18]  C. Balagué,et al.  Adeno-associated virus Rep78 protein and terminal repeats enhance integration of DNA sequences into the cellular genome , 1997, Journal of virology.

[19]  M. R. Delgado Alvira,et al.  Clades of Adeno-Associated Viruses Are Widely Disseminated in Human Tissues , 2004, Journal of Virology.

[20]  J. Wilson,et al.  Tailoring the AAV vector capsid for gene therapy , 2009, Gene Therapy.

[21]  N. Muzyczka,et al.  The adeno-associated virus (AAV) Rep protein acts as both a repressor and an activator to regulate AAV transcription during a productive infection , 1997, Journal of virology.

[22]  Theresa A. Storm,et al.  The Role of DNA-PKcs and Artemis in Opening Viral DNA Hairpin Termini in Various Tissues in Mice , 2007, Journal of Virology.

[23]  R. Samulski,et al.  Single-polarity recombinant adeno-associated virus 2 vector-mediated transgene expression in vitro and in vivo: mechanism of transduction. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[24]  M. Kay,et al.  From virus evolution to vector revolution: use of naturally occurring serotypes of adeno-associated virus (AAV) as novel vectors for human gene therapy. , 2003, Current gene therapy.

[25]  J. F. Wright,et al.  Transient transfection methods for clinical adeno-associated viral vector production. , 2009, Human gene therapy.

[26]  N. Muzyczka,et al.  Custom adeno-associated virus capsids: the next generation of recombinant vectors with novel tropism. , 2005, Human Gene Therapy.

[27]  J. Engelhardt,et al.  Intracellular trafficking of adeno-associated viral vectors , 2005, Gene Therapy.

[28]  Arun Srivastava,et al.  Adeno-Associated Virus Type 2-Mediated Gene Transfer: Altered Endocytic Processing Enhances Transduction Efficiency in Murine Fibroblasts , 2001, Journal of Virology.

[29]  D. Duan,et al.  Trans-splicing vectors expand the utility of adeno-associated virus for gene therapy. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[30]  F. Campagne,et al.  Characterization of the Mouse Adeno-Associated Virus AAVS1 Ortholog , 2004, Journal of Virology.

[31]  Michael Hallek,et al.  Combinatorial engineering of a gene therapy vector: directed evolution of adeno‐associated virus , 2006, The journal of gene medicine.

[32]  M. S. Chapman,et al.  The atomic structure of adeno-associated virus (AAV-2), a vector for human gene therapy , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[33]  B. Carter.  Adeno-associated virus and the development of adeno-associated virus vectors: a historical perspective. , 2004, Molecular therapy : the journal of the American Society of Gene Therapy.

[34]  J. Chamberlain,et al.  Recombinant adeno-associated virus transduction and integration. , 2008, Molecular Therapy.

[35]  N. Muzyczka,et al.  Mechanism of Rep-Mediated Adeno-Associated Virus Origin Nicking , 2000, Journal of Virology.

[36]  T. Baker,et al.  Structure of Adeno-Associated Virus Type 4 , 2005, Journal of Virology.

[37]  R. Samulski,et al.  Enhancement of Adeno-Associated Virus Infection by Mobilizing Capsids into and Out of the Nucleolus , 2008, Journal of Virology.

[38]  J. Tratschin,et al.  Genetic analysis of adeno-associated virus: properties of deletion mutants constructed in vitro and evidence for an adeno-associated virus replication function , 1984, Journal of virology.

[39]  R. Heilbronn,et al.  DNA amplification of adeno-associated virus as a response to cellular genotoxic stress. , 1988, Cancer research.

[40]  R. Samulski,et al.  Optimization of self-complementary AAV vectors for liver-directed expression results in sustained correction of hemophilia B at low vector dose. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[41]  M. Hallek,et al.  The VP1 capsid protein of adeno-associated virus type 2 is carrying a phospholipase A2 domain required for virus infectivity. , 2002, The Journal of general virology.

