AAV vectors have achieved positive results in many clinical and preclinical settings, including blood system diseases such as hemophilia, Gaucher's disease, hemochromatosis and porphyria. Small clinical studies allow researchers to analyze the immune response to AAV vector capsids and transgene products and develop strategies to manage these responses to achieve long-term expression of therapeutic genes. However, there is still a lack of a comprehensive understanding of the determinants of the immunogenicity of AAV vectors and the potential associated toxicity. As part of ongoing clinical research, careful immune monitoring will provide a basis for understanding the complexity of the immune response in AAV-mediated gene transfer, thereby contributing to safe and effective treatment of genetic diseases.

The AAV vector is modified from the naturally occurring parvovirus adeno-associated virus. AAV does not replicate automatically, but relies on helper viruses (such as adenovirus or herpes simplex) for replication. This initial contact during the co-infection period may be due to AAV promoting the immune response, leading to the generation of memory T cell responses to AAV.

A key concept for studying the immune response triggered by gene transfer in AAV is that viral vectors are recombinant molecules composed of eukaryotic transgenes and viral capsids. They are not viruses and cannot actually guide the synthesis of AAV. However, the recombinant capsid is an approximate mimic of the real virus capsid, or in some cases an exact copy of the real virus capsid, so the immune response to the vector will be affected by the human immune system's prior exposure to the wild-type virus.

Concepts related to kinetics, compared with wild-type viruses, one of the immune responses to the virus may not be well transformed into a viral vector. The viral vector consists of a pre-formed antigen administered in a single bolus injection. For wild-type viruses, the continuous synthesis and presentation of viral antigens are critical to the speed of the virus.

The innate immune response constitutes the front-line defense against viral infections, and is also the AAV vector with the main toxicity characteristics encountered when using adenoviral vectors to develop gene transfer strategies. On the contrary, they are also widely accepted due to their very mild pro-inflammatory profile. As a gene transfer vector in vivo. However, more and more studies have shown that the interaction between AAV vector components and the innate immune system may be an important factor in determining the outcome of gene transfer.

In the past few years, studies on humans have demonstrated the therapeutic potential of using AAV vectors for in vivo gene transfer. Initially, the researchers underestimated the degree of interaction between the recombinant viral vector and the human immune system, because these interactions were not predicted in animal studies. AAV vector is a complex biological therapy consisting of viral capsid, DNA genome and therapeutic transgene product encoded by the DNA. Each of these components can interact with the innate and adaptive immune system on multiple levels.

Consistent with current immunological concepts, the human immune response to a vector may vary greatly depending on the tissue in which it encounters the vector. The results range from anergy (for example, gene transfer in the eye) to tolerance (for example, The expression of the transgene product after expression in the liver), the removal of transduced cells (for example, the capsid T cell response in the liver). Small clinical studies have obtained a lot of information about these interactions, how to measure them, and ultimately how to adjust them. This is the key to obtaining the best results in clinical applications.

There is still much work to be done to have a more detailed understanding of the immune response of AAV vectors, and a better understanding of the potential safety hazards caused by the administration of high-dose vectors to humans. For example, apart from the total vehicle dose administered, little is known about the drivers that drive these responses. Regarding the immune response of the capsid in the liver, the rationale suggests that simultaneous T cell activation and capsid antigen presentation are required to trigger the elevation of transaminase and the loss of transduced hepatocytes; however, although measuring the former is simple, there is no clinical method for it. Measure the latter. The pharmacogenetics of gene transfer and, for example, whether certain human HLA alleles may be associated with higher vector immunogenicity are also unknown.