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

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.

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

doi

10.1073/pnas.1405186111

subject

Has Abstract

pub_date

2014-08-05 00:00:00

pages

11461-6

issue

31

eissn

0027-8424

issn

1091-6490

pii

1405186111

journal_volume

111

pub_type

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