[42]  M. Weitzman,et al.  Transduction with recombinant adeno-associated virus for gene therapy is limited by leading-strand synthesis , 1996, Journal of virology.

[43]  D. Pintel,et al.  Adeno-Associated Viruses Can Induce Phosphorylation of eIF2α via PKR Activation, Which Can Be Overcome by Helper Adenovirus Type 5 Virus-Associated RNA , 2007, Journal of Virology.

[44]  J. Engelhardt,et al.  Second-Strand Genome Conversion of Adeno-Associated Virus Type 2 (AAV-2) and AAV-5 Is Not Rate Limiting following Apical Infection of Polarized Human Airway Epithelia , 2003, Journal of Virology.

[45]  James M. Wilson,et al.  Adenovirus-adeno-associated virus hybrid for large-scale recombinant adeno-associated virus production. , 2009, Human gene therapy.

[46]  J. Grieger,et al.  Single Amino Acid Changes Can Influence Titer, Heparin Binding, and Tissue Tropism in Different Adeno-Associated Virus Serotypes , 2006, Journal of Virology.

[47]  T. Agorastos,et al.  Adeno-associated virus infection and cervical neoplasia: is there a protective role against human papillomavirus-related carcinogenesis? , 2008, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[48]  J. Trempe,et al.  Regulation of adeno-associated virus gene expression in 293 cells: control of mRNA abundance and translation , 1988, Journal of virology.

[49]  M. Labow,et al.  Genetics of adeno-associated virus: isolation and preliminary characterization of adeno-associated virus type 2 mutants , 1984, Journal of virology.

[50]  N. Muzyczka,et al.  In vitro replication of adeno-associated virus DNA , 1994, Journal of virology.

[51]  D. Grimm,et al.  Subcellular compartmentalization of adeno-associated virus type 2 assembly , 1997, Journal of virology.

[52]  N. Sharpless,et al.  Engineering and selection of shuffled AAV genomes: a new strategy for producing targeted biological nanoparticles. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[53]  S. Kattman,et al.  Site-specific integration of adeno-associated virus involves partial duplication of the target locus , 2009, Proceedings of the National Academy of Sciences.

[54]  M. Weitzman,et al.  Analysis of adeno-associated virus (AAV) wild-type and mutant Rep proteins for their abilities to negatively regulate AAV p5 and p19 mRNA levels , 1994, Journal of virology.

[55]  N. Muzyczka,et al.  The AAV origin binding protein Rep68 is an ATP-dependent site-specific endonuclease with DNA helicase activity , 1990, Cell.

[56]  T. Parmley,et al.  High prevalence of adeno-associated virus (AAV) type 2 rep DNA in cervical materials: AAV may be sexually transmitted , 2004, Virus Genes.

[57]  Yang Shi,et al.  Transcriptional repression by YY1, a human GLI-Krüippel-related protein, and relief of repression by adenovirus E1A protein , 1991, Cell.

[58]  R. Linden,et al.  The recombination signals for adeno-associated virus site-specific integration. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[59]  B. Carter,et al.  Adeno-associated virus vectors in clinical trials. , 2005, Human gene therapy.

[60]  R. Linden,et al.  Adeno-associated virus site-specifically integrates into a muscle-specific DNA region. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[61]  F. Dean,et al.  Role of the Adenovirus DNA-Binding Protein in In Vitro Adeno-Associated Virus DNA Replication , 1998, Journal of Virology.

[62]  M. Weitzman,et al.  The Mre11/Rad50/Nbs1 Complex Limits Adeno-Associated Virus Transduction and Replication , 2007, Journal of Virology.

[63]  B. Carter,et al.  Adeno-associated virus rep protein synthesis during productive infection , 1989, Journal of virology.

[64]  P. Ward.  Replication of adeno-associated virus DNA , 2005 .

[65]  D. Grimm,et al.  DNA helicase‐mediated packaging of adeno‐associated virus type 2 genomes into preformed capsids , 2001, The EMBO journal.

[66]  T. Samulski,et al.  Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors , 1996, Journal of virology.

