Cited by 114Virus-based gene therapy researchRNA Interference and Gene DeliverySARS-CoV-2 and COVID-19 Research

Adeno-Associated Virus Structural Biology as a Tool in Vector Development

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Drouin, Lauren M, Agbandje-McKenna, Mavis·2013·Future Virology

Abstract

Adeno-associated viruses (AAVs) have become important therapeutic gene delivery vectors in recent years. However, there are challenges, including intractable tissues/cell types and pre-existing immune responses, which need to be overcome for full realization of this system. This review addresses strategies aimed at improving AAV efficacy in the clinic through the creation of hybrid vectors that display altered or more targeted specific tissue tropisms, while also escaping recognition from host-derived neutralizing antibodies. Characterization of these viruses with respect to serotypes contributing to their capsid, using available 3D structures, enables the identification of regions critical for particular tropism and antigenic phenotypes. Structural information also allows for rational design of vectors with specific targeted tropisms for improved therapeutic efficacy.

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  1. [2]Yanez RJ Porter AC Therapeutic gene targeting. Gene Ther 1998 5 2 149 159 9578833
  2. [3]Peng KW Strategies for targeting therapeutic gene delivery. Mol. Med. Today 1999 5 10 448 453 10498913
  3. [4]Raper SE Chirmule N Lee FS Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. 80 Mol. Genet. Metab 2003 1–2 148 158 14567964
  4. [5]Hacein-Bey-Abina S Garrigue A Wang GP Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J. Clin. Invest 2008 118 9 3132 3142 18688285 PMC2496963
  5. [6]Daya S Berns KI Gene therapy using adeno-associated virus vectors. Clin. Microbiol. Rev 2008 21 4 583 593 18854481 PMC2570152
  6. [7]Flotte TR Carter BJ Adeno-associated virus vectors for gene therapy. Gene Ther 1995 2 6 357 362 7584109
  7. [9]Sonntag F Schmidt K Kleinschmidt JA A viral assembly factor promotes AAV2 capsid formation in the nucleolus. Proc. Natl Acad. Sci. USA 2010 107 22 10220 10225 20479244 PMC2890453
  8. [10]Sonntag F Kother K Schmidt K The assembly-activating protein promotes capsid assembly of different adeno-associated virus serotypes. J. Virol 2011 85 23 12686 12697 21917944 PMC3209379
  9. [11]Naumer M Sonntag F Schmidt K Properties of the adeno-associated virus assembly-activating protein. J. Virol 2012 86 23 13038 13048 23015698 PMC3497687
  10. [13]Summerford C Samulski RJ Membrane-associated heparan sulfate proteoglycan is a receptor for adeno-associated virus type 2 virions. J. Virol 1998 72 2 1438 1445 9445046 PMC124624
  11. [14]Akache B Grimm D Pandey K Yant SR Xu H Kay MA The 37/67-kilodalton laminin receptor is a receptor for adeno-associated virus serotypes 8, 2, 3 and 9. J. Virol 2006 80 19 9831 9836 16973587 PMC1617255
  12. [17]Qing K Mah C Hansen J Zhou S Dwarki V Srivastava A Human fibroblast growth factor receptor 1 is a co-receptor for infection by adeno-associated virus 2. Nat. Med 1999 5 1 71 77 9883842
  13. [18]Summerford C Bartlett JS Samulski RJ AlphaVbeta5 integrin: a co-receptor for adeno-associated virus type 2 infection. Nat. Med 1999 5 1 78 82 9883843
  14. [19]Uhrig S Coutelle O Wiehe T Perabo L Hallek M Buning H Successful target cell transduction of capsid-engineered rAAV vectors requires clathrin-dependent endocytosis. Gene Ther 2012 19 2 210 218 21654820
  15. [20]Nonnenmacher M Weber T Adeno-associated virus 2 infection requires endocytosis through the CLIC/GEEC pathway. Cell Host Microbe 2011 10 6 563 576 22177561 PMC3257174
  16. [21]Girod A Wobus CE Zadori Z The VP1 capsid protein of adeno-associated virus type 2 is carrying a phospholipase A2 domain required for virus infectivity. J. Gen. Virol 2002 83 Pt 5 973 978 11961250
  17. [22]Sonntag F Bleker S Leuchs B Fischer R Kleinschmidt JA Adeno-associated virus type 2 capsids with externalized VP1/VP2 trafficking domains are generated prior to passage through the cytoplasm and are maintained until uncoating occurs in the nucleus. J. Virol 2006 80 22 11040 11054 16956943 PMC1642181
