Have mice really been cured of HIV using CRISPR gene editing?

By | July 3, 2019
hiv in blood

A new strategy in the fight against HIV?

Sebastian Kaulitzki/Getty

What have researchers achieved?
The claim is they have eliminated HIV from living animals for the first time, by cutting it out of its hiding places in the body – in other words, that they have cured the animals.

How did they do it?
They used a gene-editing system called CRISPR, which is seen as a highly promising – yet still experimental – medical strategy. Unlike early forms of gene therapy, CRISPR allows precise targeting of specific genes. In this case, mice infected with HIV were injected with a different harmless virus that made a version of the CRISPR enzyme programmed to destroy HIV genes hiding in the mouse cells’ DNA.

Why would HIV be in the mouse cells’ DNA?
That’s where the virus hides out. While we have very effective medicines, called antiretroviral therapy (ART) which can get rid of most HIV from the body, it cannot affect cells where HIV has inserted itself into the DNA and gone dormant. If people stop taking their ART medicines, some of this dormant viral DNA wakes up, and blood virus levels surge back up again. So any hope of a permanent cure requires getting rid of this reservoir of virus-infected cells, found all over the body, including in the bone marrow, brain, and lymph nodes.

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Can CRISPR do that?
Not by itself, no. “The viruses are replicating so fast that CRISPR can’t catch up,” says Kamel Khalili of Temple University in Philadelphia, Pennsylvania. So his team used a two-pronged strategy of hitting the virus with both CRISPR and a highly potent form of the normal ART meds. The drug molecules were chemically tweaked to make them fat-soluble yet encased in a water-soluble molecular cage. This means just one injection into a mouse’s blood sends the drugs into immune cells where the active molecule is slowly released over time.

Could that be useful by itself?
Yes, the developer, Howard Gendelman of the University of Nebraska in Omaha, is separately trying to turn this strategy into a long-lasting form of ART, where people would need just one injection a year, instead of daily pills.

How effective are the two approaches together?
It’s not yet a useful cure. In the latest study, which tested different doses and formulations, about a third of 13 mice seemed to have HIV completely eliminated from their bodies; when the mice stopped being dosed with ART, there was no virus surge in their blood for up to five weeks. And when the animals were killed, highly sensitive genetic tests could detect no virus in the usual hiding places. The team are still tweaking their protocols to try to get higher success rates.

Was it safe?
This is the big question. In other groups’ work, the CRISPR enzyme hasn’t always been completely accurate, sometimes binding to similar genes as the one targeted. The main fear is it could introduce DNA mutations that could turn a cell cancerous. The team found no such “off-target” effects when they looked at the spleens of four treated animals. Still, that doesn’t prove it could never happen. And Allan Bradley of the University of Cambridge showed last year that even when the CRISPR enzyme hit the right target, it can sometimes lead to deletions of large flanking sequences of DNA, which could also cause cancerous mutations. “There could be damage of an adjacent gene,” says Bradley.

When could we start testing this approach in people?
As early as next year, says Khalili. The team have already started testing the approach in monkeys, a prerequisite before human trials, they announced at a conference earlier this year. But a big obstacle will be demonstrating to regulators that the technique is safe enough, given that in most people, anti-HIV meds reduce the virus to undetectable levels and give people a near-normal lifespan, as long as they keep taking their pills.

Journal reference: Nature Communications , DOI: 10.1038/s41467-019-10366-y

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