[67]  M. Weitzman,et al.  Rep-Dependent Initiation of Adeno-Associated Virus Type 2 DNA Replication by a Herpes Simplex Virus Type 1 Replication Complex in a Reconstituted System , 2001, Journal of Virology.

[68]  M. Weitzman,et al.  Processing of recombinant AAV genomes occurs in specific nuclear structures that overlap with foci of DNA-damage-response proteins , 2008, Journal of Cell Science.

[69]  R. Samulski,et al.  Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo , 2003, Gene Therapy.

[70]  J. Kleinschmidt,et al.  High-level expression of adeno-associated virus (AAV) Rep78 or Rep68 protein is sufficient for infectious-particle formation by a rep-negative AAV mutant , 1995, Journal of virology.

[71]  P. Hermonat,et al.  Ubiquitous human adeno-associated virus type 2 autonomously replicates in differentiating keratinocytes of a normal skin model. , 2000, Virology.

[72]  M. Labow,et al.  Adeno-associated virus gene expression inhibits cellular transformation by heterologous genes , 1987, Molecular and cellular biology.

[73]  A. Aggarwal,et al.  Structure of adeno-associated virus type 2 Rep40-ADP complex: insight into nucleotide recognition and catalysis by superfamily 3 helicases. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[74]  Daniel F. Lackner,et al.  Studies of the Mechanism of Transactivation of the Adeno-Associated Virus p19 Promoter by Rep Protein , 2002, Journal of Virology.

[75]  R. Samulski,et al.  Cross-Dressing the Virion: the Transcapsidation of Adeno-Associated Virus Serotypes Functionally Defines Subgroups , 2004, Journal of Virology.

[76]  N. Muzyczka,et al.  The cellular transcription factor SP1 and an unknown cellular protein are required to mediate Rep protein activation of the adeno-associated virus p19 promoter , 1997, Journal of virology.

[77]  D. Schaffer,et al.  Directed evolution of adeno-associated virus yields enhanced gene delivery vectors , 2006, Nature Biotechnology.

[78]  T. Baker,et al.  Structure of Adeno-Associated Virus Serotype 5 , 2004, Journal of Virology.

[79]  A. Epstein,et al.  Definition of Herpes Simplex Virus Type 1 Helper Activities for Adeno-Associated Virus Early Replication Events , 2009, PLoS pathogens.

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

[81]  J. Grieger,et al.  Separate Basic Region Motifs within the Adeno-Associated Virus Capsid Proteins Are Essential for Infectivity and Assembly , 2006, Journal of Virology.

[82]  M. Weitzman,et al.  Adeno-Associated Virus Replication Induces a DNA Damage Response Coordinated by DNA-Dependent Protein Kinase , 2009, Journal of Virology.

[83]  Theresa A. Storm,et al.  Increasing the size of rAAV-mediated expression cassettes in vivo by intermolecular joining of two complementary vectors , 2000, Nature Biotechnology.

[84]  N. Muzyczka,et al.  Complete In Vitro Reconstitution of Adeno-Associated Virus DNA Replication Requires the Minichromosome Maintenance Complex Proteins , 2007, Journal of Virology.

[85]  M. Weitzman,et al.  A genetic screen identifies a cellular regulator of adeno-associated virus , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[86]  Bing Wang,et al.  Adeno-associated virus serotype 8 efficiently delivers genes to muscle and heart , 2005, Nature Biotechnology.

[87]  Arun Srivastava,et al.  Transgene Expression Transfer : Role of Cellular FKBP 52 Protein in Adeno-Associated Virus Type 2-Mediated Gene , 2001 .

[88]  R. Haberman,et al.  Novel Transcriptional Regulatory Signals in the Adeno-Associated Virus Terminal Repeat A/D Junction Element , 2000, Journal of Virology.

[89]  B. Byrne,et al.  Structure of Adeno-Associated Virus Serotype 8, a Gene Therapy Vector , 2007, Journal of Virology.

[90]  R. Kotin,et al.  Characterization of a preferred site on human chromosome 19q for integration of adeno‐associated virus DNA by non‐homologous recombination. , 1992, The EMBO journal.