  18. [23]Zadori Z Szelei J Lacoste MC A viral phospholipase A2 is required for parvovirus infectivity. Dev. Cell 2001 1 2 291 302 11702787
  19. [25]Kronenberg S Bottcher B von der Lieth CW Bleker S Kleinschmidt JA A conformational change in the adeno-associated virus type 2 capsid leads to the exposure of hidden VP1 N termini. J. Virol 2005 79 9 5296 5303 15827144 PMC1082756
  20. [26]Xiao PJ Samulski RJ Cytoplasmic trafficking, endosomal escape and perinuclear accumulation of adeno-associated virus type 2 particles are facilitated by microtubule network. J. Virol 2012 86 19 10462 10473 22811523 PMC3457265
  21. [27]Xiao W Warrington KH Jr Hearing P Hughes J Muzyczka N Adenovirus-facilitated nuclear translocation of adeno-associated virus type 2. J. Virol 2002 76 22 11505 11517 12388712 PMC136768
  22. [28]Dubielzig R King JA Weger S Kern A Kleinschmidt JA Adeno-associated virus type 2 protein interactions: formation of preencapsidation complexes. J. Virol 1999 73 11 8989 8998 10516005 PMC112931
  23. [29]Duan D Sharma P Yang J Circular intermediates of recombinant adeno-associated virus have defined structural characteristics responsible for long-term episomal persistence in muscle tissue. J. Virol 1998 72 11 8568 8577 9765395 PMC110267
  24. [30]Kotin RM Siniscalco M Samulski RJ Site-specific integration by adeno-associated virus. Proc. Natl Acad. Sci. USA 1990 87 6 2211 2215 2156265 PMC53656
  25. [31]Atchison RW Casto BC Hammon WM Adenovirus-associated defective virus particles. Science 1965 149 3685 754 756 14325163
  26. [32]Srivastava A Lusby EW Berns KI Nucleotide sequence and organization of the adeno-associated virus 2 genome. J. Virol 1983 45 2 555 564 6300419 PMC256449
  27. [33]Muramatsu S Mizukami H Young NS Brown KE Nucleotide sequencing and generation of an infectious clone of adeno-associated virus 3. Virology 1996 221 1 208 217 8661429
  28. [34]Rutledge EA Halbert CL Russell DW Infectious clones and vectors derived from adeno-associated virus (AAV) serotypes other than AAV type 2. J. Virol 1998 72 1 309 319 9420229 PMC109378
  29. [35]Chiorini JA Kim F Yang L Kotin RM Cloning and characterization of adeno-associated virus type 5. J. Virol 1999 73 2 1309 1319 9882336 PMC103955
  30. [36]Chiorini JA Yang L Liu Y Safer B Kotin RM Cloning of adeno-associated virus type 4 (AAV4) and generation of recombinant AAV4 particles. J. Virol 1997 71 9 6823 6833 9261407 PMC191963
  31. [37]Schmidt M Grot E Cervenka P Wainer S Buck C Chiorini JA Identification and characterization of novel adeno-associated virus isolates in ATCC virus stocks. J. Virol 2006 80 10 5082 5085 16641301 PMC1472088
  32. [38]Schmidt M Govindasamy L Afione S Kaludov N Agbandje-McKenna M Chiorini JA Molecular characterization of the heparin-dependent transduction domain on the capsid of a novel adeno-associated virus isolate, AAV(VR-942). J. Virol 2008 82 17 8911 8916 18524816 PMC2519687
  33. [39]Schmidt M Voutetakis A Afione S Zheng C Mandikian D Chiorini JA Adeno-associated virus type 12 (AAV12): a novel AAV serotype with sialic acid- and heparan sulfate proteoglycan-independent transduction activity. J. Virol 2008 82 3 1399 1406 18045941 PMC2224443
  34. [40]Mori S Wang L Takeuchi T Kanda T Two novel adeno-associated viruses from cynomolgus monkey: pseudotyping characterization of capsid protein. Virology 2004 330 2 375 383 15567432
  35. Gao G Vandenberghe LH Alvira MR Clades of adeno-associated viruses are widely disseminated in human tissues. J. Virol 2004 78 12 6381 6388 Comparison of the transduction efficiency of adeno-associated virus (AAV) serotypes both in vitro and in vivo. 15163731 PMC416542
  36. [42]Gao GP Alvira MR Wang L Calcedo R Johnston J Wilson JM Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc. Natl Acad. Sci. USA 2002 99 18 11854 11859 12192090 PMC129358
