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

Nov 20, 2023Journal of virology

CRISPR-Cas targeting of HIV DNA may accidentally delete nearby cell DNA

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Abstract

CRISPR-Cas treatment can cause large unintended deletions, including surrounding chromosomal sequences.

HIV replication can be effectively inhibited by antiretroviral therapy, but this does not eliminate the virus.
Lifelong therapy is necessary for HIV-infected individuals to prevent viral rebound.
Preclinical studies suggest that CRISPR-Cas gene-editing systems may permanently inactivate integrated HIV-1 DNA.
Inactivation of HIV-1 DNA has been linked to small mutations and excision or inversion of viral DNA fragments.
Large unintended deletions associated with CRISPR-Cas treatment may pose a safety risk due to the potential for oncogenic transformation.

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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.

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Abstract

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