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Reengineering Life is a series from Future Human about the astonishing ways genetic technology is changing humanity and the world around us.
In2008, Timothy Ray Brown became the first person to be cured of HIV. The year before, he received a bone marrow transplant to treat his leukemia that doctors hoped would treat his HIV, too.
In a bone marrow transplant, a person receives an infusion of blood stem cells from a donor, which find their way to the bone marrow and start making new, healthy blood cells. The donor, in Brown’s case, wasn’t just any donor: It was a person who had a rare genetic mutation in a gene called CCR5 that effectively blocks HIV from entering cells. With these stem cells now in his body, making new blood cells, Brown was becoming immune to HIV, too.
Years after receiving the treatment and going off of antiretroviral drugs, doctors could no longer detect HIV in Brown’s blood. In 2019, a second HIV patient was deemed cured after receiving the same treatment as Brown. Now, scientists have successfully edited the embryos of macaque monkeys using CRISPR to bestow the same protective genetic mutation that those donor cells carried, according to a recent study in the journal Scientific Reports. They want to use the edited embryos to breed monkeys with the CCR5 mutation to better study HIV and treatments for the infection.
The mutation, which appears in a gene called CCR5, appears in people of Northern European descent. However, only about 1% of this population has two copies of the gene, which is necessary for the HIV-blocking effect; most people only have one copy. In monkeys, the mutation is rare, too.
“The CCR5 mutation is almost nonexistent in monkeys so we need to create a genetically modified animal,” Igor Slukvin, MD, PhD, a professor of pathology and laboratory medicine at the University of Wisconsin-Madison and an author on the study, tells Future Human.
The Gene Fix That Might Cure HIV
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Antiretroviral drugs make HIV manageable, but new gene therapies could eliminate the virus altogether
onezero.medium.com
In the vast majority of people, CCR5 makes a protein that HIV uses as a doorway to enter the blood cells. But people who have a mutated form of CCR5 don’t make this protein, so the virus can’t gain access to cells and make more copies of itself; essentially, they’re immune to HIV.
The CCR5 gene has been of interest to HIV researchers ever since it was discovered in the mid-1990s. It’s the same gene that Chinese scientist He Jiankui targeted when he used CRISPR to edit the genomes of human embryos, which led to the birth of the first gene-edited babies and subsequent global outcry in 2018. His intention was to make the children resistant to HIV, which is still highly stigmatized in China.
CCR5 is likely involved in other functions in the body, so deleting it, as He did, could potentially carry health consequences. As of now, nothing is known about the health of the children — or whether they are actually resistant to HIV, for that matter. Monkeys that harbor the same mutation could help answer those questions.
“Recently, there has been a lot of interest in editing human embryos for the treatment of genetic diseases,” Slukvin says. “But we don’t know too much about the safety of editing embryos.”
Slukvin and his colleagues plan to test their edited monkey embryos for accidental edits caused by CRISPR, which has been an issue with using CRISPR on human embryos in the lab. They also want to use the CCR5-edited macaques as stem cell donors for monkeys with simian immunodeficiency virus (SIV). That way, they would have a way to study how successful the transplants are against HIV. “In some cases, it works and in some cases, it doesn’t work,” Slukvin says of the procedure. “We don’t know why.”
To learn whether the animals are actually resistant to HIV, the edited animals could be exposed to SIV, the monkey equivalent of HIV.
For now, though, the researchers haven’t succeeded at producing live offspring that carry the mutation. They transferred edited embryos into surrogate female monkeys, but none became pregnant. Like IVF in people, embryo transfers in monkeys have varying success rates.
Last year, scientists in China reported that they used CRISPR to edit the blood stem cells of a healthy donor to have the CCR5 mutation then pumped the modified cells into an IV to treat a patient with both HIV and cancer. The procedure, which took place in 2017, was the first-ever attempt to do so in a human. While the treatment caused the man’s cancer to go into remission, it didn’t cure his HIV. A year and a half after the treatment, just a small percentage of the man’s cells carried the CCR5 mutation. Though disappointing, the results showed that the approach was feasible and more importantly, safe.
One hurdle with CRISPR editing is the percentage of cells it can edit. When CRISPR is applied to a bunch of cells, some cells go unedited. After transplantation, only about 5% to 8% of cells contained at least one copy of the CCR5 edit. In other words, there’s a lot of room for improving the technique.
That’s where the monkeys that the Wisconsin researchers are working on come in.
“If we can explore this approach in a monkey model, we could figure out the best way to get a cure in human patients,” Slukvin says.
