Innate and adaptive immune components recognizing Adeno-associated virus (AAV) capsid (AAV immune response components)

The innate and adaptive immune components recognizing the Adeno-associated virus (AAV) capsid represent the collective host defense mechanisms that limit the efficacy and safety of AAV-delivered gene therapies. Innate recognition is primarily driven by Toll-like receptor 9 (TLR9), which senses the viral DNA's CpG motifs within the endosome, and potentially TLR2, which interacts with the capsid surface (Srivastava, 2016). This activation triggers the MyD88 signaling pathway, leading to the secretion of Type I interferons and other pro-inflammatory cytokines that prime the adaptive immune system (Mingozzi & High, 2013). Adaptive immunity consists of B-cell-mediated production of neutralizing antibodies (NAbs) that block vector transduction and T-cell-mediated responses where CD8+ cytotoxic T cells destroy transduced cells (Verdera et al., 2020). These immune responses are a major hurdle in clinical applications, often resulting in the loss of therapeutic transgene expression and causing adverse events like hepatotoxicity (Ertl, 2021). Pharmacological intervention typically involves the use of corticosteroids, mTOR inhibitors like sirolimus, or B-cell depleting agents like rituximab to suppress these responses (Leborgne et al., 2020). Emerging strategies also include the use of IgG-degrading enzymes, such as imlifidase, to transiently clear pre-existing neutralizing antibodies before vector administration (Leborgne et al., 2020).

Other names

Anti-AAV immunityAAV-specific immune responseHost immune response to AAV vectorsAAV immunogenicity

The mechanisms of action for drugs addressing these components include glucocorticoid receptor agonism to suppress cytokine production, CD20-directed B-cell depletion to reduce antibody formation, mTOR inhibition to prevent T-cell proliferation, and enzymatic degradation of existing IgG antibodies to facilitate vector transduction.