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AAV D-sequence-mediated suppression of expression of a human major histocompatibility class II gene: Implications in the development of AAV vectors for modulating humoral immune response.

著者 Kwon HJ , Qing K , Ponnazhagan S , Wang XS , Markusic DM , Gupte S , Boye S , Srivastava A
Hum Gene Ther.2020 Mar 27 ; ():.
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A 20-nt long sequence, termed the D-sequence, in the AAV inverted terminal repeat was observed to share a partial sequence homology with the X-box in the regulatory region of the human leukocyte antigen DRA (HLA-DRA) promoter of the human major histocompatibility complex class II (MHC-II) genes. The D-sequence was also shown to specifically interact with the regulatory factor binding to the X-box (RFX), binding of which to the X-box is a critical step in the MHC-II gene expression, suggesting that D-sequence might compete for RFX transcription factor binding, thereby suppressing expression from the MHC-II promoter. In DNA-mediated transfection experiments, using a reporter gene under the control of the HLA-DRA promoter, D-sequence oligonucleotides were found to inhibit expression of the reporter gene expression in HeLa and 293 cells by approximately 93% and 96%, respectively. No inhibition was observed when non-specific synthetic oligonucleotides were used. D-sequence oligonucleotides had no effect on expression from the cytomegalovirus (CMV) immediate-early gene promoter. Interferon-γ (IFN-γ)-mediated activation of MHC-II gene expression was also inhibited by D-sequence oligonucleotides as well as following infection with either the wild-type AAV or transduction with recombinant AAV vectors. These studies suggest that the D-sequence-mediated down-regulation of the MHC-II gene expression may be exploited towards the development of novel AAV vectors capable of dampening the host humoral response, which has important implication in the optimal use of these vectors in human gene therapy.
PMID: 32220217 [PubMed - as supplied by publisher]
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