Adeno-Associated Viral Vectors at the Frontier between Tolerance and Immunity.

Abstract

In recent years, the field of in vivo gene transfer with adeno-associated virus (AAV) vectors has seen an extraordinary expansion of applications and investments. Results emerging from clinical trials (1) and the recent market approval of a gene therapy drug for lipoprotein lipase deficiency (2) contributed to the hype around this vector system (3). Indeed, AAV vectors have several features that make them an ideal tool for gene transfer, for example, parental virions are replication deficient and non-pathogenic (4), and vectors can drive expression of a transgene for several years (5, 6) despite the fact that they do not integrate efficiently into the host genome. In recent years, a portfolio of natural AAV isolates (AAV serotypes) differing in tissue tropism has been developed as vectors. This toolbox has been further expanded with engineered AAV capsids developed to enhance efficiency and specificity of gene delivery, and to escape antibody neutralization (7). At the vector genome level, availability of potent promoter/enhancer sequences, codon-optimization of transgenes, and development of self-complementary AAV vectors (8) further enhanced efficacy of gene transfer. Finally, the availability of scalable processes to produce AAV vectors in GMP contributed significantly to the expansion of the field. As the AAV vector technology reached a more mature stage, it has become clear that a better understanding of the interactions of viral vectors with the host immune system is needed. In this Research Topic of Frontiers in Immunology, the editors present a collection of reviews and research articles discussing the two sides of immune responses triggered by in vivo gene transfer. These responses in fact can be desirable when they result in induction of tolerance to the therapeutic transgene (9), or when they are exploited for vaccine development, as discussed by Nieto and Salvetti in their review article (10). Conversely, immunogenicity of the viral capsid or the transgene product can be detrimental, as it may result in lack or loss of efficacy following vector-mediated gene transfer. Evidence for the critical role of tolerance induction in the achievement of sustained therapeutic efficacy following gene transfer comes from the work of Liao and colleagues, which provides evidence that glucocorticoid-induced TNF receptor (GITR) and its ligand GITR-L are of fundamental importance for the induction of immune regulatory responses in gene transfer and that lack of expression of GITR-L on antigen presenting cells results in impaired induction of regulatory T cells (Tregs) (11). Indeed, evidence of the key function of Tregs for successful in vivo gene therapy comes from several studies (12), and Liu and colleagues further demonstrate this concept in a model of plasmid gene transfer for hemophilia A, in which a combination of B cell depleting and Treg-enhancing drugs is used to successfully modulate transgene immunogenicity (13).