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Body + BrainBody & Brain

Editing Stem Cell Genomes to Lock Out HIV

ByEleanor NelsonNOVA NextNOVA Next

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In the span of a few decades, HIV has gone from a death-sentence to a manageable illness—provided a patient has access to the right drugs. But even then, drug therapies for HIV are notoriously toxic, with heart disease, nausea, and liver damage among their side effects. That has some researchers wondering, what if they could rid the body of the virus by reprogramming a patient’s own white blood cells—the ones ravaged by HIV—to keep the virus from ever getting in?

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Human T cells are attacked by HIV, but specific mutation can make them resistant to the virus.

A small percentage of people are already naturally resistant to HIV thanks to two copies of a mutation that knocks out the receptors HIV uses to enter the body’s T-cells—something like locking the virus out and throwing away the key. This is the mutation that seems to have cured “Berlin Patient” Timothy Ray Brown, after a transplant of HIV-resistant bone marrow in 2008.

But a bone marrow transplant is no walk in the park, either: to keep the body from attacking the new marrow, the patient’s own immune system has to be demolished before the transplant, and subjected to a regimen of immunosuppressants afterward.

That’s where this new technique comes in. Yuet Kan, a hematology professor at the University of California, San Francisco, and his team started with induced pluripotent stem cells, known as iPSCs, which are adult cells that have been retroengineered to act like embryonic stem cells. Made from the patient’s own cells, they would be less likely to trigger rejection. Peter Aldhous,

writing for NewScientist, explains:

It’s fairly easy to make iPSCs from a person’s cells, which then have the potential to grow into any type of cell in the body. So if iPSCs could be given two copies of the protective mutation, it should be possible to make personalized versions of the therapy that cleared HIV from Brown’s body.

To create that mutation, Kan used a genomic editing technique called CRISPR-Cas9 that can target precise sequences of DNA. CRISPR snips out the receptor-coding gene while leaving the rest of the cell’s genome alone. After their genetic revision, the stem cells were transformed into white blood cells. Ten days after those white blood cells were exposed to HIV, they didn’t show any sign of the virus. The mutation had made them resistant.

Kan hopes to further transform the iPSCs into blood-forming stem cells, which would produce white blood cells that carry the resistance mutation. The concept has promise and some precedent. Research published earlier this year in the New England Journal of Medicine showed that extracting and gene-editing just the white blood cells alone could reduce the viral load in HIV patients. That method, though, would require repeated transfusions. The stem cells Kan’s method could make would live and multiply in the bone marrow, generating a constant supply of HIV-resistant white blood cells.

The research isn’t ready for clinical application yet; creating cells that can be transplanted into the body without being rejected or causing other problems remains a significant challenge. Encouragingly, however, the natural mutation doesn’t seem to have any medical effects other than the fortuitous HIV resistance. If the engineered solution turns out to be just as innocuous, HIV treatments could become a lot more effective and lot less taxing.

Funding for NOVA Next is provided by the Eleanor and Howard Morgan Family Foundation.

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