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Adeno-associated virus serotype 1 (AAV1)- and AAV5-antibody complex structures reveal evolutionary commonalities in parvovirus antigenic reactivity.
J Virol 2015; 89(3):1794-808JV

Abstract

The clinical utility of the adeno-associated virus (AAV) gene delivery system has been validated by the regulatory approval of an AAV serotype 1 (AAV1) vector for the treatment of lipoprotein lipase deficiency. However, neutralization from preexisting antibodies is detrimental to AAV transduction efficiency. Hence, mapping of AAV antigenic sites and engineering of neutralization-escaping vectors are important for improving clinical efficacy. We report the structures of four AAV-monoclonal antibody fragment complexes, AAV1-ADK1a, AAV1-ADK1b, AAV5-ADK5a, and AAV5-ADK5b, determined by cryo-electron microscopy and image reconstruction to a resolution of ∼11 to 12 Å. Pseudoatomic modeling mapped the ADK1a epitope to the protrusions surrounding the icosahedral 3-fold axis and the ADK1b and ADK5a epitopes, which overlap, to the wall between depressions at the 2- and 5-fold axes (2/5-fold wall), and the ADK5b epitope spans both the 5-fold axis-facing wall of the 3-fold protrusion and portions of the 2/5-fold wall of the capsid. Combined with the six antigenic sites previously elucidated for different AAV serotypes through structural approaches, including AAV1 and AAV5, this study identified two common AAV epitopes: one on the 3-fold protrusions and one on the 2/5-fold wall. These epitopes coincide with regions with the highest sequence and structure diversity between AAV serotypes and correspond to regions determining receptor recognition and transduction phenotypes. Significantly, these locations overlap the two dominant epitopes reported for autonomous parvoviruses. Thus, rather than the amino acid sequence alone, the antigenic sites of parvoviruses appear to be dictated by structural features evolved to enable specific infectious functions.

IMPORTANCE

The adeno-associated viruses (AAVs) are promising vectors for in vivo therapeutic gene delivery, with more than 20 years of intense research now realized in a number of successful human clinical trials that report therapeutic efficacy. However, a large percentage of the population has preexisting AAV capsid antibodies and therefore must be excluded from clinical trials or vector readministration. This report represents our continuing efforts to understand the antigenic structure of the AAVs, specifically, to obtain a picture of "polyclonal" reactivity as is the situation in humans. It describes the structures of four AAV-antibody complexes determined by cryo-electron microscopy and image reconstruction, increasing the number of mapped epitopes to four and three, respectively, for AAV1 and AAV5, two vectors currently in clinical trials. The results presented provide information essential for generating antigenic escape vectors to overcome a critical challenge remaining in the optimization of this highly promising vector delivery system.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida, USA.Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida, USA.Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida, USA.Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida, USA.NIDCR, NIH, Molecular Physiology and Therapeutics Branch, Bethesda, Maryland, USA.NIDCR, NIH, Molecular Physiology and Therapeutics Branch, Bethesda, Maryland, USA.Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA.Department of Chemistry and Biochemistry and Division of Biological Sciences, University of California-San Diego, San Diego, California, USA.Department of Chemistry and Biochemistry and Division of Biological Sciences, University of California-San Diego, San Diego, California, USA.German Cancer Research Center, Research Program Infection and Cancer, Heidelberg, Germany.Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida, USA mckenna@ufl.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25410874