[91]  D. McCarty,et al.  Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis , 2001, Gene Therapy.

[92]  A. Epstein,et al.  Herpes Simplex Virus Type 1 ICP0 Protein Mediates Activation of Adeno-Associated Virus Type 2 rep Gene Expression from a Latent Integrated Form , 2004, Journal of Virology.

[93]  R. Samulski,et al.  Adeno-associated virus serotypes: vector toolkit for human gene therapy. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[94]  W. Xiao,et al.  Generation and characterization of chimeric recombinant AAV vectors. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[95]  R. Linden,et al.  The cryptic life style of adenoassociated virus , 1995, BioEssays : news and reviews in molecular, cellular and developmental biology.

[96]  D. Duan,et al.  A new dual-vector approach to enhance recombinant adeno-associated virus-mediated gene expression through intermolecular cis activation , 2000, Nature Medicine.

[97]  M. Weitzman,et al.  Adeno-associated virus (AAV) Rep proteins mediate complex formation between AAV DNA and its integration site in human DNA. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[98]  T. Flotte,et al.  Clinical gene therapy using recombinant adeno-associated virus vectors , 2008, Gene Therapy.

[99]  R. Samulski,et al.  Integration of adeno-associated virus (AAV) and recombinant AAV vectors. , 2004, Annual review of genetics.

[100]  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.

[101]  A. Srivastava,et al.  Adeno‐associated virus‐mediated gene transfer , 2008, Journal of cellular biochemistry.

[102]  Y. Shi,et al.  Adeno-associated virus P5 promoter contains an adenovirus E1A-inducible element and a binding site for the major late transcription factor , 1989, Journal of virology.

[103]  J. Zhang,et al.  Rapid and highly efficient transduction by double-stranded adeno-associated virus vectors in vitro and in vivo , 2003, Gene Therapy.

[104]  N. Muzyczka,et al.  Purification of Host Cell Enzymes Involved in Adeno-Associated Virus DNA Replication , 2007, Journal of Virology.

[105]  N. Muzyczka,et al.  Adenovirus-Facilitated Nuclear Translocation of Adeno-Associated Virus Type 2 , 2002, Journal of Virology.

[106]  C. Lilley,et al.  APOBEC3A Is a Potent Inhibitor of Adeno-Associated Virus and Retrotransposons , 2006, Current Biology.

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

[108]  R. Samulski,et al.  Colocalization of adeno-associated virus Rep and capsid proteins in the nuclei of infected cells , 1992, Journal of virology.

[109]  J. Xie,et al.  Existence of transient functional double-stranded DNA intermediates during recombinant AAV transduction , 2007, Proceedings of the National Academy of Sciences.

[110]  P. Hermonat.  Down-regulation of the human c-fos and c-myc proto-oncogene promoters by adeno-associated virus Rep78. , 1994, Cancer letters.

[111]  M. Drumm,et al.  Expression of the cystic fibrosis transmembrane conductance regulator from a novel adeno-associated virus promoter. , 1993, The Journal of biological chemistry.

[112]  C. Giraud,et al.  Biology of adeno-associated virus. , 1996, Current topics in microbiology and immunology.

[113]  R. Owens,et al.  Negative regulation of the adeno-associated virus (AAV) P5 promoter involves both the P5 rep binding site and the consensus ATP-binding motif of the AAV Rep68 protein , 1995, Journal of virology.

[114]  M. Hoggan,et al.  Isolation of adenovirus-associated viruses from man. , 1967, Proceedings of the National Academy of Sciences of the United States of America.

[115]  Prerna Sharma,et al.  Circular Intermediates of Recombinant Adeno-Associated Virus Have Defined Structural Characteristics Responsible for Long-Term Episomal Persistence in Muscle Tissue , 1998, Journal of Virology.

[116]  Lynne,et al.  Site-specific integration by adeno-associated virus. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[117]  J. Trempe,et al.  Characterization of cell lines that inducibly express the adeno-associated virus Rep proteins , 1994, Journal of virology.

