Abstract:
:Interactions between viruses and the host antibody immune response are critical in the development and control of disease, and antibodies are also known to interfere with the efficacy of viral vector-based gene delivery. The adeno-associated viruses (AAVs) being developed as vectors for corrective human gene delivery have shown promise in clinical trials, but preexisting antibodies are detrimental to successful outcomes. However, the antigenic epitopes on AAV capsids remain poorly characterized. Cryo-electron microscopy and three-dimensional image reconstruction were used to define the locations of epitopes to which monoclonal fragment antibodies (Fabs) against AAV1, AAV2, AAV5, and AAV6 bind. Pseudoatomic modeling showed that, in each serotype, Fabs bound to a limited number of sites near the protrusions surrounding the 3-fold axes of the T=1 icosahedral capsids. For the closely related AAV1 and AAV6, a common Fab exhibited substoichiometric binding, with one Fab bound, on average, between two of the three protrusions as a consequence of steric crowding. The other AAV Fabs saturated the capsid and bound to the walls of all 60 protrusions, with the footprint for the AAV5 antibody extending toward the 5-fold axis. The angle of incidence for each bound Fab on the AAVs varied and resulted in significant differences in how much of each viral capsid surface was occluded beyond the Fab footprints. The AAV-antibody interactions showed a common set of footprints that overlapped some known receptor-binding sites and transduction determinants, thus suggesting potential mechanisms for virus neutralization by the antibodies.
journal_name
J Viroljournal_title
Journal of virologyauthors
Gurda BL,DiMattia MA,Miller EB,Bennett A,McKenna R,Weichert WS,Nelson CD,Chen WJ,Muzyczka N,Olson NH,Sinkovits RS,Chiorini JA,Zolotutkhin S,Kozyreva OG,Samulski RJ,Baker TS,Parrish CR,Agbandje-McKenna Mdoi
10.1128/JVI.00622-13subject
Has Abstractpub_date
2013-08-01 00:00:00pages
9111-24issue
16eissn
0022-538Xissn
1098-5514pii
JVI.00622-13journal_volume
87pub_type
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