Figure 1. Cellular and molecular mechanisms of host immune responses to viral vectors.

(A) TLRs can recognize PAMPs on viruses and trigger a signaling cascade to activate innate immune responses. Surface-bound TLR2 can sense viral capsid proteins.

(B) Endosomal TLR9 binds to specific unmethylated DNA sequences like CpG motifs on viral genomes.

(C) TLRs connects with signaling adaptor myeloid differentiation primary response gene 88 (MyD88) and leads to release of nuclear factor NF-kB.

(D) This then activates transcription of pro-inflammatory cytokines like TNF-α and IL-6,

(E) Cytosolic PRRs respond to PAMPs in the cytoplasm, including NLRs, ALRs, and RLRs.

(F) The pro-inflammatory cytokines can also promote vascular permeability and disruption of the blood-retinal barrier.

(G) CD4⁺ helper T cells interact with B cells to generate humoral responses. B cells produce antibodies that interact with Fc receptors on immune cells, complement-activating antibodies, and NAbs.

(H) Pre-existing NAbs to certain AAV serotypes can limit viral infectivity by interfering with receptor interactions between the virus and the host cells, thereby inhibiting transgene expression.

(I) Cellular adaptive immune responses are mediated by T cells, which are triggered by AAV or transgene antigens. The presentation of proteasomally-degraded antigens on class I MHC molecules induces CD8+ cytotoxic T cells, while presentation of endosomally-processed antigens on class II MHC molecules induces CD4⁺ helper T cells. Interactions of APCs with CD4+ T cells induces antigen-specific B cell responses, while APCs stimulate CD8+ T cells to directly destroy transduced cells.