Adeno-associated virus: fit to serve

Abstract

Adeno-associated virus (AAV) is a helper-dependent parvovirus which has not been linked with human disease. This aspect, in combination with its broad cell and tissue tropism, and limited viral host response has made it an attractive vector system for gene therapy. The viral protein capsid, the primary interface with the host, is the main determinant for these phenotypes, is highly variable, and is most subject to pressures during replication. Here, we explore the evolutionary path of AAV and other parvoviruses in respect to these phenotypes, as well as directed evolution and engineering strategies that have exploited the lessons learned from natural selection in order to address remaining limitations of AAV as a therapeutic gene transfer platform.

Figure 1

Phylogenetic relationship of representative members of the family Parvoviridae. Maximum likelihood phylogeny of viruses based on a full-genome alignment. Subfamilies are labeled with brackets.

Figure 2

Natural diversity of adeno-associated virus capsids. A) Maximum likelihood phylogeny of AAVs based on a multiple sequence alignment of capsids. Muscovy Duck Parvovirus was included as an out-group. B) Variability plotted on the structure of the AAV2 capsid monomer (PDB: 1LP3). Blue end of the spectrum represents more conserved positions while the red end represents more variable positions. Variability was calculated using the Shannon-entropy statistic on a multiple sequence alignment of the sequences depicted in the phylogeny, excluding MDPV. C) Variability plotted as before on the AAV2 full capsid.