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RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection.

Authors :
Hu W
Kaminski R
Yang F
Zhang Y
Cosentino L
Li F
Luo B
Alvarez-Carbonell D
Garcia-Mesa Y
Karn J
Mo X
Khalili K
Source :
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2014 Aug 05; Vol. 111 (31), pp. 11461-6. Date of Electronic Publication: 2014 Jul 21.
Publication Year :
2014

Abstract

AIDS remains incurable due to the permanent integration of HIV-1 into the host genome, imparting risk of viral reactivation even after antiretroviral therapy. New strategies are needed to ablate the viral genome from latently infected cells, because current methods are too inefficient and prone to adverse off-target effects. To eliminate the integrated HIV-1 genome, we used the Cas9/guide RNA (gRNA) system, in single and multiplex configurations. We identified highly specific targets within the HIV-1 LTR U3 region that were efficiently edited by Cas9/gRNA, inactivating viral gene expression and replication in latently infected microglial, promonocytic, and T cells. Cas9/gRNAs caused neither genotoxicity nor off-target editing to the host cells, and completely excised a 9,709-bp fragment of integrated proviral DNA that spanned from its 5' to 3' LTRs. Furthermore, the presence of multiplex gRNAs within Cas9-expressing cells prevented HIV-1 infection. Our results suggest that Cas9/gRNA can be engineered to provide a specific, efficacious prophylactic and therapeutic approach against AIDS.

Details

Language :
English
ISSN :
1091-6490
Volume :
111
Issue :
31
Database :
MEDLINE
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Publication Type :
Academic Journal
Accession number :
25049410
Full Text :
https://doi.org/10.1073/pnas.1405186111