[118]  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.

[119]  J. Qiu,et al.  The Adeno-Associated Virus Type 2 Rep Protein Regulates RNA Processing via Interaction with the Transcription Template , 2002, Molecular and Cellular Biology.

[120]  N. Muzyczka,et al.  The adeno-associated virus type 2 p40 promoter requires a proximal Sp1 interaction and a p19 CArG-like element to facilitate Rep transactivation , 1997, Journal of virology.

[121]  Xiao Xiao,et al.  Highly EfficientEx Vivo Gene Delivery into Human Corneal Endothelial Cells by Recombinant Adeno-Associated Virus , 2005, Current eye research.

[122]  N. Stow,et al.  Role of the Herpes Simplex Virus Helicase-Primase Complex during Adeno-Associated Virus DNA Replication , 2006, Journal of Virology.

[123]  R. Samulski,et al.  Regulated high level expression of a human gamma-globin gene introduced into erythroid cells by an adeno-associated virus vector. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[124]  Giovanni Di Pasquale,et al.  Identification of PDGFR as a receptor for AAV-5 transduction , 2003, Nature Medicine.

[125]  R. König,et al.  Global Analysis of Host-Pathogen Interactions that Regulate Early-Stage HIV-1 Replication , 2008, Cell.

[126]  S. Ponnazhagan,et al.  Rescue and replication signals of the adeno-associated virus 2 genome. , 1995, Journal of molecular biology.

[127]  J. Kleinschmidt,et al.  Identification of a Heparin-Binding Motif on Adeno-Associated Virus Type 2 Capsids , 2003, Journal of Virology.

[128]  N. Muzyczka,et al.  Adeno-Associated Virus Type 2 VP2 Capsid Protein Is Nonessential and Can Tolerate Large Peptide Insertions at Its N Terminus , 2004, Journal of Virology.

[129]  R. Samulski,et al.  Infectious Entry Pathway of Adeno-Associated Virus and Adeno-Associated Virus Vectors , 2000, Journal of Virology.

[130]  R. Samulski,et al.  Marker Rescue of Adeno-Associated Virus (AAV) Capsid Mutants: a Novel Approach for Chimeric AAV Production , 2003, Journal of Virology.

[131]  R. Samulski,et al.  Production of High-Titer Recombinant Adeno-Associated Virus Vectors in the Absence of Helper Adenovirus , 1998, Journal of Virology.

[132]  R. Kotin,et al.  Producing recombinant adeno-associated virus in foster cells: overcoming production limitations using a baculovirus-insect cell expression strategy. , 2009, Human gene therapy.

[133]  M. Weitzman,et al.  The Rep Protein of Adeno-Associated Virus Type 2 Interacts with Single-Stranded DNA-Binding Proteins That Enhance Viral Replication , 2004, Journal of Virology.

[134]  V. Choi,et al.  Host Cell DNA Repair Pathways in Adeno-Associated Viral Genome Processing , 2006, Journal of Virology.

[135]  M. R. Delgado Alvira,et al.  Adeno-associated viruses undergo substantial evolution in primates during natural infections , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[136]  Eric D. Adler,et al.  Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population , 2008, Nature.

[137]  M. S. Chapman,et al.  Atomic structure of viral particles , 2005 .

[138]  N. Muzyczka,et al.  Identification of Amino Acid Residues in the Capsid Proteins of Adeno-Associated Virus Type 2 That Contribute to Heparan Sulfate Proteoglycan Binding † , 2002 .

[139]  Philip R. Johnson,et al.  Molecular Characterization of Adeno-Associated Viruses Infecting Children , 2005, Journal of Virology.

[140]  G. Natsoulis,et al.  Adeno-associated virus Rep proteins target DNA sequences to a unique locus in the human genome , 1997, Journal of virology.

[141]  R. Samulski,et al.  Adenovirus E1B 55-Mr polypeptide facilitates timely cytoplasmic accumulation of adeno-associated virus mRNAs , 1988, Journal of virology.