Citation

Tseng, Yu-Shan, et al. "Adeno-associated Virus Serotype 1 (AAV1)- and AAV5-antibody Complex Structures Reveal Evolutionary Commonalities in Parvovirus Antigenic Reactivity." Journal of Virology, vol. 89, no. 3, 2015, pp. 1794-808.
Tseng YS, Gurda BL, Chipman P, et al. Adeno-associated virus serotype 1 (AAV1)- and AAV5-antibody complex structures reveal evolutionary commonalities in parvovirus antigenic reactivity. J Virol. 2015;89(3):1794-808.
Tseng, Y. S., Gurda, B. L., Chipman, P., McKenna, R., Afione, S., Chiorini, J. A., ... Agbandje-McKenna, M. (2015). Adeno-associated virus serotype 1 (AAV1)- and AAV5-antibody complex structures reveal evolutionary commonalities in parvovirus antigenic reactivity. Journal of Virology, 89(3), pp. 1794-808. doi:10.1128/JVI.02710-14.
Tseng YS, et al. Adeno-associated Virus Serotype 1 (AAV1)- and AAV5-antibody Complex Structures Reveal Evolutionary Commonalities in Parvovirus Antigenic Reactivity. J Virol. 2015;89(3):1794-808. PubMed PMID: 25410874.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Adeno-associated virus serotype 1 (AAV1)- and AAV5-antibody complex structures reveal evolutionary commonalities in parvovirus antigenic reactivity. AU - Tseng,Yu-Shan, AU - Gurda,Brittney L, AU - Chipman,Paul, AU - McKenna,Robert, AU - Afione,Sandra, AU - Chiorini,John A, AU - Muzyczka,Nicholas, AU - Olson,Norman H, AU - Baker,Timothy S, AU - Kleinschmidt,Jürgen, AU - Agbandje-McKenna,Mavis, Y1 - 2014/11/19/ PY - 2014/11/21/entrez PY - 2014/11/21/pubmed PY - 2015/4/8/medline SP - 1794 EP - 808 JF - Journal of virology JO - J. Virol. VL - 89 IS - 3 N2 - UNLABELLED: The clinical utility of the adeno-associated virus (AAV) gene delivery system has been validated by the regulatory approval of an AAV serotype 1 (AAV1) vector for the treatment of lipoprotein lipase deficiency. However, neutralization from preexisting antibodies is detrimental to AAV transduction efficiency. Hence, mapping of AAV antigenic sites and engineering of neutralization-escaping vectors are important for improving clinical efficacy. We report the structures of four AAV-monoclonal antibody fragment complexes, AAV1-ADK1a, AAV1-ADK1b, AAV5-ADK5a, and AAV5-ADK5b, determined by cryo-electron microscopy and image reconstruction to a resolution of ∼11 to 12 Å. Pseudoatomic modeling mapped the ADK1a epitope to the protrusions surrounding the icosahedral 3-fold axis and the ADK1b and ADK5a epitopes, which overlap, to the wall between depressions at the 2- and 5-fold axes (2/5-fold wall), and the ADK5b epitope spans both the 5-fold axis-facing wall of the 3-fold protrusion and portions of the 2/5-fold wall of the capsid. Combined with the six antigenic sites previously elucidated for different AAV serotypes through structural approaches, including AAV1 and AAV5, this study identified two common AAV epitopes: one on the 3-fold protrusions and one on the 2/5-fold wall. These epitopes coincide with regions with the highest sequence and structure diversity between AAV serotypes and correspond to regions determining receptor recognition and transduction phenotypes. Significantly, these locations overlap the two dominant epitopes reported for autonomous parvoviruses. Thus, rather than the amino acid sequence alone, the antigenic sites of parvoviruses appear to be dictated by structural features evolved to enable specific infectious functions. IMPORTANCE: The adeno-associated viruses (AAVs) are promising vectors for in vivo therapeutic gene delivery, with more than 20 years of intense research now realized in a number of successful human clinical trials that report therapeutic efficacy. However, a large percentage of the population has preexisting AAV capsid antibodies and therefore must be excluded from clinical trials or vector readministration. This report represents our continuing efforts to understand the antigenic structure of the AAVs, specifically, to obtain a picture of "polyclonal" reactivity as is the situation in humans. It describes the structures of four AAV-antibody complexes determined by cryo-electron microscopy and image reconstruction, increasing the number of mapped epitopes to four and three, respectively, for AAV1 and AAV5, two vectors currently in clinical trials. The results presented provide information essential for generating antigenic escape vectors to overcome a critical challenge remaining in the optimization of this highly promising vector delivery system. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/25410874/Adeno_associated_virus_serotype_1__AAV1___and_AAV5_antibody_complex_structures_reveal_evolutionary_commonalities_in_parvovirus_antigenic_reactivity_ L2 - http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=25410874 DB - PRIME DP - Unbound Medicine ER -