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The Genetic Mutation Behind the Only Apparent Cure for HIV

March 14, 2019


HIV infecting a CD4 cell

HIV infecting a CD4 cell. (Credit: NIAID)


The news last week that a second patient may have been cured of HIV using a bone marrow transplant from a donor with known HIV resistance has brought new attention to a gene mutation that many researchers believe is key to ending the epidemic.

The CCR5 delta 32 mutation, which was discovered over 20 years ago, disables the CCR5 receptor on the surface of white blood cells. HIV uses this receptor almost like a key -- it latches onto it to get into the cell. Without a working version of CCR5, HIV is essentially locked out of person's immune system. The mutation is most common among people of Northern European descent. Approximately 10% of people in Europe and the United States have inherited this from one of their parents, but it is only protective in the 1% who are homozygotes -- meaning they inherited a mutated gene from both of their parents. Studies have shown that these individuals are 100 times less likely to contract HIV if exposed to the virus.

In the future, this may be the driving force behind gene therapy and vaccines, but the mutation has a past that is just as fascinating. It pre-dates HIV by thousands of years, and scientists can't agree on its exact origins. It was also at the center of last year's ethical debate over a set of twins who were genetically modified as embryos using CRISPR technology.

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The Ancient History of the CCR5 Delta 32 Mutation

Geneticists say that the CCR5 delta 32 mutation existed as many as 2,500 years ago, but back then it likely occurred in only 1 in 20,000 Europeans, as compared to 1 in 10 today. They believe that some viral disease provided the selection pressure needed to increase the frequency of the mutation. In other words, there were outbreaks of a virus that was more likely to kill off the people who did not have this mutation, leaving a higher proportion of those with it to live on and reproduce. As this process repeats in generation after generation, the mutation becomes more common. Of course, this virus could not have been HIV, because it did not develop until centuries later.

Some researchers have hypothesized that bubonic plague was the culprit, but that's unlikely, because it was caused by a bacterial infection, not a virus. Smallpox has also been suggested, but the late researcher Christopher Duncan of the University of Liverpool thought that was unlikely, because that virus did not develop until the 1600s -- which, genetically speaking, was not long enough ago to have exerted this much selection pressure.

In 2005, Duncan and fellow researcher Susan Scott used computer modeling to determine which epidemics would explain why the mutation is found in high concentrations in Europe and Scandinavia but infrequently near the Mediterranean. Their research points to the plagues of the Middle Ages that struck Europe between 1340 and 1660. They believed that these plagues were recurring outbreaks of a lethal, viral hemorrhagic fever that used CCR5 to get into the immune system of Europe's ancestors.

Duncan and Scott said this accounts for sufficient selection pressure, because it impacted multiple generations and was 100% lethal. Moreover, it explains the geographic pattern of today's mutation, because these outbreaks continued in places like Hungary, Poland, Russia, Sweden, and Copenhagen through the 1700s.

Not all researchers, however, agree with this conclusion. For one thing, some scientists believe that like the bubonic plague, the plagues of the Middle Ages were bacterial and not viral.

A More Recent CCR5 Controversy

In November 2018, Chinese researcher He Jiankui, Ph.D., announced the births of twin girls from embryos that had been genetically altered to resemble those with the CCR5 delta 32 mutation. This was the first birth from seven HIV-discordant couples who sought fertility treatments from He. In each couple, the father was HIV positive and the mother was HIV negative. He told the Associated Press that he had altered the embryos not to protect them from getting HIV from their fathers (which is highly unlikely), but as a way to protect them against HIV later in life.

There is no published study on this work, but He reported that one of the twins has two altered genes, which should make her resistant to most HIV. The other twin has one altered gene, which is not enough for protection.

The international scientific community roundly criticized He for this research, which they said was premature and unnecessary. For one thing, we still do not know all of the potential negative effects of having non-functioning CCR5 receptors. There is research, for example, that suggests that people with the mutation are more susceptible to West Nile virus.

Gene editing can also bring on new issues called "off target" effects that could change other things about how embryos develop. No one yet knows what the unforeseen effects of disabling CCR5 could be, though some research that came out just last month found that it altered brain function in mice (it actually improved their motor ability). Because He altered the embryos at such an early stage (before sperm and egg cells develop), any off-target effects would be carried into subsequent generations. As Eric Topol, M.D., the head of Scripps Research Translational Institute in California, told the Associated Press: "This is far too premature. We're dealing with the operating instructions of a human being. It's a big deal."

