July 1, 2016
CRISPR/Cas9, a gene-editing tool that snips HIV DNA in latently infected CD4 cells, removed the virus from target cells and protected them -- as well as unedited cells -- from further HIV infection in a study at Temple University. But researchers at McGill University found that CD4 cells protected from HIV by CRISPR/Cas9 editing evolved mutations within two weeks that permitted new rounds of infection and ultimately made the virus stronger.
HIV-1 proviral DNA integrated into the host cell genome is impervious to antiretroviral therapy and explains rapid viral rebound if therapy stops. Extirpating HIV from resting CD4 cells is a key goal of HIV cure strategies.
In the Temple University study, the CRISPR/Cas9 DNA editing system excised the entire HIV-1 genome from proviral DNA integrated into latently infected human CD4 cells. Whole-genome sequencing of these cells showed that the editing did not compromise cell health or the integrity of the host genome. Persistent expression of Cas9 protected these cells from new infection with HIV-1 and "drastically reduced" viral load in ex vivo cultures of CD4 cells from people infected with HIV-1.
The resistance that developed after gene editing did not result from the faulty viral DNA copying that can spawn resistance to antiretrovirals. Rather, the CD4 cells themselves provided the mutations. "The surprise is that the resistance mutations are not the products of error-prone viral DNA copying, but rather are created by the cells own repair machinery," principal investigator Chen Liang told New Scientist.
Understanding how HIV-1 mutates to escape CRISPR control could help scientists develop more effective CRISPR-based strategies, Liang proposed. For example, the genetic scissors could snip multiple DNA sites rather than the single site targeted in their experiment. Or, CRISPR could be linked to an enzyme other than Cas9 that does not so readily allow resistance to evolve.
Mark Mascolini writes about HIV infection.
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