CRISPR/Cas9-Derived Mutations Both Inhibit HIV-1 Replication and Accelerate Viral Escape
Gene Editing
0301 basic medicine
Base Sequence
QH301-705.5
Virus Replication
Cell Line
3. Good health
03 medical and health sciences
INDEL Mutation
DNA, Viral
Mutation
HIV-1
Humans
Biology (General)
CRISPR-Cas Systems
Immune Evasion
DOI:
10.1016/j.celrep.2016.03.042
Publication Date:
2016-04-09T21:33:07Z
AUTHORS (8)
ABSTRACT
Cas9 cleaves specific DNA sequences with the assistance of a programmable single guide RNA (sgRNA). Repairing this broken DNA by the cell's error-prone non-homologous end joining (NHEJ) machinery leads to insertions and deletions (indels) that often impair DNA function. Using HIV-1, we have now demonstrated that many of these indels are indeed lethal for the virus, but that others lead to the emergence of replication competent viruses that are resistant to Cas9/sgRNA. This unexpected contribution of Cas9 to the development of viral resistance is facilitated by some indels that are not deleterious for viral replication, but that are refractory to recognition by the same sgRNA as a result of changing the target DNA sequences. This observation illustrates two opposite outcomes of Cas9/sgRNA action, i.e., inactivation of HIV-1 and acceleration of viral escape, thereby potentially limiting the use of Cas9/sgRNA in HIV-1 therapy.
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