  37. [43]Zincarelli C Soltys S Rengo G Rabinowitz JE Analysis of AAV serotypes 1–9 mediated gene expression and tropism in mice after systemic injection. Mol. Ther 2008 16 6 1073 1080 18414476
  38. [44]Asokan A Conway JC Phillips JL Reengineering a receptor footprint of adeno-associated virus enables selective and systemic gene transfer to muscle. Nat. Biotechnol 2010 28 1 79 82 20037580 PMC2912150
  39. [45]Asokan A Schaffer DV Samulski RJ The AAV vector toolkit: poised at the clinical crossroads. Mol. Ther 2012 20 4 699 708 22273577 PMC3321598
  40. [46]Kotchey NM Adachi K Zahid M A potential role of distinctively delayed blood clearance of recombinant adeno-associated virus serotype 9 in robust cardiac transduction. Mol. Ther 2011 19 6 1079 1089 21364543 PMC3129802
  41. [48]Govindasamy L DiMattia MA Gurda BL Structural insights into adeno-associated virus serotype 5. J. Virol 2013 87 20 11187 11199 23926356 PMC3807309
  42. Govindasamy L Padron E McKenna R Structurally mapping the diverse phenotype of adeno-associated virus serotype 4. J. Virol 2006 80 23 11556 11570 Reports on AAV capsid surface loop variable regions and their functional roles. 16971437 PMC1642620
  43. [50]Kronenberg S Kleinschmidt JA Bottcher B Electron cryo-microscopy and image reconstruction of adeno-associated virus type 2 empty capsids. EMBO Rep 2001 2 11 997 1002 11713191 PMC1084133
  44. [51]Lerch TF Xie Q Chapman MS The structure of adeno-associated virus serotype 3B (AAV-3B): insights into receptor binding and immune evasion. Virology 2010 403 1 26 36 20444480 PMC2885149
  45. [53]Nam HJ Lane MD Padron E Structure of adeno-associated virus serotype 8, a gene therapy vector. J. Virol 2007 81 22 12260 12271 17728238 PMC2168965
  46. [54]Ng R Govindasamy L Gurda BL Structural characterization of the dual glycan binding adeno-associated virus serotype 6. J. Virol 2010 84 24 12945 12957 20861247 PMC3004313
  47. [55]Walters RW Agbandje-McKenna M Bowman VD Structure of adeno-associated virus serotype 5. J. Virol 2004 78 7 3361 3371 15016858 PMC371067
  48. Xie Q Bu W Bhatia S The atomic structure of adeno-associated virus (AAV-2), a vector for human gene therapy. Proc. Natl Acad. Sci. USA 2002 99 16 10405 10410 Reports on the high-resolution crystal structure of AAV2. 12136130 PMC124927
  49. [57]Venkatakrishnan B Yarbrough J Domsic J Structure and dynamics of adeno-associated virus serotype 1 VP1-unique N-terminal domain and its role in capsid trafficking. J. Virol 2013 87 9 4974 4984 23427155 PMC3624325
  50. [58]McCraw DM O'Donnell JK Taylor KA Stagg SM Chapman MS Structure of adeno-associated virus-2 in complex with neutralizing monoclonal antibody A20. Virology 2012 431 1–2 40 49 22682774 PMC3383000
  51. Gurda BL DiMattia MA Miller EB Capsid antibodies to different adeno-associated virus serotypes bind common regions. J. Virol 2013 87 16 9111 9124 First comprehensive structural study of antigenic epitopes on the AAV capsid. 23760240 PMC3754064
  52. [60]Gurda BL Raupp C Popa-Wagner R Mapping a neutralizing epitope onto the capsid of adeno-associated virus serotype 8. J. Virol 2012 86 15 7739 7751 22593150 PMC3421660
  53. [63]Lochrie MA Tatsuno GP Christie B Mutations on the external surfaces of adeno-associated virus type 2 capsids that affect transduction and neutralization. J. Virol 2006 80 2 821 834 16378984 PMC1346838
  54. [64]O'Donnell J Taylor KA Chapman MS Adeno-associated virus-2 and its primary cellular receptor – Cryo-EM structure of a heparin complex. Virology 2009 385 2 434 443 19144372 PMC2684845
  55. [65]Opie SR Warrington KH Jr Agbandje-McKenna M Zolotukhin S Muzyczka N Identification of amino acid residues in the capsid proteins of adeno-associated virus type 2 that contribute to heparan sulfate proteoglycan binding. J. Virol 2003 77 12 6995 7006 12768018 PMC156206
  56. [67]Wu P Xiao W Conlon T Mutational ana lysis of the adeno-associated virus type 2 (AAV2) capsid gene and construction of AAV2 vectors with altered tropism. J. Virol 2000 74 18 8635 8647 10954565 PMC102071
