A Chinese scientist sparked worldwide controversy in November 2018 when he announced he had used a new gene-editing technique to genetically modify twin embryos. The result was Lulu and Nana, twins born shortly before the announcement. The experiment was intended to make the babies resistant to HIV infection, and the scientist had not published his results at the time he announced his experiment.

Some geneticists compared the work by He Jiankui of the Southern University of Science and Technology in Shenzhen, China, to the pioneering in vitro fertilization efforts that resulted in the birth of Louise Brown in 1978. Many others criticized the scientist for the ethical issues his experiment raised. A local medical ethics board said it would investigate him. (https://n.pr/2r6Ls5R)

The researcher claimed to have used Crispr-Cas9 to disable the CCR5 gene that makes the protein HIV needs to enter cells. (https://nyti.ms/2FFVg0A)

The CCR5 gene also is the target of entirely different research examining ways to cure people who are HIV-positive. These studies also raise thorny ethical questions — but with less controversy and publicity than the birth of the genetically-altered twin girls.

What Constitutes a Cure?

CCR5 studies into curing HIV are causing hand-wringing across the research community, says Rowena Johnston, PhD, vice president and director of research of amfAR, the Foundation for AIDS Research, in New York City.

The foundation is funding research aimed at eradicating the virus and achieving post-treatment control, where the patient can stop treatment and the virus remains undetectable, she says.

“This is a very interesting and rapidly evolving field, and I think regulators in particular are having trouble keeping up with the way new data are affecting research,” she says.

HIV cure studies raise a number of ethical questions, including the following:

• Should investigators include regulatory agencies as they initiate these studies?

• How can investigators and IRBs ensure study participants fully understand the study’s risks and benefits?

• What is the definition of a “cure” in HIV?

“A person living with HIV in the community might have an understanding that a cure means eradicating the virus,” Johnston says.

“In the research community, there is a group of people who would like to eradicate the virus and do what we think of as a cure,” she says. “Others say we should aim for post-treatment control, and that seems more attainable.”

Of course, from amfAR’s perspective, Johnston says, the former would be ideal: “Even if eradication is more difficult, I believe that is a more desirable outcome in the end.”

And there is one case in which a man was cured of HIV infection. In 2008, an American man living in Berlin had HIV infection and a cancer that required a stem cell transplant. “His HIV was doing okay,” she says.

The man’s physician was intrigued by the discovery that a small number of Europeans lacked the HIV receptor protein CCR5 in their bodies, and they never became infected with HIV — despite exposure that would lead to infection in anyone else, she explains.

The patient’s doctor sought to find a stem cell donor who had this CCR5 mutation. He screened people for a stem cell match and CCR5 mutation and found one. “The Berlin patient got the transplant, and since then he has not had cancer, and he no longer needed to take antiretroviral therapy [ART],” Johnston says.

“No one has found any virus in his body through tissue biopsies and blood draws, and he’s never experienced a viral rebound,” she adds. “He’s very active in the HIV advocacy area and goes to conferences to share his experience.”

amfAR, which is funding a large consortium in Europe, decided that because the genetic mutation is most common in Europe, it would fund research involving people living with HIV who also have cancer and need stem cell transplants.

“Stem cell transplants are risky procedures, and they should only be done if there is a medically sound reason to do that,” Johnston notes. “So this group in Europe has identified the largest cohort of people living with HIV who also received stem cell transplants.”

The people enrolled include cancer and HIV survivors who received stem cell transplants from people with the CCR5 mutation (and some without it). Researchers are following them to see if more people are cured from HIV.

“Recently, they published a paper that describes six interesting patients in whom they cannot find any virus after their stem cell transplant,” Johnston says.

One of the ethical challenges of reaching a conclusion that the stem cell transplant cured these patients involves the gold standard method for determining whether someone is cured.

It is called analytic treatment interruption (ATI), and it involves taking a patient off antiretroviral therapy to see if he or she experiences a viral rebound, she says. (See story in this issue on HIV research and ethical challenges.)

“It’s the most stringent test we have of whether or not this was a cure,” Johnston explains. “If a person only has three viruses left in their body, then how do we find them? Maybe the virus is in the left lymph node but you have sampled the right one; it’s philosophically impossible to prove a negative, so the only way to see if it’s a cure is to take them off ART and see if the virus comes back.”

The HIV/cancer patients were not randomly assigned to stem cell donors with the mutation. They were treated according to their medical needs.

When a patient needed a stem cell transplant, the doctor had to find the best donor possible, regardless of whether the person had the mutation.

“We funded prescreening of several million donors to preidentify the ones with a genetic mutation,” Johnston says. “So if the doctor reaches the point of finding someone who is a tissue match, there was information about whether a donor had the CCR5 mutation.”

In some cases, the physician had to proceed immediately with a transplant that did not have the mutation, and in other cases there were no matching donors with the mutation, she adds.

The HIV/cancer research participants likely fully understand ATI and the risks of being involved in HIV cure research, Johnston notes. The challenge is that stopping antiretroviral therapy goes against everything HIV patients have learned and experienced, which makes it a difficult choice.

“We’ve spent a lot of years driving home the importance of taking ART and adhering to it daily, and that it is extremely important. Your life and health depend on those medications,” Johnston says.

“So now we’re entering into a phase in the history of HIV research and the epidemic where we ask people to stop taking ART, and that’s a big ask,” she says. “We’re asking participants to put their trust in a clinical trial where people have to let go of their lifeline and see what happens.”

In addition to the physical risks of stopping antiretroviral therapy, there are emotional risks: “There’s really a lot of angst on the part of trial participants in letting go of ART in the name of research in order to find out if they’re really cured,” Johnston says. “There are competing motivations because people want to know if they’re cured.”