Cell-Mediated Immunity to AAV Vectors, Evolving Concepts and Potential Solutions

Abstract

Adeno-associated virus (AAV) vectors are one of the most efficient in vivo gene delivery platforms. Over the past decade, clinical trials of AAV vector-mediated gene transfer led to some of the most exciting results in the field of gene therapy and, recently, to the market approval of an AAV-based drug in Europe. With clinical development, however, it became obvious that the host immune system represents an important obstacle to successful gene transfer with AAV vectors. In this review article, we will discuss the issue of cytotoxic T cell responses directed against the AAV capsid encountered on human studies. While over the past several years the field has acquired a tremendous amount of information on the interactions of AAV vectors with the immune system, a lot of questions are still unanswered. Novel concepts are emerging, such as the relationship between the total capsid dose and the T cell-mediated clearance of transduced cells, the potential role of innate immunity in vector immunogenicity highlighted in preclinical studies, and the cross talk between regulatory and effector T cells in the determination of the outcome of gene transfer. There is still a lot to learn about immune responses in AAV gene transfer, for example, it is not well understood what are the determinants of the kinetics of activation of T cells in response to vector administration, why not all subjects develop detrimental T cell responses following gene transfer, and whether the intervention strategies currently in use to block T cell-mediated clearance of transduced cells will be safe and effective for all gene therapy indications. Results from novel preclinical models and clinical studies will help to address these points and to reach the important goal of developing safe and effective gene therapy protocols to treat human diseases.

Keywords: AAV vectors; T cell responses; gene therapy; immune modulation; immunogenicity.

Figure 1

Adeno-associated virus vector:host interactions. The components of AAV vectors interact with the host in determining the outcome of gene transfer. For the AAV vector, the total capsid dose, the genome (single-stranded vs. self-complementary, CpG content, etc.), and the transgene product (to which the host may not be tolerant), represent some of the elements that could contribute to vector immunogenicity. On the host side, the characteristics of the target tissue (immunoprivilege, presence of inflammation, tolerogenic properties, etc.), the genetic background of the host (underlying disease-causing mutation, HLA haplotype, etc.), and the pre-exposure to the wild-type virus, can contribute to shape the overall response to vector delivery.