[142]  P. Senapathy,et al.  Replication of adeno-associated virus DNA. Complementation of naturally occurring rep- mutants by a wild-type genome or an ori- mutant and correction of terminal palindrome deletions. , 1984, Journal of molecular biology.

[143]  M. Labow,et al.  Positive and negative autoregulation of the adeno-associated virus type 2 genome , 1986, Journal of virology.

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

[145]  A. Srivastava,et al.  Rescue and replication of the adeno-associated virus 2 genome in mortal and immortal human cells. , 1989, Intervirology.

[146]  B. Byrne,et al.  Large-scale adeno-associated viral vector production using a herpesvirus-based system enables manufacturing for clinical studies. , 2009, Human gene therapy.

[147]  James M. Wilson,et al.  New recombinant serotypes of AAV vectors. , 2005, Current gene therapy.

[148]  R. Kotin,et al.  Asymmetric replication in vitro from a human sequence element is dependent on adeno-associated virus Rep protein , 1995, Journal of virology.

[149]  R. Linden,et al.  Transcriptional Analysis of the Adeno-Associated Virus Integration Site , 2009, Journal of Virology.

[150]  O. Danos,et al.  Intracellular Trafficking of Adeno-Associated Virus Vectors: Routing to the Late Endosomal Compartment and Proteasome Degradation , 2001, Journal of Virology.

[151]  J. Chiorini,et al.  PKA/PrKX activity is a modulator of AAV/adenovirus interaction , 2003, The EMBO journal.

[152]  R. Kotin,et al.  Organization of adeno-associated virus DNA in latently infected Detroit 6 cells. , 1989, Virology.

[153]  M. Weitzman,et al.  Recruitment of wild-type and recombinant adeno-associated virus into adenovirus replication centers , 1996, Journal of virology.

[154]  B. Stillman,et al.  Cellular Proteins Required for Adeno-Associated Virus DNA Replication in the Absence of Adenovirus Coinfection , 1998, Journal of Virology.

[155]  R. Kotin,et al.  Structural unity among viral origin binding proteins: crystal structure of the nuclease domain of adeno-associated virus Rep. , 2002, Molecular cell.

[156]  R. Mandel,et al.  Circulating Anti-Wild-Type Adeno-Associated Virus Type 2 (AAV2) Antibodies Inhibit Recombinant AAV2 (rAAV2)-Mediated, but Not rAAV5-Mediated, Gene Transfer in the Brain , 2004, Journal of Virology.

[157]  N. Muzyczka,et al.  Sequences required for coordinate induction of adeno-associated virus p19 and p40 promoters by Rep protein , 1991, Journal of virology.

[158]  H. D. Mayor,et al.  Antibodies to adeno-associated satellite virus and herpes simplex in sera from cancer patients and normal adults. , 1976, American journal of obstetrics and gynecology.

[159]  M. Weitzman,et al.  Identification of a DNA-binding domain in the amino terminus of adeno-associated virus Rep proteins , 1993, Journal of virology.

[160]  K. Berns,et al.  In vitro replication of adeno-associated virus DNA: enhancement by extracts from adenovirus-infected HeLa cells , 1996, Journal of virology.

[161]  Michael Hallek,et al.  Recent developments in adeno‐associated virus vector technology , 2008, The journal of gene medicine.

[162]  Theresa A. Storm,et al.  Rapid Uncoating of Vector Genomes Is the Key toEfficient Liver Transduction with Pseudotyped Adeno-Associated VirusVectors , 2004, Journal of Virology.

[163]  D. Mccarty.  Self-complementary AAV vectors; advances and applications. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[164]  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.

[165]  D. Housman,et al.  Targeted integration of adeno‐associated virus (AAV) into human chromosome 19. , 1991, The EMBO journal.

[166]  N. Muzyczka,et al.  Identification of Cellular Proteins That Interact with the Adeno-Associated Virus Rep Protein , 2008, Journal of Virology.

[167]  A. Aggarwal,et al.  Crystal structure of the SF3 helicase from adeno-associated virus type 2. , 2003, Structure.