Six animals suppressed AIDS virus after one shot of treatment that makes cell-receptor antibody
A gene-therapy approach to thwart the AIDS virus that has long struggled to gain traction may have new momentum after a study found it could “functionally cure” at least some monkeys.
In the experiment, reported today in Science Translational Medicine, researchers delivered a gene into the animals that produces an antibody blocking CCR5, a receptor on cell surfaces that HIV binds to establish an infection in people. Six monkeys infected with a labmade virus known as SHIV—a mashup of the AIDS virus and its simian cousin, SIV—have controlled their infections for more than 1 year after a single injection of this potential gene therapy.
The strategy doesn’t completely rid the body of the virus—the ultimate goal in HIV cure research—but given the difficulty of doing that, many researchers see this type of gene therapy as a promising compromise that could free infected people from lifelong use of antiretroviral drugs.
“This is an exciting proof of concept that gene-therapy delivery of a host-targeted antibody could potentially lead to long-term suppression of virus,” says Sharon Lewin, an HIV cure researcher who heads the Doherty Institute. “The real challenge now will be to transfer these findings into safe and effective clinical trials in humans.”
The experiment builds on two lines of research. One involves success—albeit limited—in monkeys with a similar gene therapy that delivers highly potent, “broadly neutralizing” antibodies (bNAbs) against SHIV. The other exploits the finding that a rare mutation in the CCR5 gene cripples the receptor, and that people who inherit this mutation from both parents are highly resistant to HIV infection and suffer no significant problems because of it. This discovery has helped truly cure HIV infections in a handful of people who also had blood cancers: They received stem cell transplants—a risky procedure that can’t be widely used—from donors who had the protective mutation in both CCR5 genes. “There’s a love story between HIV and CCR5, and if you can stop HIV from accessing its dance partner, it’s not going to tango,” says Jonah Sacha, an immunologist at Oregon Health & Science University (OHSU) who led the new study.
Sacha and colleagues treated the monkeys with an adeno-associated virus (AAV) constructed to deliver a gene that codes for the CCR5-blocking antibody. Gene therapies that use AAV as a “vector” have come to market to treat several other diseases, including types of hemophilia, muscular dystrophy, and hearing loss, and although AAVs rarely harm people naturally, infusions of high doses of the virus—often necessary to infect enough cells for a therapy to work—have led to serious toxicities and even deaths. The new experiment, in contrast, used a single, low-dose AAV injection to the muscles of the monkeys, and Sacha’s team saw no serious side effects.
The gene therapy appears to have functionally cured only six of the 19 monkeys that received it. In seven of the animals, the immune system saw the CCR5 blocker as a foreign protein and launched robust attacks against it, producing so-called antidrug antibodies (ADA). When the same CCR5 antibody is injected as a cancer treatment—it putatively stops the spread of tumors—monkeys mount a stronger ADA attack than many humans do, “for whatever reason,” Sacha says. This leads him to suspect that ADA may be less of a problem when the anti-HIV gene therapy is tried in people.
The genes delivered by AAVs persist in the nucleus of muscle cells as a circular DNA “episome” outside of chromosomes, which means the therapy could last for life. Oddly, four monkeys that mounted ADA responses had the CCR5 antibody return after roughly 5 to 14 months. “We forgot about them, and then they just happened to start re-expressing the antibody spontaneously,” Sacha says. “That’s my favorite aspect of all this.” He says it’s possible that, over time, the animals developed a tolerance to the foreign antibody by some unknown mechanism.
Researchers in 2009 showed that using AAVs to deliver bNAb genes to uninfected monkeys could protect them from an intentional injection with the AIDS virus—in other words, they acted as a vaccine of sorts. When this approach was tested in small trials of uninfected people, it only produced low levels of the antibody, according to a 2019 report.
That same year, virologist Ronald Desrosiers at the University of Miami described how an AAV that coded for more powerful bNAbs drove SHIV in one monkey down to undetectable levels for 3 years. Even today, 10 years after the treatment, no virus can be found in that monkey, despite intensive studies of its blood and lymph nodes. Two other monkeys given one shot of the therapy have controlled the virus for 7 years. A small human study of a similar approach had mixed, but encouraging results, as researchers reported in Nature Medicine in 2023. “Why aren’t people jumping on this like crazy?” asks Desrosiers, who 2 years ago co-founded a company, Marguron, to take his team’s bNAb gene therapy into humans.
Sacha is skeptical whether his group’s CCR5 antibody gene-therapy construct would functionally cure humans. “I don’t think this, by itself, is going to work,” he says. “Frankly, I think you’d have to combine it with a bNAb.”
Steven Deeks, a cure researcher at the University of California San Francisco, says the gene-therapy approach to a functional cure has enormous promise. “If I had to choose one strategy for the field to invest in, it would be this one,” Deeks says.
But Deeks and others still have safety concerns. Will periodic blood checks in a person detect failure of the gene therapy fast enough to prevent HIV levels from going up again and causing serious harm? If the artificial antibody proves dangerous, can a vector have a “kill switch”? If the vector infects nonmuscle cells, could it damage the liver, as seen in other AAV gene therapies?
“It’s exciting but still early, and more work will be needed,” says OHSU immunologist Louis Picker. “I hope the money is there to work out the devil’s details.”
