CRISPR-Cas attack of HIV-1 proviral DNA can cause unintended deletion of surrounding cellular DNA

Although HIV replication can be effectively inhibited by antiretroviral therapy, this does not result in a cure as the available drugs do not inactivate the integrated HIV-1 DNA in infected cells. Consequently, HIV-infected individuals need lifelong therapy to prevent viral rebound. Several preclini...

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Bibliographic Details
Published in:Journal of virology 2023-12, Vol.97 (12), p.e0133423
Main Authors: Liu, Ye, Binda, Caroline S, Berkhout, Ben, Das, Atze T
Format: Article
Language:English
Subjects:
CRISPR-Cas Systems
DNA, Viral - genetics
Editor’s Pick
Gene Editing
HIV Infections
HIV-1 - genetics
Host-Microbial Interactions
Humans
Virus-Cell Interactions
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Summary:Although HIV replication can be effectively inhibited by antiretroviral therapy, this does not result in a cure as the available drugs do not inactivate the integrated HIV-1 DNA in infected cells. Consequently, HIV-infected individuals need lifelong therapy to prevent viral rebound. Several preclinical studies indicate that CRISPR-Cas gene-editing systems can be used to achieve permanent inactivation of the viral DNA. It was previously shown that this inactivation was due to small inactivating mutations at the targeted sites in the HIV genome and to excision or inversion of the viral DNA fragment between two target sites. We, here, demonstrate that CRISPR-Cas treatment also causes large unintended deletions, which can include surrounding chromosomal sequences. As the loss of chromosomal sequences may cause oncogenic transformation of the cell, such unintended large deletions form a potential safety risk in clinical application of this antiviral application and possibly all CRISPR-Cas gene-editing approaches.
ISSN:0022-538X
1098-5514
1098-5514
DOI:10.1128/jvi.01334-23