  57. [68]Bleker S Pawlita M Kleinschmidt JA Impact of capsid conformation and Rep-capsid interactions on adeno-associated virus type 2 genome packaging. J. Virol 2006 80 2 810 820 16378983 PMC1346863
  58. Hermonat PL Muzyczka N Use of adeno-associated virus as a mammalian DNA cloning vector: transduction of neomycin resistance into mammalian tissue culture cells. Proc. Natl Acad. Sci. USA 1984 81 20 6466 6470 First study demonstrating that AAV could be used as a vector to transfer DNA into human cells. 6093102 PMC391945
  59. [70]McLaughlin SK Collis P Hermonat PL Muzyczka N Adeno-associated virus general transduction vectors: ana lysis of proviral structures. J. Virol 1988 62 6 1963 1973 2835501 PMC253280
  60. [71]Matsushita T Elliger S Elliger C Adeno-associated virus vectors can be efficiently produced without helper virus. Gene Ther 1998 5 7 938 945 9813665
  61. [72]Kohlbrenner E Aslanidi G Nash K Successful production of pseudotyped rAAV vectors using a modified baculovirus expression system. Mol. Ther 2005 12 6 1217 1225 16213797 PMC1351154
  62. [73]Urabe M Ding C Kotin RM Insect cells as a factory to produce adeno-associated virus type 2 vectors. Hum. Gene Ther 2002 13 16 1935 1943 12427305
  63. [74]Urabe M Nakakura T Xin KQ Scalable generation of high-titer recombinant adeno-associated virus type 5 in insect cells. J. Virol 2006 80 4 1874 1885 16439543 PMC1367135
  64. [76]Dong JY Fan PD Frizzell RA Quantitative ana lysis of the packaging capacity of recombinant adeno-associated virus. Hum. Gene Ther 1996 7 17 2101 2112 8934224
  65. [77]Hirsch ML Agbandje-McKenna M Samulski RJ Little vector, big gene transduction: fragmented genome reassembly of adeno-associated virus. Mol. Ther 2010 18 1 6 8 20048740 PMC2839225
  66. [80]Ginn SL Alexander IE Edelstein ML Abedi MR Wixon J Gene therapy clinical trials worldwide to 2012 - an update. J. Gene Med 2013 15 2 65 77 23355455
  67. [81]Maguire AM High KA Auricchio A Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a Phase 1 dose–escalation trial. Lancet 2009 374 9701 1597 1605 19854499 PMC4492302
  68. [83]Simonelli F Maguire AM Testa F Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol. Ther 2010 18 3 643 650 19953081 PMC2839440
  69. Manno CS Pierce GF Arruda VR Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat. Med 2006 12 3 342 347 Landmark AAV gene therapy clinical trial to treat hemophilia B. 16474400
  70. [85]Nathwani AC Tuddenham EG Rangarajan S Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N. Engl. J. Med 2011 365 25 2357 2365 22149959 PMC3265081
  71. Gaudet D de Wal J Tremblay K Review of the clinical development of alipogene tiparvovec gene therapy for lipoprotein lipase deficiency. Atheroscler. Suppl 2010 11 1 55 60 Clinical development of the first gene therapy treatment approved for use in the western world. 20427244
  72. Boutin S Monteilhet V Veron P Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8 and 9 in the healthy population: implications for gene therapy using AAV vectors. Hum. Gene Ther 2010 21 6 704 712 Reports the prevalence of pre-existing neutralizing antibodies against AAVs in the human population. 20095819
  73. [88]Grifman M Trepel M Speece P Incorporation of tumor-targeting peptides into recombinant adeno-associated virus capsids. Mol. Ther 2001 3 6 964 975 11407911
  74. [89]Srivastava A Hematopoietic stem cell transduction by recombinant adeno-associated virus vectors: problems and solutions. Hum. Gene Ther 2005 16 7 792 798 16000061
  75. [90]Loiler SA Conlon TJ Song S Targeting recombinant adeno-associated virus vectors to enhance gene transfer to pancreatic islets and liver. Gene Ther 2003 10 18 1551 1558 12907946
  76. [92]Nicklin SA Buening H Dishart KL Efficient and selective AAV2-mediated gene transfer directed to human vascular endothelial cells. Mol. Ther 2001 4 3 174 181 11545607
  77. [93]Calcedo R Vandenberghe LH Gao G Lin J Wilson JM Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J. Infect. Dis 2009 199 3 381 390 19133809 PMC10826927
