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RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection.
- 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.
- Subjects :
- Base Sequence
Cell Line
Clustered Regularly Interspaced Short Palindromic Repeats genetics
Genome, Human genetics
HEK293 Cells
HIV Infections immunology
HIV Long Terminal Repeat genetics
Humans
Molecular Sequence Data
Vaccination
RNA, Small Untranslated
HIV Infections prevention & control
HIV Infections virology
HIV-1 genetics
RNA genetics
RNA Editing genetics
Virus Latency genetics
Subjects
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