Abstract
The recombinant adeno-associated virus (rAAV) gene delivery system is entering a crucial and exciting phase with the promise of more than 20 years of intense research now realized in a number of successful human clinical trials. However, as a natural host to AAV infection, anti-AAV antibodies are prevalent in the human population. For example, ~70% of human sera samples are positive for AAV serotype 2 (AAV2). Furthermore, low levels of pre-existing neutralizing antibodies in the circulation are detrimental to the efficacy of corrective therapeutic AAV gene delivery. A key component to overcoming this obstacle is the identification of regions of the AAV capsid that participate in interactions with host immunity, especially neutralizing antibodies, to be modified for neutralization escape. Three main approaches have been utilized to map antigenic epitopes on AAV capsids. The first is directed evolution in which AAV variants are selected in the presence of monoclonal antibodies (MAbs) or pooled human sera. This results in AAV variants with mutations on important neutralizing epitopes. The second is epitope searching, achieved by peptide scanning, peptide insertion, or site-directed mutagenesis. The third, a structure biology-based approach, utilizes cryo-electron microscopy and image reconstruction of AAV capsids complexed to fragment antibodies, which are generated from MAbs, to directly visualize the epitopes. In this review, the contribution of these three approaches to the current knowledge of AAV epitopes and success in their use to create second generation vectors will be discussed.
Highlights
Adeno-associated viruses (AAVs) are a promising gene delivery vector system
Residue 587 is in VRVIII (Figure 2) and it is located proximal to residues involved in heparan sulfate proteoglycan (HSPG) receptor binding in AAV serotype 2 (AAV2) [65, 66]
We review the current AAV:fragment antigen binding (Fab) complexes and the antigenic sites arising from these studies
Summary
Adeno-associated viruses (AAVs) are a promising gene delivery vector system. They are small (~26 nm) non-enveloped viruses belonging to the Parvoviridae, are assembled with T = 1 icosahedral capsid symmetry, and package a 4.7 kb single-stranded (ss) DNA genome [1]. With sufficient information on the AAV antigenic structure, combined with data on capsid determinants of tissue tropism and transduction, it would be feasible to design a neutralization-escaping vector, which can evade the host antibody immune response while retaining desired tissue tropism and transduction efficiency. The most detrimental immune threat that AAV vectors encounter soon after administration is the B-cell mediated antibody response [42, 43] Antibodies use their complementarity determining region (CDR), located on the end of Fab region, to interact with antigens by specific surface complementarities [44]. A new generation of AAV vectors is needed to circumvent the neutralization effects from pre-existing antibodies The development of these new vectors will largely depend on available AAV antigenic and structure information. The N50 value, the amount of serum required to decrease www.frontiersin.org
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