  78. [96]Raupp C Naumer M Muller OJ Gurda BL Agbandje-McKenna M Kleinschmidt JA The threefold protrusions of adeno-associated virus type 8 are involved in cell surface targeting as well as postattachment processing. J. Virol 2012 86 17 9396 9408 22718833 PMC3416165
  79. Bowles DE McPhee SW Li C Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Mol. Ther 2012 20 2 443 455 First AAV gene therapy vector generated using the rational capsid-engineering approach. 22068425 PMC3277234
  80. [98]Pulicherla N Shen S Yadav S Engineering liver-detargeted AAV9 vectors for cardiac and musculoskeletal gene transfer. Mol. Ther 2011 19 6 1070 1078 21364538 PMC3129791
  81. [99]Wu Z Asokan A Samulski RJ Adeno-associated virus serotypes: vector toolkit for human gene therapy. Mol. Ther 2006 14 3 316 327 16824801
  82. [100]Yang L Jiang J Drouin LM A myocardium tropic adeno-associated virus (AAV) evolved by DNA shuffling and in vivo selection. Proc. Natl Acad. Sci. USA 2009 106 10 3946 3951 19234115 PMC2656185
  83. [101]Emsley P Cowtan K Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr 2004 60 Pt 12 Pt 1 2126 2132 15572765
  84. [102]Carrillo-Tripp M Shepherd CM Borelli IA VIPERdb2: an enhanced and web API enabled relational database for structural virology. Nucleic Acids Res 2009 37 Database issue D436 D442 18981051 PMC2686430
  85. [103]Pettersen EF Goddard TD Huang CC UCSF chimera – a visualization system for exploratory research and ana lysis. J. Comput. Chem 2004 25 13 1605 1612 15264254
  86. [104]Xiao C Rossmann MG Interpretation of electron density with stereographic roadmap projections. J. Struct. Biol 2007 158 2 182 187 17116403 PMC1978246
  87. [105]Grimm D Lee JS Wang L In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses. J. Virol 2008 82 12 5887 5911 18400866 PMC2395137
  88. [106]Lerch TF O'Donnell JK Meyer NL Structure of AAV-DJ, a retargeted gene therapy vector: cryo-electron microscopy at 4.5 A resolution. Structure 2012 20 8 1310 1320 22727812 PMC3418430
  89. [107]Li W Zhang L Johnson JS Generation of novel AAV variants by directed evolution for improved CFTR delivery to human ciliated airway epithelium. Mol. Ther 2009 17 12 2067 2077 19603002 PMC2801879
  90. [108]Zhong L Li B Jayandharan G Tyrosine-phosphorylation of AAV2 vectors and its consequences on viral intracellular trafficking and transgene expression. Virology 2008 381 2 194 202 18834608 PMC2643069
  91. [109]Zhong L Li BZ Mah CS Next generation of adeno-associated virus 2 vectors: point mutations in tyrosines lead to high-efficiency transduction at lower doses. Proc. Natl Acad. Sci. USA 2008 105 22 7827 7832 18511559 PMC2402387
  92. [110]Aslanidi GV Rivers AE Ortiz L Optimization of the capsid of recombinant adeno-associated virus 2 (AAV2) vectors: the final threshold? PLoS ONE 2013 8 3 e59142 23527116 PMC3602601
  93. [111]Larkin MA Blackshields G Brown NP Clustal W and Clustal X version 2.0. Bioinformatics 2007 23 21 2947 2948 17846036

Authors
Drouin, L. M., & Agbandje-McKenna, M.
Affiliations
  • University of Florida (US)
  • Department of Biochemistry & Molecular Biology, Center for Structural Biology, The McKnight Brain Institute, College of Medicine, 1600 SW Archer Road, PO Box 100245, University of Florida, Gainesville, FL32610, USA
Venue
Future Virology
Published
2013-11-28
Volume
8
Issue
12
Pages
1183-1199
ISSN
  • 1746-0794 (ISSN-L)
  • 1746-0808
OpenAlex
W2142972494
Cited by
114
References
117
Citations by year
2026: 16 · 2025: 14 · 2024: 16 · 2023: 12 · 2022: 10 · 2021: 12 · 2020: 6 · 2019: 11 · 2018: 5 · 2017: 3 · 2016: 2 · 2015: 5 · 2014: 2
FWCI
1.99
Type
journal article
Language
en
Open access
Locations
  • Future Virology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (R01 GM082946, R01 HL51811, T32 GM008799)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Keywords
adeno-associated virus, adeno-associated virus vectors, gene therapy, gene therapy delivery, capsid structure, hybrid vectors, tissue tropism, neutralizing antibodies, serotypes, structural biology

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