In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 20, No. 7 ( 2024-7-8), p. e1012344-
Abstract:
AAV-mediated gene therapy typically requires a high dose of viral transduction, risking acute immune responses and patient safety, part of which is due to limited understanding of the host-viral interactions, especially post-transduction viral genome processing. Here, through a genome-wide CRISPR screen, we identified SMCHD1 (Structural Maintenance of Chromosomes Hinge Domain 1), an epigenetic modifier, as a critical broad-spectrum restricting host factor for post-entry AAV transgene expression. SMCHD1 knock-down by RNAi and CRISPRi or knock-out by CRISPR all resulted in significantly enhanced transgene expression across multiple viral serotypes, as well as for both single-strand and self-complementary AAV genome types. Mechanistically, upon viral transduction, SMCHD1 effectively repressed AAV transcription by the formation of an LRIF1-HP1-containing protein complex and directly binding with the AAV genome to maintain a heterochromatin-like state. SMCHD1 -KO or LRIF1 -KD could disrupt such a complex and thus result in AAV transcriptional activation. Together, our results highlight the host factor-induced chromatin remodeling as a critical inhibitory mechanism for AAV transduction and may shed light on further improvement in AAV-based gene therapy.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1012344
DOI:
10.1371/journal.ppat.1012344.g001
DOI:
10.1371/journal.ppat.1012344.g002
DOI:
10.1371/journal.ppat.1012344.g003
DOI:
10.1371/journal.ppat.1012344.g004
DOI:
10.1371/journal.ppat.1012344.g005
DOI:
10.1371/journal.ppat.1012344.g006
DOI:
10.1371/journal.ppat.1012344.g007
DOI:
10.1371/journal.ppat.1012344.s001
DOI:
10.1371/journal.ppat.1012344.s002
DOI:
10.1371/journal.ppat.1012344.s003
DOI:
10.1371/journal.ppat.1012344.s004
DOI:
10.1371/journal.ppat.1012344.s005
DOI:
10.1371/journal.ppat.1012344.s006
DOI:
10.1371/journal.ppat.1012344.s007
DOI:
10.1371/journal.ppat.1012344.s008
DOI:
10.1371/journal.ppat.1012344.s009
DOI:
10.1371/journal.ppat.1012344.s010
DOI:
10.1371/journal.ppat.1012344.s011
DOI:
10.1371/journal.ppat.1012344.s012
DOI:
10.1371/journal.ppat.1012344.s013
DOI:
10.1371/journal.ppat.1012344.s014
DOI:
10.1371/journal.ppat.1012344.r001
DOI:
10.1371/journal.ppat.1012344.r002
DOI:
10.1371/journal.ppat.1012344.r003
DOI:
10.1371/journal.ppat.1012344.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2024
detail.hit.zdb_id:
2205412-1
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