It is unclear whether He provided sufficient informed consent to the parents when he described the project as a potential HIV vaccine. Many also accuse him of doing this particular experiment to prove that gene editing could be done rather than to solve a real problem in individuals' lives. Anthony Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), told Science magazine: "There are so many ways to adequately, efficiently, and definitively protect yourself against HIV that the thought of editing the genes of an embryo to get to an effect that you could easily do in so many other ways in my mind is unethical."

The London and Berlin Patients

The controversy over He's studies suggests that it will be years before mainstream researchers are comfortable using gene editing technology to disable the normal CCR5 gene in embryos and create a generation with HIV immunity. But all eyes are still on this mutation, because it played a key role in the treatment received by both of the men now thought to have been cured of HIV.

The men -- referred to as the Berlin patient and the London patient, respectively -- received allogenic hematopoietic stem cell transplantation as a treatment for cancer. These transplants are designed to replace cells damaged by disease, infection, or chemotherapy with healthy cells from a donor so that the patient's body can essentially rebuild its immune system. In these cases, doctors chose donors with the CCR5 delta 32 mutation in the hopes that when the immune system rebuilt with the new cells, it could also fight off HIV without medication. The treatment, however, is very intense, as it requires patients first to kill the existing marrow cells with chemotherapy or radiation and to take drugs to suppress their immune system so that it does not attack the donor cells.

The Berlin patient was later identified as Timothy Ray Brown and has now been HIV-free without medication for 12 years. Brown, who was being treated for leukemia at the time, came close to death during his treatment and was even put into a medically induced coma at one point.

Researchers tried for years to replicate the success they had with Brown, but HIV kept returning in subsequent patients. Some worried that Brown's success was not proof that the CCR5 delta 32 mutation was the key to treating HIV as hoped, but instead just a fluke brought on by intense, nearly fatal, radiation.

Then, in March 2019, researchers announced the success of the London patient (who has asked not to be named). He received a bone marrow transplant to treat Hodgkin's lymphoma. His treatment was less intense than Brown's, and he was never as sick. He has now been HIV-free without medication for 18 months. The London patient is one of 38 patients who received similar treatment who are currently being followed by a group of researchers. A second patient in the group has been HIV-free for four months.

While experts are eager to see how those patients fare, there appears to be consensus that this treatment is too intense to ever become common, especially in an era when medication can make the virus undetectable and untransmittable.

Still, the London patient's success is significant, because it proves that Brown's case was not a fluke and, as such, it puts the focus squarely back on CCR5. Paula Cannon, Ph.D., a molecular microbiologist who studies HIV at the University of Southern California's Keck School of Medicine, told Wired magazine: "There's a nice menu of things that we could possibly do now. What these two patients have shown us is that attacking the reservoir of infected cells while at the same time providing shiny, new HIV-resistant immune cells can result in a cure."

Other Potential Ways to Take Advantage of CCR5 Delta 32

There is already a drug called maraviroc (Selzentry, Celsentri) that simulates the mutation by binding to the CCR5 receptor, making it impossible for HIV to do so. Like other HIV medications, however, this drug has to be taken every day. Researchers are hoping to create a version that could last longer.

Two gene therapies developed using older genetic-editing tools are already in human trials. These treatments alter immune cells in people with HIV to destroy their CCR5 receptors, making the engineered cells resistant to HIV. Other studies using similar strategies with CRISPR technologies are still in the earlier phases. Researchers from Temple University presented some of their positive findings from experiments with monkeys last week as well.

It is also important to note that the CCR5 delta 32 mutation does not protect against all HIV. One patient who had the bone marrow treatment was later found to have a form of HIV called CXCR4-tropic, which uses a different receptor to enter cells. Doctors do not know whether the patient contracted this type of virus after the treatment or whether some patients harbor a small amount of CXCR4-tropic virus that starts to multiply when other types of HIV are not present.

This is why HIV research continues on many fronts -- from gene therapy to vaccine trials to new injectable versions of antiretroviral therapies that could provide the same results with only a monthly shot -- only some of which rely on the CCR5 delta 32 mutation. As Timothy Henrich, M.D., an HIV researcher at the University of California, San Francisco, told Popular Science: "We have to have patience. There are many strategies, and they're in early stages. We don't need to give up just because we haven't found a scalable, cost-effective cure for everyone. This reminds us that the scientific process can be slow, but if done correctly, we can make advances."

Martha Kempner is a freelance writer, consultant, and sexual health expert.


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This article was provided by TheBodyPRO.
 



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