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    HIV resists CRISPR gene-editing attack

    At least half a dozen papers over the past three years have explored using the popular CRISPR–Cas9 gene editing technique to combat HIV, but the latest finding, described in a study published on 7 April in Cell Reports discovered that HIV can defeat efforts to cripple it with CRISPR gene-editing technology. And the very act of editing — involving snipping at the virus’s genome — may introduce mutations that help it to resist attack.
    Stretches of DNA altered by the human immunodeficiency virus (HIV) can be targeted by the CRISPR/Cas9 endonuclease system, resulting in strategically placed cuts, imperfect repairs to those cuts, and—finally—the end of viral replication. But in some cases, the battle-scarred DNA that CRISPR/Cas9 leaves behind won’t give up the fight. Worse, this DNA becomes harder to recognize, by dint of its scars, and becomes even more dangerous. It acquires a form of resistance, the ability to duck renewed attacks from CRISPR/Cas9.
    This study was carried out by an international team of scientists that represented McGill University, the University of Montreal, the Chinese Academy of Medical Sciences, and Peking Union Medical College. These scientists, led by McGill’s Chen Liang, Ph.D., found that when CRISPR/Cas9 is used to mutate HIV-1 within cellular DNA, two outcomes are possible: (1) inactivation of HIV-1 and (2) acceleration of viral escape. This finding, the researchers cautioned, potentially limits the use of CRISPR/Cas9 in HIV-1 therapy.
    A team led by molecular biologist Atze Das at the University of Amsterdam reported similar results in Molecular Therapy in February. Das says he is not surprised that HIV can overcome CRISPR: “What is surprising is the speed —- how fast it goes.” Both he and Liang think that the problem can be surmounted, for instance by inactivating several essential HIV genes at once, or by using CRISPR in combination with HIV-attacking drugs. Gene-editing therapies that make T cells resistant to HIV invasion (by altering human, not viral, genes) would also be harder for the virus to overcome. A clinical trial is under way to test this approach using another gene-editing tool, zinc-finger nucleases.
    This approach seemed simple and efficient in tissue culture, says Bryan Cullen, a virologist at Duke University in Durham, North Carolina, who has been using CRISPR to target viruses including HIV. Cullen agrees that the resistance does not mean that there will never be a CRISPR-based treatment or cure for HIV. But he questions whether a therapy using CRISPR — which would require genetically modifying a substantial number of a patients’ T cells — is suited for tackling the virus; especially since it is increasingly possible to manage most HIV infections with cocktails of antiretroviral drugs. “To me, it’s pie in the sky,” he says.