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
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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