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Targeted Chromatinization and Repression of HIV-1 Provirus Transcription with Repurposed CRISPR/Cas9.

Authors :
Olson, Alex
Basukala, Binita
Lee, Seunghee
Gagne, Matthew
Wong, Wilson W.
Henderson, Andrew J.
Source :
Viruses (1999-4915); Oct2020, Vol. 12 Issue 10, p1154, 1p
Publication Year :
2020

Abstract

The major barrier to HIV-1 cure is the persistence of latent provirus, which is not eradicated by antiretroviral therapy. The "shock and kill" approach entails stimulating viral production with latency-reversing agents followed by the killing of cells actively producing the virus by immune clearance. However, this approach does not induce all intact proviruses, leaving a residual reservoir. CRISPR/Cas9 has been utilized to excise integrated Human Immunodeficiency Virus (HIV) DNA from infected cells in an RNA-guided, sequence-specific manner. Here, we seek to epigenetically silence the proviral DNA by introducing nuclease-deficient disabled Cas9 (dCas9) coupled with a transcriptional repressor domain derived from Kruppel-associated box (KRAB). We show that specific guide RNAs (gRNAs) and dCas9-KRAB repress HIV-1 transcription and reactivation of latent HIV-1 provirus. This repression is correlated with chromatin changes, including decreased H3 histone acetylation and increased histone H3 lysine 9 trimethylation, histone marks that are associated with transcriptional repression. dCas9-KRAB-mediated inhibition of HIV-1 transcription suggests that CRISPR can be engineered as a tool for block-and-lock strategies. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
19994915
Volume :
12
Issue :
10
Database :
Complementary Index
Journal :
Viruses (1999-4915)
Publication Type :
Academic Journal
Accession number :
146654499
Full Text :
https://doi.org/10.3390/v12101154