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The recent wave of clinical studies highlighted the enormous potential of gene therapy as an approach to the treatment of inherited disorders. While in recent years lentiviral vectors have dominated the field of ex vivo gene transfer applications in man, adeno-associated virus (AAV) vectors have become the platform of choice for the in vivo correction of many diseases. Despite these successes, however, studies in humans evidenced the immune system as one of the last few hurdles to be overcome in order to achieve sustained disease correction, particularly with AAV vectors. These observations spurred a decade of enormous efforts by gene therapists to understand the factors that contribute to the vector immunogenicity, including the prevalence of B cell and T cell immunity to wild type AAV in humans, and the interaction of AAV vectors with the innate immune system. Our knowledge is still rudimental. This is partly due to the fact that the basic knowledge on the complex balance between tolerance and immunity to an antigen keeps evolving rapidly. The lack of predictive animal models has also been a major limitation to the advancement of our understanding of vector immunogenicity, limiting studies to the use of specimens from human trials or in vitro models. Furthermore, immunomonitoring studies in AAV gene transfer trials were conducted by multiple laboratories and with different assays, making results comparison difficult.Continuing work towards a better definition of the interaction of viral vectors with the immune system, however, has led to significant advances in the knowledge of the factors influencing the outcome of gene transfer, such as the target tissue, the vector dose, and the induction of tolerance to an antigen. A better understanding of the structure function of the viral capsid has boosted the development of novel immune-escape vector variants, and novel immunomodulatory or immunosuppressive strategies to prevent, overcome or reduce anti-capsid immunity have been developed and tested in the preclinical and clinical settings. Together, these advances are bringing us closer to the goal of achieving safe and sustained therapeutic gene transfer in humans.In this exciting research topic, hosted by Frontiers in Immunology, we will highlight critical aspects in the bench-to-bedside cycle of development of AAV therapeutics as they relate with the issue of immunity to viral vectors. For this purpose, a collection of Original Research articles, Review Articles, and Methods Articles will discuss both our basic knowledge in immunology and AAV biology, and the preclinical and clinical experience with AAV vectors, including the tools used to decipher the complex interactions between a gene transfer vehicle and the host immune system.

Immunologic diseases. --- Gene therapy. --- Therapy, Gene --- Genetic engineering --- Therapeutics --- Immune diseases --- Immune disorders --- Immune system --- Immunologic disorders --- Immunological diseases --- Diseases --- antibody response --- Clinical Trial --- Gene Therapy --- Regulatory T Cell --- Immunomodulation --- Tolerance induction --- adaptive and innate immunity --- adeno-associated virus --- Vaccine --- Epitopes