Until that moment, scientists had only hoped to control the insidious disease, through drugs like PrEP that cut down on transmission or antiretroviral treatments that prop up patients’ immune systems. The Berlin Patient made them believe total virus annihilation was, in fact, possible.
His story galvanized labs and companies across the world to do it using genetic engineering. In 2009, California-based Sangamo Therapeutics launched the first human trials of gene-editing to treat HIV, using an older technology called zinc-finger nucleases. Those trials, which edit a person’s T cells, have produced some limited successes.
A better approach, many contend, is to instead edit the cells that make T-cells (and all the other blood and immune cells) deep inside a person’s bones. Known as hematopoietic stem cells, they tend to be more resistant to editing, and require more risk and discomfort to deliver. But if you succeed, you can provide a patient with a lifetime supply of HIV-immune blood and immune cells. That’s what Crispr seems to offer.
The Chinese research team that conducted the latest study had previously transplanted Crispr-edited CCR5 mutant human cells into mice, making them resistant to HIV infection. In the spring of 2017 they registered a small human trial, to be conducted at the 307 Hospital of the People’s Liberation Army in Beijing. So far, the researchers have only enrolled and treated the single patient, according to Hongkui Deng, director of Peking University’s Stem Cell Research Center and one of the study’s coauthors. But Deng expects the trial to expand once they improve the efficiency of their technique.
To edit the donor stem cells, Deng’s team put them into a machine that applies a mild electrical shock. This allows the Crispr components—a DNA-chopping enzyme and GPS guides that tell it where to cut—to slip through the cell membrane and get to work. This approach minimizes potential mistakes, known as off-target effects, because Crispr is only in the cells for a short period of time, meaning they aren’t as likely to go rogue and break DNA they’re not supposed to. But it also means not all the cells get edited.
In an ideal world, both copies of the CCR5 gene would get snipped in all of the 163 million or so stem cells they isolated from the donor’s bone marrow. That would replicate what the Berlin Patient received from his donor. What the researchers got instead was much lower. After transplantation, only between 5.2 and 8.3 percent of the patient’s bone marrow cells carried at least one copy of the CCR5 edit. (The study authors didn’t report how many cells had both copies versus one copy edited.)
That number stayed more or less stable over the 19 months that researchers have so far tracked the patient. But the more telling question is whether T cells in the patient’s blood also retain the edit. In the specific kind of T cells that HIV uses to infiltrate the immune system, the broken version of CCR5 was present in only about 2 percent of them.
“That leaves a lot of room for improvement,” says Paula Cannon, a molecular microbiologist who studies HIV and gene-editing at the University of Southern California’s Keck School of Medicine. “At those levels, the cells would not be expected to have much of an effect against the virus.”
Another clinical trial, run by the City of Hope in Los Angeles, is investigating using zinc-finger nucleases to edit the hematopoietic stem cells of HIV-positive people, with a less aggressive bone marrow-clearing-out step, what you might call “chemo-lite.” So far six patients have been treated, and again, after 500 days only about two to four percent of cells carried the mutation, according to data presented at an HIV/AIDS conference last month in Seattle.